Aristocrat French Bulldogs-Breeding Better Dogs (and Eng. Bulldog Stud Service)

Click here to edit subtitle

Welcome

Recent Blog Entries

Recent Videos

2586 views - 0 comments

Newest Members

Featured Etsy Items

No featured products.

SURVIVAL OF THE CUTEST :)

'Survival of the Cutest' Proves Darwin Right

ScienceDaily (Jan. 21, 2010) — Domestic dogs have followed their own evolutionary path, twisting Darwin's directive 'survival of the fittest' to their own needs -- and have proved him right in the process, according to a new study by biologists Chris Klingenberg, of The University of Manchester and Abby Drake, of the College of the Holy Cross in the US.



The study, published in The American Naturalist on January 20,  2010, compared the skull shapes of domestic dogs with those of different species across the order Carnivora, to which dogs belong along with cats, bears, weasels, civets and even seals and walruses.

It found that the skull shapes of domestic dogs varied as much as those of the whole order. It also showed that the extremes of diversity were farther apart in domestic dogs than in the rest of the order. This means, for instance, that a Collie has a skull shape that is more different from that of a Pekingese than the skull shape of the cat is from that of a walrus.

Dr Drake explains: "We usually think of evolution as a slow and gradual process, but the incredible amount of diversity in domestic dogs has originated through selective breeding in just the last few hundred years, and particularly after the modern purebred dog breeds were established in the last 150 years."

By contrast, the order Carnivora dates back at least 60 million years. The massive diversity in the shapes of the dogs' skulls emphatically proves that selection has a powerful role to play in evolution and the level of diversity that separates species and even families can be generated within a single species, in this case in dogs.

Much of the diversity of domestic dog skulls is outside the range of variation in the Carnivora, and thus represents skull shapes that are entirely novel.

Dr Klingenberg adds: "Domestic dogs are boldly going where no self respecting carnivore ever has gone before.

"Domestic dogs don't live in the wild so they don't have to run after things and kill them -- their food comes out of a tin and the toughest thing they'll ever have to chew is their owner's slippers. So they can get away with a lot of variation that would affect functions such as breathing and chewing and would therefore lead to their extinction.

"Natural selection has been relaxed and replaced with artificial selection for various shapes that breeders favour."

Domestic dogs are a model species for studying longer term natural selection. Darwin studied them, as well as pigeons and other domesticated species.

Drake and Klingenberg compared the amazing amount of diversity in dogs to the entire order Carnivora. They measured the positions of 50 recognizable points on the skulls of dogs and their 'cousins' from the rest of the order Carnivora, and analyzed shape variation with newly developed methods.

The team divided the dog breeds into categories according to function, such as hunting, herding, guarding and companion dogs. They found the companion (or pet) dogs were more variable than all the other categories put together.

According to Drake, "Dogs are bred for their looks not for doing a job so there is more scope for outlandish variations, which are then able to survive and reproduce."

Dr Klingenberg concludes: "I think this example of head shape is characteristic of many others and is showing it so clearly, showing what happens when you consistently and over time apply selection.

"This study illustrates the power of Darwinian selection with so much variation produced in such a short period of time. The evidence is very strong."

CANINE GENETICS & THE IMPORTANCE IN BREEDING!

Some of the info below is thanks to John W. Kimbal link http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SexChromosomes.html

 

Sex Chromosomes

The nuclei of human cells contain 22 autosomes and 2 sex chromosomes. In females, the sex chromosomes are the 2 X chromosomes. Males have one X chromosome and one Y chromosome. The presence of the Y chromosome is decisive for unleashing the developmental program that leads to a baby boy.

The Y Chromosome

In making sperm by meiosis, the X and Y chromosomes must separate in anaphase just as homologous autosomes do. This occurs without a problem because, like homologous autosomes, the X and Y chromosome synapse during prophase of meiosis I. There is a small region of homology shared by the X and Y chromosome and synapsis occurs at that region.

This image, courtesy of C. Tease, shows synapsis of the X and Y chromosomes of a mouse during prophase of meiosis I. Crossing over occurs in two regions of pairing, called the pseudoautosomal regions. These are located at opposite ends of the chromosome.

The Pseudoautosomal Regions

The pseudoautosomal regions get their name because any genes located within them (so far only 9 have been found) are inherited just like any autosomal genes. Males have two copies of these genes: one in the pseudoautosomal region of their Y, the other in the corresponding portion of their X chromosome. So males can inherit an allele originally present on the X chromosome of their father and females can inherit an allele originally present on the Y chromosome of their father.

This diagram shows the structure of the human Y chromosome.

Genes outside the pseudoautosomal regions

Although 95% of the Y chromosome lies between the pseudoautosomal regions, fewer than 80 genes have been found here. Over half of this region is genetically-barren heterochromatin. Of the 80-odd genes found in the euchromatin, some encode proteins used by all cells. The others encode proteins that appear to function only in the testes. A key player in this latter group is SRY.

SRY

SRY (for sex-determining region Y) is a gene located on the short (p) arm just outside the pseudoautosomal region. It is the master switch that triggers the events that converts the embryo into a male. Without this gene, you get a female instead.

What is the evidence?
  1. On very rare occasions aneuploid humans are born with such karyotypes as XXY, XXXY, and even XXXXY. Despite their extra X chromosomes, all these cases are male.
  2. This image (courtesy of Robin Lovell-Badge from Nature 351:117, 1991) shows two mice with an XX karyotype (and thus they should be female). However, as you may be able to see, they have a male phenotype. This is because they are transgenic for SRY. Fertilized XX eggs were injected with DNA carrying the SRY gene.
    see Making Transgenic Animals
    Although these mice have testes, male sex hormones, and normal mating behavior, they are sterile.
  3. Another rarity: XX humans with testicular tissue because a translocation has placed the SRY gene on one of the X chromosomes
  4. Still another rarity that demonstrates the case: women with an XY karyotype who, despite their Y chromosome, are female because of a destructive mutation in SRY.

(In 1996, a test based on a molecular probe for SRY was used to ensure that potential competitors for the women's Olympic events in Atlanta had no SRY gene. But because of possibilities like that in case 4, this testing is no longer used to screen female Olympic athletes.)

The X Chromosome

The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex. However, the inheritance of these genes follows special rules. These arise because:
  • males have only a single X chromosome
  • almost all the genes on the X have no counterpart on the Y; thus
  • any gene on the X, even if recessive in females, will be expressed in males.
Genes inherited in this fashion are described as sex-linked or, more precisely, X-linked.

X-Linkage: An Example

Hemophilia A is a blood clotting disorder caused by a mutant gene encoding the clotting factor VIII. This gene is located on the X chromosome (shown here in red). With only a single X chromosome, males who inherit the defective gene (always from their mother) will be unable to produce factor VIII and suffer from difficult-to-control episodes of bleeding. In heterozygous females, the unmutated copy of the gene will provide all the factor VIII they need. Heterozygous females are called "carriers" because although they show no symptoms, they pass the gene on to approximately half their sons, who develop the disease, and half their daughters, who also become carriers.

X Y
X XX XY
Xh XhX XhY

Women rarely suffer from hemophilia A because to do so they would have to inherit a defective gene from their father as well as their mother. Until recently, few hemophiliacs ever became fathers.

Click here for a discussion of red-green colorblindness; another example of X-linked inheritance.

X-Inactivation

Human females inherit two copies of every gene on the X chromosome, whereas males inherit only one (with some exceptions: the 9 pseudoautosomal genes and the small number of "housekeeping" genes found on the Y). But for the hundreds of other genes on the X, are males at a disadvantage in the amount of gene product their cells produce? The answer is no, because females have only a single active X chromosome in each cell.

During interphase, chromosomes are too tenuous to be stained and seen by light microscopy. However, a dense, stainable structure, called a Barr body (after its discoverer) is seen in the interphase nuclei of female mammals. The Barr body is one of the X chromosomes. Its compact appearance reflects its inactivity. So, the cells of females have only one functioning copy of each X-linked gene — the same as males.

X-inactivation occurs early in embryonic development. In a given cell, which of a female's X chromosomes becomes inactivated and converted into a Barr body is a matter of chance (except in marsupials like the kangaroo, where it is always the father's X chromosome that is inactivated). After inactivation has occurred, all the descendants of that cell will have the same chromosome inactivated. Thus X-inactivation creates clones with differing effective gene content. An organism whose cells vary in effective gene content and hence in the expression of a trait, is called a genetic mosaic.

Mechanism of X-inactivation

Inactivation of an X chromosome requires a gene on that chromosome called XIST.

  • XIST encodes a large molecule of RNA (of a type different from those, e.g., mRNA, used in protein synthesis).
  • XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of the other hundreds of genes on that chromosome.
  • XIST RNA does not travel over to any other X chromosome in the nucleus.
  • Barr bodies are inactive X chromosomes "painted" with XIST RNA.

The Sequence of Events

  • During the first cell divisions of the female mouse zygote, the XIST locus on the father's X chromosome is expressed so most of his X-linked genes are silent.
  • By the time the blastocyst has formed, the silencing of the paternal X chromosome still continues in the trophoblast but
  • in the inner cell mass (ICM) transcription of XIST ceases on the paternal X chromosome allowing its hundreds of other genes to be expressed. The shut-down of the XIST locus is done by methylating XIST regulatory sequences. So the pluripotent stem cells of the ICM express both X chromosomes.
  • However, as embryonic development proceeds, X-inactivation begins again. But this time it is entirely random. There is no predicting whether it will be the maternal X or the paternal X that is inactivated in a given cell.

Some genes on the X chromosome escape inactivation.

What about those 18 genes that are found on the Y as well as the X? There should be no need for females to inactivate one copy of these to keep in balance with the situation in males. And, as it turns out, these genes escape inactivation in females. Just how they manage this has yet to be discovered.

X-Chromosome Abnormalities

As we saw above, people are sometimes found with abnormal numbers of X chromosomes. Unlike most cases of aneuploidy, which are lethal, the phenotypic effects of aneuploidy of the X chromosome are usually not severe. Examples:
  • Females with but a single X chromosome: the most common cause of Turner's syndrome. The phenotypic effects are mild because each cell has a single functioning X chromosome like those of XX females. Number of Barr bodies = zero.
  • XXX, XXXX, XXXXX karyotypes: all females with mild phenotypic effects because in each cell all the extra X chromosomes are inactivated. Number of Barr bodies = number of X chromosomes minus one.
  • Klinefelter's syndrome: people with XXY or XXXY karyotypes are males (because of their Y chromosome). But again, the phenotypic effects of the extra X chromosomes are mild because, just as in females, the extra Xs are inactivated and converted into Barr bodies.

Sex Determination in Other Animals

Although the male fruit fly, Drosophila melanogaster, is X-Y, the Y chromosome does not dictate its maleness but rather the absence of a second X.

In birds, moths, schistosomes, and some lizards, the male has two of the same chromosome (designated ZZ), whereas the female has "heterogametic" chromosomes (designated Z and W). In chickens, a single gene on the Z chromosome (designated DMRT1), when present in a double dose (ZZ), produces males while the presence of only one copy of the gene produces females (ZW).

Environmental Sex Determination

In some cold-blooded vertebrates
  • some fishes
  • many reptiles (e.g. certain snakes, lizards, turtles, and all crocodiles and alligators)
as well as in some invertebrates (e.g. certain crustaceans),
sex is determined after fertilization — not by sex chromosomes deposited in the egg.

The choice is usually determined by the temperature at which early embryonic development takes place.

  • In some cases (e.g. many turtles and lizards), a higher temperature during incubation favors the production of females.
  • In other cases (e.g., alligators), a higher temperature favors the production of males.

Even in cases (e.g. some lizards) where there are sex chromosomes, a high temperature can convert a genotypic male (ZZ) into a female.

Hermaphrodites

Hermaphrodites have both male and female sex organs. Many species of fish are hermaphroditic.

Some start out as one sex and then, in response to stimuli in their environment, switch to the other.

Other species have both testes and ovaries at the same time (but seldom fertilize themselves). (However, populations of C. elegans consist mostly of hermaphrodites and these only fertilize themselves — Link to a discussion.)

Hermaphroditic fishes have no sex chromosomes.



Genetic linkage is a term which describes the tendency of certain loci or alleles to be inherited together. Genetic loci on the same chromosome are physically close to one another and tend to stay together during meiosis, and are thus genetically linked. This is called autosomal linkage.


[edit] Background

At the beginning of normal meiosis, a chromosome pair (made up of a chromosome from the mother and a chromosome from the father) intertwine and exchange sections or fragments of chromosome. The pair then breaks apart to form two chromosomes with a new combination of genes that differs from the combination supplied by the parents. Through this process of recombining genes, organisms can produce offspring with new combinations of maternal and paternal traits that may contribute to or enhance survival.

This crossing over of DNA can cause alleles perviously on the same chromosome to be separated and end up in different daughter cells. The further the two alleles are apart, the greater the chance that a cross-over event may occur between them, possibly separating the alleles.

The relative distance between two genes can be calculated using the offspring of an organism showing two linked genetic traits, and finding the percentage of the offspring where the two traits do not run together. The higher the percentage of descendants that does not show both traits, the farther apart on the chromosome the two genes are.

Among individuals of an experimental population or species, some phenotypes or traits occur randomly with respect to one another in a manner known as independent assortment. Today scientists understand that independent assortment occurs when the genes affecting the phenotypes are found on different chromosomes or separated by a great enough distance on the same chromosome that recombination occurs at least half of the time.

An exception to independent assortment develops when genes appear near one another on the same chromosome. When genes occur on the same chromosome, they are usually inherited as a single unit. Genes inherited in this way are said to be linked, and are referred to as "linkage groups." For example, in fruit flies the genes affecting eye color and wing length are inherited together because they appear on the same chromosome.

[edit] Discovery

Genetic linkage was first discovered by the British geneticists William Bateson and Reginald Punnett shortly after Mendel's laws were rediscovered. The understanding of genetic linkage was expanded by the work of Thomas Hunt Morgan. Morgan's observation that the amount of crossing over between linked genes differs led to the idea that crossover frequency might indicate the distance separating genes on the chromosome.

Alfred Sturtevant, a student of Morgan's, first developed genetic maps, also known as linkage maps. Sturtevant proposed that the greater the distance between linked genes, the greater the chance that non-sister chromatids would cross over in the region between the genes. By working out the number of recombinants it is possible to obtain a measure for the distance between the genes. This distance is called a genetic map unit (m.u.), or a centimorgan and is defined as the distance between genes for which one product of meiosis in 100 is recombinant. A recombinant frequency (RF) of 1 % is equivalent to 1 m.u. A linkage map is created by finding the map distances between a number of traits that are present on the same chromosome, ideally avoiding having significant gaps between traits to avoid the inaccuracies that will occur due to the possibility of multiple recombination events.

[edit] Linkage map

A linkage map is a genetic map of a species or experimental population that shows the position of its known genes or genetic markers relative to each other in terms of recombination frequency, rather than as specific physical distance along each chromosome. Linkage mapping is critical for identifying the location of genes that cause genetic diseases.

A genetic map is a map based on the frequencies of recombination between markers during crossover of homologous chromosomes. The greater the frequency of recombination (segregation) between two genetic markers, the farther apart they are assumed to be. Conversely, the lower the frequency of recombination between the markers, the smaller the physical distance between them. Historically, the markers originally used were detectable phenotypes (enzyme production, eye color) derived from coding DNA sequences; eventually, confirmed or assumed noncoding DNA sequences such as microsatellites or those generating restriction fragment length polymorphisms (RFLPs) have been used.

Genetic maps help researchers to locate other markers, such as other genes by testing for genetic linkage of the already known markers.

A genetic map is not a physical map (such as a radiation reduced hybrid map) or gene map.

[edit] LOD score method for estimating recombination frequency

The LOD score (logarithm (base 10) of odds) is a statistical test often used for linkage analysis in human populations, and also in animal and plant populations. The LOD score compares the likelihood of obtaining the test data if the two loci are indeed linked, to the likelihood of observing the same data purely by chance. Positive LOD score favor the presence of linkage, whereas negative LOD scores indicate that linkage is less likely. The test was developed by Newton E. Morton. Computerized LOD score analysis is a simple way to analyze complex family pedigrees in order to determine the linkage between Mendelian traits (or between a trait and a marker, or two markers).

The method is described in greater detail by Strachan and Read [1]. Briefly, it works as follows:

  1. Establish a pedigree
  2. Make a number of estimates of recombination frequency
  3. Calculate a LOD score for each estimate
  4. The estimate with the highest LOD score will be considered the best estimate

The LOD score is calculated as follows:

 
\begin{align}
LOD = Z & = \log_{10} \frac{
\mbox{probability of birth sequence with a given linkage value}
}{
\mbox{probability of birth sequence with no linkage}
} \\
 & = \log_{10} \frac{(1-\theta)^{NR} \times \theta^R}{ 0.5^{(NR + R)} }
\end{align}

NR denotes the number of non-recombinant offspring, and R denotes the number of recombinant offspring. The reason 0.5 is used in the denominator is that any alleles that are completely unlinked (e.g. alleles on separate chromosomes) have a 50% chance of recombination, due to independent assortment.

Theta is the recombinant fraction, it is equal to R / (NR + R)

In practice, LOD scores are looked up in a table which lists LOD scores for various standard pedigrees and various values of recombination frequency.

By convention, a LOD score greater than 3.0 is considered evidence for linkage. A LOD score of +3 indicates 1000 to 1 odds that the linkage being observed did not occur by chance. On the other hand, a LOD score less than -2.0 is considered evidence to exclude linkage. Although it is very unlikely that a LOD score of 3 would be obtained from a single pedigree, the mathematical properties of the test allow data from a number of pedigrees to be combined by summing the LOD scores. It is important to keep in mind that this traditional cutoff of LOD>+3 is an arbitrary one and that the difference between certain types of linkage studies, particularly analyses of complex genetic traits with hundreds of markers, these criteria should probably be modified to a somewhat higher cutoff.

[edit] Recombination frequency

Recombination frequency (è) is the frequency that a chromosomal crossover will take place between two loci (or genes) during meiosis. Recombination frequency is a measure of genetic linkage and is used in the creation of a genetic linkage map. A centimorgan (cM) is a unit that describes a recombination frequency of 1%.

During meiosis, chromosomes assort randomly into gametes, such that the segregation of alleles of one gene is independent of alleles of another gene. This is stated in Mendel's Second Law and is known as the law of independent assortment. The law of independent assortment always holds true for genes that are located on different chromosomes, but for genes that are on the same chromosome, it does not always hold true.

As an example of independent assortment, consider the crossing of the pure-bred homozygote parental strain with genotype AABB with a different pure-bred strain with genotype aabb. A and a and B and b represent the alleles of genes A and B. Crossing these homozygous parental strains will result in F1 generation offspring with genotype AaBb. The F1 offspring AaBb produces gametes that are AB, Ab, aB, and ab with equal frequencies (25%) because the alleles of gene A assort independently of the alleles for gene B during meiosis. Note that 2 of the 4 gametes (50 %)—Ab and aB—were not present in the parental generation. These gametes represent recombinant gametes. Recombinant gametes are those gametes that differ from both of the haploid gametes that made up the diploid cell. In this example, the recombination frequency is 50% since 2 of the 4 gametes were recombinant gametes.

The recombination frequency will be 50% when two genes are located on different chromosomes or when they are widely separated on the same chromosome. This is a consequence of independent assortment.

When two genes are close together on the same chromosome, they do not assort independently and are said to be linked. Whereas genes located on different chromosomes assort independently and have a recombination frequency of 50%, linked genes have a recombination frequency that is less than 50%.

As an example of linkage, consider the classic experiment by William Bateson and Reginald Punnett. They were interested in trait inheritance in the sweet pea and were studying two genes—the gene for flower colour (P, purple, and p, red) and the gene affecting the shape of pollen grains (L, long, and l, round). They crossed the pure lines PPLL and ppll and then self-crossed the resulting PpLl lines. According to Mendelian genetics, the expected phenotypes would occur in a 9:3:3:1 ratio of PL:Pl:pL:pl. To their surprise, they observed an increased frequency of PL and pl and a decreased frequency of Pl and pL (see table below).

Bateson and Punnett experiment
Phenotype and genotype Observed Expected from 9:3:3:1 ratio
Purple, long (PpLl) 284 216
Purple, round (Ppll) 21 72
Red, long (ppLl) 21 72
Red, round (ppll) 55 24

Their experiment revealed linkage between the P and L alleles and the p and l alleles. The frequency of P occurring together with L and with p occurring together with l is greater than that of the recombinant Pl and pL. The recombination frequency cannot be computed directly from this experiment, but intuitively it is less than 50%.

The progeny in this case received two dominant alleles linked on one chromosome (referred to as coupling or cis arrangement). However, after crossover, some progeny could have received one parental chromosome with a dominant allele for one trait (eg Purple) linked to a recessive allele for a second trait (eg round) with the opposite being true for the other parental chromosome (eg red and Long). This is referred to as repulsion or a trans arrangement. The phenotype here would still be purple and long but a test cross of this individual with the recessive parent would produce progeny with much greater proportion of the two crossover phenotypes. While such a problem may not seem likely from this example, unfavorable repulsion linkages do appear when breeding for disease resistance in some crops.

When two genes are located on the same chromosome, the chance of a crossover producing recombination between the genes is related to the distance between the two genes. Thus, the use of recombination frequencies has been used to develop linkage maps or genetic maps.


Genes and Alleles

Genes contain information about a specific characteristic or trait and can either be dominant or recessive. Genes are found on chromosomes and each gene has a designated place on every chromosome, called a locus. Not all copies of a gene are identical and alternative forms of a gene, called alleles, lead to the alternative form of a trait. Alleles are a way of identifying the two members of a gene pair which produce opposite contrasting phenotypes. An allele of a gene is it's partner gene, for example b is an allele of B and vice versa. When the alleles are identical, the individual is homozygous for that trait. While if the pair is made of two different alleles, the individual is heterozygous. A homozygous pair of can be either dominant (AA, BB) or recessive (aa, bb). Heterozygous pairs are made up of one dominant and one recessive allele (Aa, Bb). In heterozygous individuals only one allele, the dominant, gains expression while the other allele, the recessive, is hidden but still present. Capital letters represent dominant genes and lower case letters, recessive genes. The word genotype is was created to identify genes of an individual and phenotype for the expression of the trait and genes. Phenotype and genotype are terms used to describe the difference between the visible expression of the trait vs. the actual gene makeup. An individual which expresses a dominant trait may carry a recessive allele, but the recessive expression is hidden by it's dominant partner.

In Mendel's garden pea experiment, he also crossed plants that had two different pairs of alleles. He made a dihybrid cross of round, yellow seeds vs. wrinkled green seeds. The genes for round and yellow are dominant over their alleles of wrinkled and green. In the F1 generation all seeds were round and yellow as expected. Out of 556 plants in the F2 generation, 315 were round and yellow, 108 were round and green, 101 were wrinkled and yellow and 35 were wrinkled and green. When brought down to its lowest terms, it comes to a ratio of nearly 9:3:3:1. Mendel observed that the results were the same as the product of two monohybrid crosses. This lead to the law of probability which states that "the chance of two or more independent events occurring together is the product of the chances of their separate occurrences." For example, crosses between parents that differ in three traits, called trihybrid crosses, are a combination of three monohybrid crosses together. Mendel also noticed that the pairs of alleles separated and behaved independently with respect to the other pair. Mendel then wrote the law of independent assortment which observes that independent combinations of different pairs of alleles may occur. Mendel believed that a single gene was responsible for one single trait all by itself. We now know that many genes have control over the production of traits. Individuals inherit genes from their parents, not traits. Another important fact is that genes behave as separate units and traits are the product of complex gene interaction.

Recessive Genes
Recessive genes can only be expressed in homozygous (aa) individuals. There are more heterozygous (Aa) carriers than homozygous (aa) carriers who actually express the trait. All three genotypes (AA, aa, Aa) are possible throughout any population. Even in carriers that are not phenotypically expressed (Aa), the recessive allele can be identified in a cross.

The three criteria for identifying recessive genes:

  • The first appearance of the recessive trait within a family usually is in the children of the unaffected parents.
  • 25% of the children will be express trait.
  • Both males and females can express the trait unless it is a recessive sex linked gene.

Dominant Genes
If a gene (A) is completely dominant, AA and Aa are phenotypically alike. Phenotypes specified by single gene substitutions are called dominants and those that require homozygous combinations for expression are called recessives. Dominants are easier to find than recessives, for dominants are fully expressed when paired with either allele. The individual's genotype may be homozygous or heterozygous if they express a dominant trait. In dominant the trait will be expressed in all generations.

The 4 criteria for identifying dominant genes:

  • If the trait if dominant, it will be expressed in all generations.
  • The trait is passed from the affected parent to about 50% of his/her children.
  • Any parent that does not express the trait does not transmit it to any of his/her children.
  • Both males and females can express and transmit the trait.

Incomplete Dominance
Alleles are not always recessive or dominant, but have a range of dominance. In simple or complete dominance the heterozygote, even though genetically different, has the exact same phenotype as one of the homozygotes. This leads to the conclusion that Aa is equal to AA, phenotypically speaking. The recessive gene is present in the heterozygote but hidden by the dominant. Dominance is then considered a physiological effect.

In Mendel's experiments all the chosen genes showed complete dominance, except flowering time. One of his plants flowered early, one late and surprisingly two flowered somewhere in the middle. Even though the genotype ratio remains the same, it is the phenotype ratio of 3:1 dominant-recessive that changes to 1:2:1. The absence of complete dominance makes every genotype different. The examples of dominance in the garden peas were flower color and seed shape. But in other plants the flower color is not necessarily one color or the other, meaning that the plant may express a color between the two. Ever since the time of Mendel, examples of partial of incomplete dominance have been discovered in animals and plants. In incomplete dominance the heterozygote shows a phenotype which in between the homozygous recessive and homozygous dominant phenotypes.

Snapdragons
Snapdragon Crosses
An excellent example of incomplete dominance are snapdragon flowers. When one crosses a red flowered snapdragon with a white flowered, all of the F1 generation have pink heterozygous flowers. It appears that the red and white colors were mixed together two create a pink pigment, but this proves to be untrue when you cross two plants from the F1 generation. The F2 generation have all three colors; red, pink and white, with a ratio of 1:2:1. This is a definite exception to the 3:1 ratio that is observed with all examples of complete dominance. Incomplete dominance causes a distortion of the normal phenotypic ratio. For one to fully understand the possibility of pink flowers, remember that the gene for flower color controls the amount of pigment in the flower petals. Each allele is a code for a specific amount of pigment. When both alleles for pigment are present the petals have a dark red color due to the heavy production of pigment. On the other hand if none of the alleles for pigment exist, the flower is then white. When one of the alleles is present, only half the pigment is produced, creating a pink shade. If the heterozygous phenotype (Rr) coincides with the phenotype of one of the homozygotes phenotypic effect of the heterozygote (rr) can then be termed incomplete dominance.

Codominance and Blood Types
Two alleles in a gene pair are each associated with different substances. When both substances appear together in heterozygotes, codominance occurs. The two alleles of a pair at a specific locus are not identical but the expression of both is observed. Codominance is clearly different than incomplete dominance. An example of codominance is the ABO blood typing system used to determine the type of human blood. It is common knowledge that a blood transfusion can only take place between two people who have compatible types of blood. Human blood is separated into different classifications because of the varying proteins contained in each blood type's red blood cells. These proteins are there to identify whether or not the blood in the individual's body is it's own and not something the immunity system should destroy.

The protein's structure is controlled by three alleles; i, IA and IB. The first allele is, i, the recessive of the three, and IA and IB are both codominant when paired together. If the recessive allele i is paired with IB or IA, it's expression is hidden and is not shown. When the IB and IA are together in a pair, both proteins A and B are present and expressed.

The ABO system is called a multiple allele system for there are more than two possible allele pairs for the locus. The individual's blood type is determined by which combination of alleles he/she has. There are four possible blood types in order from most common to most rare: O, A, B and AB. The O blood type represents an individual who is homozygous recessive (ii) and does not have an allele for A or B. Blood types A and B are codominant alleles. Codominant alleles are expressed even if only one is present. The recessive allele i for blood type O is only expressed when two recessive alleles are present. Blood type O is not apparent if the individual has an allele for A or B. Individuals who have blood type A have a genotype of IAIA or IAi and those with blood type B, IBIB or IBi, but an individual who is IAIB has blood type AB.

Blood Type Chart
Parent 1
Parent 2
Child
Type O (i i)
Type O
Type O (i i)
Type A (IA)
Type A (IA)
Type A (IAIA)
Type B (IB)
Type B (IB)
Type B (IBIB)
Type A (IA)
Type O (i i)
Type A (IAi)
Type B (IB)
Type O (i i)
Type B (IBi)
Type A (IA)
Type B (IB)
Type AB (IAIB)

Multiple Alleles
The source of new alleles was recognized as a gene change or a mutation. Alleles are located in corresponding parts of homologous chromosomes, only one member of a pair can be present in a given chromosome and only two are present in a cell of a diploid. Alleles are genes that are members of the same gene pair, each kind of allele affecting a trait differently than the other. A diploid organism has, by its definition, only two alleles at one time, yet exceptions to the rules do appear. Many examples were found where more than two alternative alleles, also called multiple alleles, are present. In these cases two or more different mutations must have taken place at the same locus but in different individuals or at different times. Multiple alleles are alternative states at the same locus. The different alleles of a series are usually represented by the same symbol. Subscripts and superscripts are used to identify different members of a series of alleles. Most alleles produce variations of the same trait, but some produce very different phenotypes.

The most famous example of multiple alleles was discovered in rabbits. It was known that Albino rabbits were produced on occasion in variously colored rabbit populations. After conducting a monohybrid cross between a colored and Albino rabbit, it was discovered that the members of a pair of alternative genes, either c or c+, must be responsible for colored or albino rabbits. A cross of homozygous colored (c+ c+) and albino (c c) rabbits was made and the F1 generation were all colored, while the F2 generation had three colored and one albino. This showed that one pair of alleles was involved, the wild c+ and the mutant allele c. It was determined that c+ was dominant over c.


Analyzing Pedigrees

The pedigree method consists of an analysis for a particular trait, when the results have already been made. Usually diagrams or charts are used to attempt to find patterns of inheritance. Pedigrees are the oldest methods of genetic information and are still used in studies of human inheritance and animal breeding. The first step is to determine whether the gene being studied is dominant or recessive. Recessive genes are difficult to keep track of, for they are hidden by their dominant alleles one generation after another. An important thing to remember is that one can not determine offhand which individual is a carrier of a specific trait, until the trait is expressed in someone.

Traits that are dependent on certain recessive genes may suddenly appear without any previous record of a relative having this trait. Recessives are more likely to become expressed in families where the father and mother are closely related, or descended from a common ancestor. Next one must identify the genotypes of as many family members as possible with the information given. For example if a man expresses the recessive gene for the trait of adherent earlobes, the man must be homozygous (aa) for his genotype. Both of his parents must be heterozygous (Aa) carriers for each to have contributed a gene to their son. One may then conclude that his brothers and sisters must have the genotype of AA or Aa, but not aa for they do not express the trait of adherent earlobes. The best probability is that each parent is Aa, therefore the likelihood of a child having free earlobes with a genotype of Aa is two-thirds and a genotype of AA, one-third. Without any more information one can assume that the man's sibling's can be Aa with two-thirds probability and a fifty percent chance for being a carrier of the recessive gene, if their parents are also carriers.

Family Pedigree

Sample Pedigree
Pedigree Diagram
Pedigrees are very similar to family trees, except pedigrees study a certain trait within a family. Every generation is represented by a Roman numeral, and each member of the generation by an Arabic numeral. Males are represented by a square and females by a circle. If the symbol is shaded that person expresses or has the studied trait. For example, the two generation pedigree below shows that the father expresses the trait, as does his daughter, but no other family members

Making your own family pedigree is easy. All the materials you will need is paper, a pencil or pen and a colored marker. Draw an outline of your family starting with your grandparents, leading to your parents, uncles, aunts and then yourself, any siblings or cousins. The ability to roll one's tongue is a noticeable dominant trait. Anyone who can roll their tongue has the dominant allele R while those who cannot have the genotype rr. Find out if you can roll your own tongue, if not enter your genotype on the pedigree as rr. If you can, write your genotype as one R for you have the dominant gene. Ask family members on your pedigree if they are able to roll their tongues. Then write down the appropriate genotypes by their symbol on the chart.


Mendel's Laws

The principles of heredity were written by the Augustinian monk Gregor Mendel in 1865. Mendel discovered that by crossing white flower and purple flower plants, the result was a hybrid offspring. Rather than being a mix of the two, the offspring was purple flowered. He then conceived the idea of heredity units, which he called "factors", one which is a recessive characteristic and the other dominant. Mendel said that factors, later called genes, normally occur in pairs in ordinary body cells, yet segregate during the formation of sex cells. Each member of the pair becomes part of the separate sex cell. The dominant gene, such as the purple flower in Mendel's plants, will hide the recessive gene, the white flower. After Mendel self-fertilized the F1 generation and obtained the 3:1 ratio, he correctly theorized that genes can be paired in three different ways for each trait; AA, aa, and Aa. The capital A represents the dominant factor and lowercase a represent the recessive.

Mendel stated that each individual has two factors for each trait, one from each parent. The two factors may or may not contain the same information. If the two factors are identical the individual is called homozygous for the trait. If the two factors have different information, the individual is called heterozygous. The alternative forms of a factor are called alleles. The genotype of an individual are made up of the many alleles it possesses. An individual's physical appearance or phenotype is determined by its alleles. An individual possesses two alleles for each trait; one allele is given by the female parent and the other by the male parent. They are passed on when an individual matures and produces gametes, egg and sperm. When gametes form the paired alleles separate randomly so that each gamete receives a copy of one of the two alleles. The presence of an allele doesn't promise that the trait will be expressed in the individual that possesses it. In heterozygous individuals the only allele that in expressed is the dominant. The recessive allele is present but its expression is hidden.

Mendel summarized his findings in two laws; the Law of Segregation and the Law of Independent Assortment. The Law of Segregation states that the members of each pair of alleles separate when gametes are formed. A gamete will receive one allele or the other. The Law of Independent assortment states that two or more pairs of alleles segregate independently of one another during gamete formation.


Thomas Hunt Morgan and Sex-Linked Traits

In 1910 Morgan studied the Drosophila fly and found a mutant male fly, which expressed the trait of white eyes instead of the normal red eyes. This trait was very unusual in that species and Morgan wanted to see if the trait would be passed on to its offspring. He experimented to find if this strange trait would be inherited according to Mendel's research. First he crossed the mutant male fly with a normal female with red eyes, to observe whether the white or red eyes were dominant. The F1 generation all had red eyes, which made Morgan conclude that red eyes were dominant over white. He continued the steps of Mendel's experiment by crossing two flies from the F1 generation with each other. Out of 4252 flies in his F2 generation, 782 had white eyes but surprisingly all the flies with white eyes were also male. This strange observation puzzled Morgan to wonder why there weren't any females with white eyes. He then crossed flies from the F1 generation with the original male fly with white eyes. This cross resulted in white-eyed and red-eyed males and females, making a 1:1:1:1 ratio.

In Drosophila the sex is determined by the number of copies of the X chromosome. An individual that has two X chromosomes is female and an individual with one X chromosome, which then joins with the Y chromosome, is male. During fertilization, if the egg joins with an X sperm, the zygote is XX, which becomes female. If the Y sperm is involved in fertilization, there is a XY zygote, which develops into a male. The reasoning for Morgan's results is due to the fact that the gene for while eyes in Drosophila is located on the X chromosome and not the Y chromosome. Genes on the X chromosome that determine a trait are called sex linked. After one understands how the white-eye trait is recessive to the red-eye trait, one can easily notice that Morgan's results follow Mendel's assortment of chromosomes. Morgan's experiment has been called one of the most important events in genetics. His work with Drosophila proved Sutton's theory that Mendel's "traits" are found on chromosomes.

Basic Genetics III: Linkage and Crossing Over

Up until now we have assumed that all genes were inherited independently. However, we have also said that genes are arranged on chromosomes, which are essentially long strands of DNA residing in the nucleus of the cell. This certainly opens the possibility that two otherwise unrelated genes could reside on the same chromosome. Does independent inheritance hold for these genes?

To start with, we need to consider the rather complex process that forms gametes (egg and sperm cells, each with only one copy of each chromosome) from normal cells with two copies of each chromosome., one derived from each parent. I am not going to go into the details, beyond remarking that at one stage of this process, the maternally-derived chromosome lines up with the corresponding paternally-derived chromosome, and only one of the two goes to a specific gamete. If this were all there were to it dogs, having 39 chromosome pairs, would have only 39 "genes", each of which would code for a wide variety of traits. In fact, things are a little more complicated yet, because while the paternal and maternal chromosomes are lined up, they can and do exchange segments, so that at the time they actually separate, each of the two chromosomes will most likely contain material from both parents.

At this point we need to define a couple of terms. Two genes are linked if they are close together on the same chromosome and thus tend to be inherited together. Linkage in common usage, however, may apply to a single gene having more than one effect. An example which is not linkage in the sense used here is the association between deafness and extreme white spotting. White spotting is due to the melanocytes, the cells which produce pigment, not managing to migrate to all parts of the fetus. Now it turns out that in order for the inner ear to develop properly, it must have melanocytes. If the gene producing white spotting also prevents the precursors of the melanocytes from reaching the inner ear, the result will be deafness in that ear. In other words, the same gene could easily influence both processes. Thus deafness and white spotting are associated, but they are not linked. They are due to what is called pleiotropic (affecting the whole body) effects of a single gene.

In true linkage, there is always the possibility that linked genes can cross over. Imagine each chromosome as a piece of rope, with the genes marked by colored stripes. The matching of the maternal and paternal chromosomes is more or less controlled by the colored stripes, which tend to line up. But the chromosomes are flexible. They bend and twist around each other. They are also self healing, and when both the maternal and paternal chromosomes break, they may heal onto the paired chromosome. This happens often enough that genes far apart on long chromosomes appear to be inherited independently, but if genes are close together, a break is much less likely to form between them than at some other part of the paired chromosomes.

Such breaks, called "crossing over" do occur, and occur often enough that they are used to map where genes genes are located on specific chromosomes. In general, neither linkage nor crossing over is of much importance to the average dog breeder, though one should certainly keep in mind the possibility that the spread of an undesirable gene through a breed is due to the undesirable gene being linked to a gene valued in the breed ring. Crossing over is also important in the use of marker genes for testing whether a dog carries a specific gene, most often a gene producing a health problem.

There are two distinct ways of using DNA testing to identify dogs carrying specific, undesirable genes. The first (and preferable) is actually to sequence the undesirable gene and its normal allele. This allows determination of whether the dog is homozygous normal, a heterozygous carrier, or homozygous affected. Since the genes themselves are being looked at, the results should be unambiguous. (The breeding decisions based on these results are still going to depend on the priorities of the breeders.)

In some tests, however, a marker gene is found that appears to be associated with the trait of interest, but is not actually the gene producing that trait. Such a marker is tightly linked to the gene actually causing that trait. This does not work at all badly providing that the group on which the test was validated is closely related to the group to which the test was applied. Use of this type of test on humans usually requires that the test be validated on close relatives, and applied only to people closely related to the validation group.

It is true that dogs of a given breed tend to be closely related to each other. However, the breed-wide relationship is generally through more distant ancestors than most people can trace in their own genealogy. In Shetland Sheepdogs, for instance, almost all US show stock can be traced to dogs imported from the British Isles between 1929 and 1936, with only a tiny influence of imports after 1950. This means that a crossover appearing on one side of the Atlantic since 1950 (20 or so dog generations) might not show up on the other side. Marker tests that work on U.S. populations might not work at all on British dogs, or on a dog with recent British ancestry.

Even without physical separation here is always the possibility that at some point in the breed history a crossover occurred. Quite a large fraction of the breed may have the original relationship between the marker gene and the problem gene, but if a crossover occurred in an individual who later had a considerable influence on the breed, the breed may also contain individuals in which the marker gene is associated with the opposite form of the problem gene. Since the relationship between individuals of the same breed may go back 30 generations or more, and there is a chance of a crossover occurring in each generation, linked markers need to be used with caution and with constant checking that marker test results correlate with clinical results.

Let's look more closely at this.

Let our marker gene be ma, with maa being the gene associated with the healthy gene, and mab being the marker that seems to be associated with the defective gene, both being true for the test population. For the genes actually producing the problem, we will use H, with Hh being the normal, healthy gene and hd being the recessive gene which causes the problem. In the original test population, maa was always on the same chromosome with Hh, and mab was on the same chromosome with hd. In other words, chromosomes are either maaHh or mabhd, never maahd or mabHh. If a dog has maa on both chromosomes, it is also Hh on both chromosomes, a genetic clear. If it has maa on one chromosome and mab on the other, it also has one Hh gene and one hd gene, and is a carrier. If it has mab on both chromosomes, it has hd on both chromosomes and is a genetic affected. At least, that is the assumption on which marker tests are based.

Now suppose that at some point a crossover occurred between the ma and H loci. The probability of a crossover may be very small in any individual breeding, but remember that there are a lot of breedings behind any particular dog. We can still assume that most of the chromosomes will still be of the maaHh or mabhd type, or the original validation of the marker test would have failed. But now suppose that a small fraction of the chromosomes are of types maahd and/or mabHh. We now have four chromosome types, and sixteen possible combinations. Some of these will test the same, since the only difference is in which chromosome comes from the mother and which from the father, but there are still sixteen possible outcomes. In the table below both the marker results (upper) and the true results (lower) are shown for each possible combination:


maaHh

mabhd

maahd

mabHh

maaHh

clear maamaa

carrier maamab

clear maamaa

carrier maamab


clear HhHh

carrier Hhhd

carrier Hhhd

clear HhHh

mabhd

carrier maamab

affected mabmab

carrier maamab

affected mabmab


carrier Hhhd

affected hdhd

affected hdhd

carrier Hhhd

maahd

clear maamaa

carrier maamab

clear maamaa

carrier maamab


carrier Hhhd

affected hdhd

affected hdhd

carrier Hhhd

mabHh

carrier maamab

affected mabmab

carrier maamab

affected mabmab


clear HhHh

carrier Hhhd

carrier Hhhd

clear HhHh

Note that in only six of the sixteen possible types is the marker indication of genotype correct. If the crossover genotypes are rare (as would normally be the case if the marker test verified at all) most of the population will be in the upper left quarter of the table, where the marker will correctly predict the true genotype. But if any of the chromosomes trace back to a crossover, a marker test may give a false sense of security (carrier or affected shows clear by marker testing) or result in discarding a healthy dog (carrier or clear shows affected or carrier by marker testing.)

If only three chromosome types are available, the two verifying types plus one crossover, then if the marker gene is associated at times with the healthy allele, (mabHh) the result will include dogs which are affected or carriers by marker analysis which are genetically carriers or clears (false positives.) If the other chromosome type has the undesirable allele not always associated with the marker (maahd) the results will include dogs clear or carriers by marker analysis that are actually carriers or affected (false negatives.) However, the existance of one crossover chromosome type would make me suspicious that the other might also exist in the breed.

So are marker tests of any use at all?

Yes! In the first place, they demonstrate that the actual gene is on a relatively limited portion of a known chromosome. The marker gene can thus assist in finding and sequencing the gene actually causing the health problem.

In the second place, marker tests are accurate so long as neither parent of an individual has a crossover chromosome. In humans, such tests are most likely to be used when a problem runs in a particular family. The linkage of a marker with the genes actually producing the problem is generally based on studies of how the marker is linked to the genes in that particular family. With dogs, the verification is normally done on a breed basis, and the fact that breeds may actually be split into groups (color, size, country of origin) which interbreed rarely if ever is likely to be ignored. Dogs closely related via close common ancestors to the test population are the best candidates for marker testing. In general, keep up conventional testing side by side with the marker testing. If the marker testing and the conventional testing disagree (e.g, affected dog tests clear or clear dog tests affected) consider the possibility of a crossover, and notify the organization doing the test.


Animal Genetics



Basic Genetics (still under construction - how genes work, dominant, incompletely dominant and recessive genes, breeding probabilities, Punnett squares, etc.)
  • Part I, single locus
  • Part II, multiple Loci
  • Part III, linkage and crossing over
  • Part IV, relationship of traits to genes (single locus)
  • Part V, relationship of traits to genes (complex inheritance)
  • Test breeding I: to determine whether a dog carries a recessive gene
  • Test breeding II: to test whether a gene is at a particular locus
  • Test breeding III: to determine the genetics of a trait

Population Genetics (also still under construction.) How selection of different kinds can change the overall genetic makeup of a breeding population.

  • Part I, selecting against an undesirable gene when gene frequency is relatively low
  • Part II, Reducing a high gene frequency while retaining genetic diversity

Inbreeding and line breeding. What are the effects on the genome?

Coat Color Genetics in Dogs (Basic color genetics, all breeds, including comments on colors where genetics are questionable.)

Size as an example of additive inheritance (A possible explanation of why size is such a problem in breeding Shetland Sheepdogs)

Relationships between color genes and deafness in dogs (off site).

Movement - the gaits used by quadrupeds.

References for the genetics section, including links to other genetics websites.

What color is that puppy in the window, (Black, yellow and chocolate in Labrador Retrievers) (off site)

Palomino and Merle -- Too much of a good thing (Overdominance) (off site)

We are Siamese if you please (The Himalayan color gene) (off site)

"Ringstreaked, speckled, and spotted" (White markings in domesticated mammals) (off site)

Hair color (The agouti gene) (off site)

Merle Genetics (Practical information on breeding merles)

Sable Merle photographs.

History of color breakdown in Shelties, using dogs registered in the UK Stud Book and Shelties who are US Champions.

Analysis of the inheritance of merle in US Shelties.

Photo list of Shelties on this site, indexed by color. Some unusual, rare and undesirable colors are included.


Basic Genetics

The basis for order in life lies in a very large molecule called deoxyribonucleic acid, mercifully abbreviated to DNA. A related molecule, ribonucleic acid (RNA) provides the genetic material for some microbes, and also helps read the DNA to make proteins.

Read?

Yes, read.

DNA has a shape rather like a corkscrewed ladder. The "rungs" of the ladder are of four different types. The information in DNA comes in how those types are ordered along the molecule, just as the information in Morse code comes in how the dashes and dots are ordered. The information in three adjacent rungs is "read" by a kind of RNA that hooks onto a particular triad of rungs at one end and grabs a particular amino acid at the other. Special triads say "start here" and "end here" and mark off regions of the DNA molecule we call discrete genes. The eventual result is a chain of amino acids that makes up a protein, with each amino acid corresponding to a set of three rungs along the DNA molecule. There are also genes that tell the cell when to turn on or turn off another gene. The proteins produced may be structural or they may be enzymes that facilitate chemical reactions in the body.

We now know that chromosomes are essentially DNA molecules. In an advanced (eukaryotic) cell, these chromosomes appear as threadlike structures packaged into a more or less central part of the cell, bound by a membrane and called the nucleus. What is more important is that the chromosomes in a body cell are arranged in pairs, one from the father and one from the mother. Further, the code for a particular protein is always on the same place on the same chromosome. This place, or location, is called a locus (plural loci.)

There are generally a number of slightly different genes that code for forms of the same protein, and fit into the same locus. Each of these genes is called an allele. Each locus, then, will have one allele from the mother and one from the father. How?

When an animal makes an egg or a sperm cell (gametes, collectively) the cells go through a special kind of division process, resulting in a gamete with only one copy of each chromosome. Unless two genes are very close together on the same chromosome, the selection of which allele winds up in a gamete is strictly random. Thus a dog who has one gene for black pigment and one for brown pigment may produce a gamete which has a gene for black pigment OR for brown pigment. If he's a male, 50% of the sperm cells he produces will be B (black) and 50% will be brown (b).

When the sperm cell and an egg cell get together, a new cell is created which once again has two of each chromosome in the nucleus. This implies two alleles at each locus (or, in less technical terms, two copies of each gene, one derived from the mother and one from the father,) in the offspring. The new cell will divide repeatedly and eventually create an animal ready for birth, the offspring of the two parents. How does this combination of alleles affect the offspring?

There are several ways alleles can interact. In the example above, we had two alleles, B for black and b for brown. If the animal has two copies of B, it will be black. If it has one copy of B and one of b, it will be just as black. Finally, if it has two copies of b, it will be brown, like a chocolate Labrador. In this case we refer to B as dominant to b and b as recessive to B. True dominance implies that the dog with one B and one b cannot be distinguished from the dog with two B alleles. Now, what happens when two black dogs are bred together?

We will use a diagram called a Punnett square. For our first few examples, we will stick with the B locus, in which case there are two possibilites for sperm (which we write across the top) and two for eggs (which we write along the left side. Each cell then gets the sum of the alleles in the egg and the sperm. To start out with a very simple case, assume both parents are black not carrying brown, that is, they each have two genes for black. We then have:


B

B

B

BB (black)

BB (black)

B

BB (black)

BB (black)

All of the puppies are black if both parents are BB (pure for black.

Now suppose the sire is pure for black but the dam carries a recessive gene for brown. In this case she can produce either black or brown gametes, so


B

B

B

BB (pure for black)

BB (pure for black)

b

Bb (black carrying brown)

Bb (black carrying brown)

This gives appoximately a 50% probability that any given puppy is pure for black, and a 50% probability that it is black carrying brown. All puppies appear black. We can get essentially the same diagram if the sire is black carrying brown and the dam is pure for black. Now suppose both parents are blacks carrying brown:


B

b

B

BB (pure for black

Bb (black carrying brown)

b

Bb (black carrying brown)

bb (brown)

This time we get 25% probabilty of pure for black, 50% probability of black carrying brown, and - a possible surprise if you don't realize the brown gene is present in both parents - a 25% probability that a pup will be brown. Note that only way to distinguish the pure for blacks from the blacks carrying brown is test breeding or possibly DNA testing - they all look black.

Another possible mating would be pure for black with brown:


B

B

b

Bb (black carrying brown)

Bb (black carrying brown)

b

Bb (black carrying brown)

Bb (black carrying brown)

In this case, all the puppies will be black carrying brown.

Suppose one parent is black carrying brown and the other is brown:


B

b

b

Bb (black carrying brown)

bb (brown)

b

Bb (black carrying brown)

bb (brown)

In this case, there is a 50% probability that a puppy will be black carrying brown and a 50% probability that it will be brown.

Finally, look at what happens when brown is bred to brown:


b

b

b

bb (brown)

bb (brown)

b

bb (brown)

bb (brown)

Recessive to recessive breeds true - all of the pups will be brown.

Note that a pure for black can come out of a mating with both parents carrying brown, and that such a pure for black is just as pure for black as one from ten generations of all black parentage. THERE IS NO MIXING OF GENES. They remain intact through their various combinations, and B, for instance, will be the same B no matter how often it has been paired with brown. This, not the dominant-recessive relationship, is the real heart of Mendelian genetics.

This type of dominant-recessive inheritance is common (and at times frustrating if you are trying to breed out a recessive trait, as you can't tell by looking which pups are pure for the dominant and which have one dominant and one recessive gene.) Note that dominant to dominant can produce recessive, but recessive to recessive can only produce recessive. The results of a dominant to recessive breeding depends on whether the dog that looks to be the dominant carries the recessive. A dog that has one parent expressing the recessive gene, or that produces a puppy that shows the recessive gene, has to be a carrier of the recessive gene. Otherwise, you really don't know whether or not you are dealing with a carrier, bar genetic testing or test breeding.

One more bit of terminology before we move on - an animal that has matching alleles (BB or bb) is called homozygous. An animal that has two different alleles at a locus (Bb) is called heterozygous.

A pure dominant-recessive relationship between alleles implies that the heterozygous state cannot be distinguished from the homozygous dominant state. This is by no means the only possibility, and in fact as DNA analysis advances, it may become rare. Even without such analysis, however, there are many loci where three phenotypes (appearances) come from two alleles. An example is merle in the dog. This is often treated as a dominant, but in fact it is a type of inheritance in which there is no clear dominant - recessive relationship. It is sometimes called overdominance, if the heterozyote is the desired state. I prefer incomplete dominance, recognising that in fact neither of the alleles is truly dominant or recessive relative to the other.

As an example, we will consider merle. Merle is a diluting gene, not really a color gene as such. If the major pigment is eumelanin, a dog with two non-merle genes (mm) is the expected color - black, liver, blue, tan-point, sable, recessive red. If the dog is Mm, it has a mosaic appearance, with random patches of the expected eumelanin pigment in full intensity against a background of diluted eumelanin. Phaeomelanin (tan) shows little visual effect, though there is a possibility that microscopic examination of the tan hair would show some effect of M. Thus a black or black tan-point dog is a blue merle, a brown or brown tan-point dog is red merle, and a sable dog is sable merle, though the last color, with phaeomelanin dominating, may be indistinguishable from sable in an adult. (The effect of merle on recessive red is unknown, and I can't think of a breed that has both genes.) What makes this different from the black-brown situation is that an MM dog is far more diluted than is an Mm dog. In those breeds with white markings in the full-color state the MM dog is often almost completely white with a few diluted patches, and has a considerable probablity of being deaf, blind, and/or sterile. Even in the daschund, which generally lacks white markings, the so-called double dapple (MM) has extensive white markings and may have reduced eye size. Photographs of Shelties with a number of combinations of merle with other genes are available on this site, but the gene also occurs in Australian Shepherds, Collies, Border Collies, Cardiganshire Welsh Corgis, Beaucerons (French herding breed), harlequin Great Danes, Catahoula leopard dogs, and Daschunds, at the least.

Note that both of the extremes - normal color and double merle white - breed true when mated to another of the same color, very much like the Punnett squares above for the mating of two browns or two pure for blacks. I will skip those two and go to the more interesting matings involving merles.

First, consider a merle to merle mating. Remember both parents are Mm, so we get:


M

m

M

MM (sublethal double merle)

Mm (merle)

m

Mm (merle)

mm (non-merle)

Assuming that merle is the desired color, this predicts that each pup has a 25% probability of inheriting the sublethal (and in most cases undesirable by the breed standards) MM combination, only 50% will be the desired merle color, and 25% will be acceptable full-color individuals. (In fact there is some anecdotal evidence that MM puppies make up somewhat less than 25% of the offspring of merle to merle breedings, but we'll discuss that separately.) Merle, being a heterozygous color, cannot breed true.

Merle to double merle would produce 50% double merle and is almost never done intentionally. The Punnet square for this mating is:


M

M

M

MM (sublethal double merle)

MM (sublethal double merle)

m

Mm (merle)

Mm (merle)

Merle to non-merle is the "safe" breeding, as it produces no MM individuals:


m

m

M

Mm (merle)

Mm (merle)

m

mm (non-merle)

mm (non-merle)

We get exactly the same probability of merle as in the merle to merle breeding (50%) but all of the remaining pups are acceptable full-colored individuals.

There is one other way to breed merles, which is in fact the only way to get an all-merle litter. This is to breed a double merle (MM) to a non-merle (mm). This breeding does not a use a merle as either parent, but it produces all merle puppies. (The occasional exception will be discussed elsewhere.) In this case,


M

M

m

Mm (merle)

Mm (merle)

m

Mm (merle)

Mm (merle

The problem with this breeding is that it requires the breeder to maintain a dog for breeding which in most cases cannot be shown and which may be deaf or blind. Further, in order to get that one MM dog who is fertile and of outstanding quality, a number of other MM pups will probably have been destroyed, as an MM dog, without testing for vision and hearing, is a poor prospect for a pet. In Shelties, the fact remains that several double merles have made a definite contribution to the breed. This does not change the fact that the safe breeding for a merle is to a nonmerle.

Thus far, we have concentrated on single locus genes, with two alleles to a locus. Even something as simple as coat color, however, normally involves more than one locus, and it is quite possible to have more than two alleles at a locus. What happens when two or more loci are involved in one coat color?

Basic Genetics II: Multiple Loci

Usually more than one gene locus is involved in coat color. We'll take one of the simplest, in which the two loci each have two alleles, with a simple dominant-recessive relationship. The model we will use is the Labrador Retriever. One locus we have already examined: the brown locus. We will now add a second locus, on a different chromosome, called E. An EE or Ee dog will show whatever eumelanin pigment is possible. An ee dog apparently can manufacture only phaeomelanin in the hair, though the skin and eye pigment still includes melanin (of whatever color is allowed by the B series).

A black Lab may be BBEE, BBEe, BbEE or BbEe - any combination that includes at least one B and one E gene.

A chocolate (brown) Lab may be bbEE or bbEe.

A yellow Lab with a black nose may be BBee or Bbee

A yellow Lab with a liver nose is bbee - but since ee dogs tend in many cases to lose nose pigment in winter, this may not be easy to distinguish from BBee or Bbee.

Suppose we mate two BbEe dogs, both blacks carrying brown and yellow:


BE

Be

bE

be

BE

BBEE (pure for black)

BBEe (black carrying yellow)

BbEE (black carrying brown)

BbEe (black carrying brown and yellow)

Be

BBEe (black carrying yellow)

BBee (pure for yellow, black nose)

BbEe (black carrying brown and yellow)

Bbee (yellow carrying brown)

bE

BbEE (black carrying brown)

BbEe (black carrying brown and yellow)

bbEE (pure for brown)

bbEe (brown carrying yellow)

be

BbEe (black carrying brown and yellow)

Bbee (yellow carrying brown)

bbEe (brown carrying yellow)

bbee (brown-nosed yellow)

Each puppy has one chance in sixteen of having the combination shown in any section of the table above. In this mating between two black dogs both carrying brown and yellow, there is a 9/16 probability that a particular pup will be black, a 3/16 probability that the pup will be brown, a 3/16 probability that the pup will be a black-nosed yellow, and a 1/16 probability of a brown-nosed yellow. Since nose color does not come into registration, the registered colors would be 9 black:3 brown:4 yellow.

What happens if more than two loci are involved? The basic principle is the same - put all of the possible combinations in a sperm cell along the top and all of the possible combinations in an egg cell along the left side. The problem is that the number of possible combinations doubles for each additional locus. For a single locus, we had a 2 x 2 square with 4 cells. For two loci, we had a 4 x 4 square with 16 cells. With three loci, we have an 8 x 8 square with 64 cells. Besides, we've pretty well exhausted the acceptable colors for Labs.

Shetland Sheepdogs might be a good model for our three-locus model. For the moment we'll omit the recessive black, and consider that Sheltie color is determined by three loci.

At the A (agouti) locus, ay is sable and at is tan-point (black and tan = referred to as tricolor if a white spotting gene is present.) An ayat dog is sable, but generally somewhat darker than an ayay dog. The difference is generally of the same order as the difference within ayay or within ayat, so it is not possible to be absolutely sure whether at is present by looking at the dog.

At the M locus, Shelties have both M and m, as discussed earlier. Mm produces blue merle in atat dogs and sable merle on ayat and ayay.

At the S (spotting) locus most correctly marked Shelties have two copies of si, Irish spotting. A sisi dog generally ranges from white on the chest and feet to high white stockings, white tail tip, and a full shawl collar. The probability of the full collar, as well as white stifles, seems to be somewhat enhanced if the dog is sisw, so sw, color headed white, tends to be maintained in the breed as well. (I am keeping it simple by ignoring sp, piebald, which may also occur in Shelties.) swsw dogs are predominantly white with color on the head and perhaps a few body spots. While healthy, they cannot be shown.

Suppose we mate two white-factored, tri-factored sable merles (not a likely mating, but this is an illustration!) The genetic formula for each parent is ayatMmsisw. There are eight possible gametes for each sex:


ayMsi

ayMsw

aymsi

aymsw

atMsi

atMsw

atmsi

atmsw

ayMsi

DMS

DMS

SM

SM

DMS

DMS

StM

StM

ayMsw

DMS

DMS*

SM

WSM

DMS

DMS*

StM

WStM

aymsi

SM

SM

S

S

StM

StM

St

St

aymsw

SM

WSM

S

WS

StM

WStM

St

WSt

atMsi

DMS

DMS

StM

StM

DM

DM

BM

BM

atMsw

DMS

DMS*

StM

WStM

DM

DM*

BM

WBM

atmsi

StM

StM

St

St

BM

BM

T

T

atmsw

StM

WStM

St

WSt

BM

WBM

T

WT

There is no way I could fill in this chart with the detail I used in the 2-loci charts and still have it fit readably into a browser window, so I have used a shorthand to indicate the apparent color:

  • S = pure for sable with Irish markings (3)
  • St = tri-factored sable with Irish markings (6)
  • T = tricolor with Irish markings (3)
  • SM = pure for sable merle with Irish markings (6)
  • StM = tri-factored sable merle with Irish markings (12)
  • BM = blue merle with Irish markings (6)
  • WS = white with pure for sable head (1)
  • WSt = white with trifactored sable head (2)
  • WT = white with tricolor head (1)
  • WSM = white with pure for sable merle head (2)
  • WStM = white with tri-factored sable merle head (4)
  • WBM = white with blue merle head. (2)
  • DMS = homozygous merle, dilute sable markings (12)
  • DM = normal homozygous merle (4)

I have not distinguished white-factored from Irish dogs, and I have ignored the possibility that the MMswsw pups (starred in chart) might not be viable. In practice such a breeding would probably never be made, as Sheltie breeders tend to avoid breeding merle to merle and white factor to white factor, but it does illustrate the variety that can be obtained with two alleles at each of three loci.

In this case, all three loci are visibly affecting the color. The only exception is the interaction between color-headed white and double merle, and this is frankly an unknown. There are times, however, when a particular gene combination at one locus can block expression of a gene combination at another locus. I will follow Searle on nomenclature and distinguish between a dominant-recessive relationship between alleles at a particular locus and an epistatic-hypostatic relationship between two loci.

The first example is very obvious, but only because the gene action is clear-cut. Consider Cocker Spaniels. They have two alleles at the S locus (S, fully colored, and sp, piebald.) An SS dog is solid color, an Ssp dog may have minor white marking (and is often unshowable) and an spsp dog is a parti-color. The second gene is ticking. Ticking works by producing flecks of color in white areas. TT produces ticks of color in any white areas on the dog, tt has clear white areas, and Tt probably produces less ticking than TT, with considerable variation among breeds. spsp and probably Ssp dogs will show ticking if T is present, since they have white areas that are "available" for ticking, though if the base color is red, tan or cream the ticking may not be obvious. But if the dog is SS, there are no white spots for the ticking to show up on. SS is thus epistatic to ticking.

The final example involves the genes for dominant black, which may or may not (my feeling is probably not, as there are records of dominant black to tricolor producing both sables and tris) be the top dominant in the A series where it is generally placed. I will assume it is at a separate locus K, with K being dominant black, epistatic to anything at the A series, while kk allows the A series to show through. We also have the E series, in which E allows the A series to show through while ee allows only red-yellow pigment in the hair. Functionally we can consider that the A locus determines where eumelanin and phaeomelanin are produced, the K locus allows only eumelanin to be produced if E is at the E locus, but ee at the E locus overrides that to allow only phaeomelanin production. Sounds like a mess? You bet it does! K at the K locus is epistatic to the A locus, but ee (pure recessive at the E locus) is epistatic to both the A and the K locus. But it agrees with what is observed.

Let's look at a breed cross between two "red" dogs. We'll take an accidental breeding I know of between a Belgian Tervuren (ayayEEkk) and a Golden Retriever (??eeKK). Note that ee is epistatic to the A series, so if dominant black is not at the A locus, we do not know what the normal A allele is in the Golden. The gametes are ayEk for the Terv and ?eK for the Golden. Every puppy inherits ay?EeKk and is black, as was in fact observed (to the initial astonishment of the owner.) If we mated two of these pups, we would get a 16/64 probability of ee which would be red regardless of what was at other loci. Of the other 48/64 (Ee and EE dogs), 75% would be Kk or KK, and hence black. so there is a 36/64 probability that a particular puppy will be black. The remaining 12/64 will show what is present at the A locus. Of the 12, we expect that 9 will have the ay gene in at least one dose, and with dominant black moved to the K locus ay is dominant over all other A alleles. So there is only a 3/64 chance that a given puppy will actually show what A allele is normal in a Golden - if in fact all Goldens have the same allele at A!

Note that in this particular case we can get identical results in the first generation by postulating a top dominant As dominant black at the A locus, with As- dogs having solid eumelanin pigmentation (unless overridden by ee.) In this case the parent gametes would be Ase and ayE, giving AsayEe black pups. In the next generation we would again get 4/16 ee red, 9/16 As-E- black, and 3/16 ayayE- sables. If we could be absolutely sure that the Terv used was not ayat, the appearance of a tricolor would be good evidence for the first hypothesis.

We still need to discuss penetrance, variable expression, and threshold traits, as well as linkage and crossing over (and their influence on the accuracy of DNA testing), test breeding, and testing whether a suspected allele is in fact at a particular locus. Some further comments about merle are also in the works.

Basic Genetics III: Linkage and Crossing Over

Up until now we have assumed that all genes were inherited independently. However, we have also said that genes are arranged on chromosomes, which are essentially long strands of DNA residing in the nucleus of the cell. This certainly opens the possibility that two otherwise unrelated genes could reside on the same chromosome. Does independent inheritance hold for these genes?

To start with, we need to consider the rather complex process that forms gametes (egg and sperm cells, each with only one copy of each chromosome) from normal cells with two copies of each chromosome., one derived from each parent. I am not going to go into the details, beyond remarking that at one stage of this process, the maternally-derived chromosome lines up with the corresponding paternally-derived chromosome, and only one of the two goes to a specific gamete. If this were all there were to it dogs, having 39 chromosome pairs, would have only 39 "genes", each of which would code for a wide variety of traits. In fact, things are a little more complicated yet, because while the paternal and maternal chromosomes are lined up, they can and do exchange segments, so that at the time they actually separate, each of the two chromosomes will most likely contain material from both parents.

At this point we need to define a couple of terms. Two genes are linked if they are close together on the same chromosome and thus tend to be inherited together. Linkage in common usage, however, may apply to a single gene having more than one effect. An example which is not linkage in the sense used here is the association between deafness and extreme white spotting. White spotting is due to the melanocytes, the cells which produce pigment, not managing to migrate to all parts of the fetus. Now it turns out that in order for the inner ear to develop properly, it must have melanocytes. If the gene producing white spotting also prevents the precursors of the melanocytes from reaching the inner ear, the result will be deafness in that ear. In other words, the same gene could easily influence both processes. Thus deafness and white spotting are associated, but they are not linked. They are due to what is called pleiotropic (affecting the whole body) effects of a single gene.

In true linkage, there is always the possibility that linked genes can cross over. Imagine each chromosome as a piece of rope, with the genes marked by colored stripes. The matching of the maternal and paternal chromosomes is more or less controlled by the colored stripes, which tend to line up. But the chromosomes are flexible. They bend and twist around each other. They are also self healing, and when both the maternal and paternal chromosomes break, they may heal onto the paired chromosome. This happens often enough that genes far apart on long chromosomes appear to be inherited independently, but if genes are close together, a break is much less likely to form between them than at some other part of the paired chromosomes.

Such breaks, called "crossing over" do occur, and occur often enough that they are used to map where genes genes are located on specific chromosomes. In general, neither linkage nor crossing over is of much importance to the average dog breeder, though one should certainly keep in mind the possibility that the spread of an undesirable gene through a breed is due to the undesirable gene being linked to a gene valued in the breed ring. Crossing over is also important in the use of marker genes for testing whether a dog carries a specific gene, most often a gene producing a health problem.

There are two distinct ways of using DNA testing to identify dogs carrying specific, undesirable genes. The first (and preferable) is actually to sequence the undesirable gene and its normal allele. This allows determination of whether the dog is homozygous normal, a heterozygous carrier, or homozygous affected. Since the genes themselves are being looked at, the results should be unambiguous. (The breeding decisions based on these results are still going to depend on the priorities of the breeders.)

In some tests, however, a marker gene is found that appears to be associated with the trait of interest, but is not actually the gene producing that trait. Such a marker is tightly linked to the gene actually causing that trait. This does not work at all badly providing that the group on which the test was validated is closely related to the group to which the test was applied. Use of this type of test on humans usually requires that the test be validated on close relatives, and applied only to people closely related to the validation group.

It is true that dogs of a given breed tend to be closely related to each other. However, the breed-wide relationship is generally through more distant ancestors than most people can trace in their own genealogy. In Shetland Sheepdogs, for instance, almost all US show stock can be traced to dogs imported from the British Isles between 1929 and 1936, with only a tiny influence of imports after 1950. This means that a crossover appearing on one side of the Atlantic since 1950 (20 or so dog generations) might not show up on the other side. Marker tests that work on U.S. populations might not work at all on British dogs, or on a dog with recent British ancestry.

Even without physical separation here is always the possibility that at some point in the breed history a crossover occurred. Quite a large fraction of the breed may have the original relationship between the marker gene and the problem gene, but if a crossover occurred in an individual who later had a considerable influence on the breed, the breed may also contain individuals in which the marker gene is associated with the opposite form of the problem gene. Since the relationship between individuals of the same breed may go back 30 generations or more, and there is a chance of a crossover occurring in each generation, linked markers need to be used with caution and with constant checking that marker test results correlate with clinical results.

Let's look more closely at this.

Let our marker gene be ma, with maa being the gene associated with the healthy gene, and mab being the marker that seems to be associated with the defective gene, both being true for the test population. For the genes actually producing the problem, we will use H, with Hh being the normal, healthy gene and hd being the recessive gene which causes the problem. In the original test population, maa was always on the same chromosome with Hh, and mab was on the same chromosome with hd. In other words, chromosomes are either maaHh or mabhd, never maahd or mabHh. If a dog has maa on both chromosomes, it is also Hh on both chromosomes, a genetic clear. If it has maa on one chromosome and mab on the other, it also has one Hh gene and one hd gene, and is a carrier. If it has mab on both chromosomes, it has hd on both chromosomes and is a genetic affected. At least, that is the assumption on which marker tests are based.

Now suppose that at some point a crossover occurred between the ma and H loci. The probability of a crossover may be very small in any individual breeding, but remember that there are a lot of breedings behind any particular dog. We can still assume that most of the chromosomes will still be of the maaHh or mabhd type, or the original validation of the marker test would have failed. But now suppose that a small fraction of the chromosomes are of types maahd and/or mabHh. We now have four chromosome types, and sixteen possible combinations. Some of these will test the same, since the only difference is in which chromosome comes from the mother and which from the father, but there are still sixteen possible outcomes. In the table below both the marker results (upper) and the true results (lower) are shown for each possible combination:


maaHh

mabhd

maahd

mabHh

maaHh

clear maamaa

carrier maamab

clear maamaa

carrier maamab


clear HhHh

carrier Hhhd

carrier Hhhd

clear HhHh

mabhd

carrier maamab

affected mabmab

carrier maamab

affected mabmab


carrier Hhhd

affected hdhd

affected hdhd

carrier Hhhd

maahd

clear maamaa

carrier maamab

clear maamaa

carrier maamab


carrier Hhhd

affected hdhd

affected hdhd

carrier Hhhd

mabHh

carrier maamab

affected mabmab

carrier maamab

affected mabmab


clear HhHh

carrier Hhhd

carrier Hhhd

clear HhHh

Note that in only six of the sixteen possible types is the marker indication of genotype correct. If the crossover genotypes are rare (as would normally be the case if the marker test verified at all) most of the population will be in the upper left quarter of the table, where the marker will correctly predict the true genotype. But if any of the chromosomes trace back to a crossover, a marker test may give a false sense of security (carrier or affected shows clear by marker testing) or result in discarding a healthy dog (carrier or clear shows affected or carrier by marker testing.)

If only three chromosome types are available, the two verifying types plus one crossover, then if the marker gene is associated at times with the healthy allele, (mabHh) the result will include dogs which are affected or carriers by marker analysis which are genetically carriers or clears (false positives.) If the other chromosome type has the undesirable allele not always associated with the marker (maahd) the results will include dogs clear or carriers by marker analysis that are actually carriers or affected (false negatives.) However, the existance of one crossover chromosome type would make me suspicious that the other might also exist in the breed.

So are marker tests of any use at all?

Yes! In the first place, they demonstrate that the actual gene is on a relatively limited portion of a known chromosome. The marker gene can thus assist in finding and sequencing the gene actually causing the health problem.

In the second place, marker tests are accurate so long as neither parent of an individual has a crossover chromosome. In humans, such tests are most likely to be used when a problem runs in a particular family. The linkage of a marker with the genes actually producing the problem is generally based on studies of how the marker is linked to the genes in that particular family. With dogs, the verification is normally done on a breed basis, and the fact that breeds may actually be split into groups (color, size, country of origin) which interbreed rarely if ever is likely to be ignored. Dogs closely related via close common ancestors to the test population are the best candidates for marker testing. In general, keep up conventional testing side by side with the marker testing. If the marker testing and the conventional testing disagree (e.g, affected dog tests clear or clear dog tests affected) consider the possibility of a crossover, and notify the organization doing the test.


Basic Genetics IV:
the relationship of genes to traits (single locus)

With the exception of the few DNA tests available, we cannot know the genetic makeup of our dogs, only the physical makeup, or phenotype. We tend to break that phenotype up into traits, some breed specific, some more general. For instance, we might know that a Sheltie is 15" tall, a black-nosed sable merle with full white collar, feet and Teletype and a narrow face blaze, OFA good, is missing one premolar, has natural ears, and had double rear decals. All of these "traits" are defined by human beings. Very few of them actually refer to single genes that might be inherited as dominant, recessive, incompletely dominant or co-dominant.

In some cases we can break down a trait into a specific combination of genes. In the case of color, for instance, we know of a considerable number of genes that affect color through specific processes. In some cases, this knowledge has fed back on what we consider to be traits. Thus in the case given, the dog is:

  • Sable ay- (as opposed to black with or without tan-point markings).
  • Black (as opposed to brown) B-
  • Merle Mm
  • Irish-marked sisi or sisw
  • Possibly a face-marking gene

In addition, the dog's color can be affected by minor genes (such as the modifier genes determining how much of the dog is white) by random factors (which probably influence the exact pattern of both white spotting and the location of the dark patches in the merling) and by environmental factors (such as uterine environment, nutrition or excessive exposure to the sun.) The point is that very few of the traits that humans have chosen are in fact due solely to the effect of a single pair of alleles at a single locus. We have looked at some such simple traits as regards color.

However, the height of the dog, the ears, the hip rating, the missing premolar, and the double rear decals are probably not single-gene traits, but rely on the interaction of several pairs of genes, with perhaps some influence from the environment.

In general I am using dominant, recessive, co-dominant or intermediate to refer to genes at the same location on a single pair of chromosomes, i.e., alleles at the same locus. There are cases where genes at one locus can "hide" genes at another locus. An example in dogs is recessive yellow, ee, in which recessive yellow, although a recessive at its own locus, can hide whatever the dog carries at the A locus and the proposed K (dominant black) locus. This type of relationship among different loci is called epistatic. The locus that is hidden is referred to as hypostatic. In some cases (e.g., E at the E locus) an epistatic locus has an allele that allows the hypostatic locus to show its effects.

We will consider a number of types of inheritance. The first group actually refer to single-gene traits. Any of these types of inheritance may also be involved in the inheritance of multiple-gene traits.

Single-locus inheritance

More complex inheritance will be covered on the next page, and includes

  • Modifier genes
  • Polygenic additive
  • Threshold traits
  • Variable expression
  • Incomplete penetrance
  • Polygenic recessive or dominant
  • Mixed polygenic

Dominant-recessive inheritance

Black and brown provide a clear example of a dominant-recessive relationship among alleles. Every dog has two genes at the black/brown locus. If both genes are for black, or if one is for black and one is for brown, the dog is black, most readily identified by nose color. If both genes are for brown, the dog is brown, again most readily identified by nose color. BB cannot be distinguished from Bb without genetic tests or breeding tests.

Many genetic diseases, especially those that can be traced to an inactive or wrongly active form of a particular protein, are inherited in a simple recessive fashion. van Willebrand's disease (vWD) for instance, is inherited as a simple recessive within the Shetland Sheepdog breed.

Intermediate inheritance

Warning! Although this type of inheritance is common, it has a variety of names (incomplete dominance and overdominance are two common ones) some of which are also used for other things entirely. Here I will use it to refer to the type of inheritance in which the animal carrying two identical alleles shows one phenotype, the animal carrying two different identical alleles shows a different phenotype, and the animal carrying one copy of each of the alleles shows a third phenotype, usually intermediate between the two extremes but clearly distinguishable from either.

In dogs, merle color is a good example of this type of inheritance. If we define M as merle and m as non-merle, we find we have three genotypes:

  • mm non-merle, with normal intense color
  • Mm merle, with normal color diluted in a rather patchy fashion
  • MM homozygous merle, extreme dilution, dog mostly white if a white-spotting gene is also present, and often with anomalies in hearing, vision and/or fertility.

Note that there is really a continuum between dominant-recessive and intermediate inheritance. In Shetland Sheepdogs, for instance, sables carrying one gene for tan-point have on average more dark shading than dogs with two sable genes. However, the darkest shading on dogs pure for sable is probably darker than the lightest shading on dogs carrying a gene for tan-point. In practice, intermediate inheritance is often treated as if it were a special case of dominant-recessive inheritance, as can be seen by the symbols used for merle and non-merle - usually the capital letter refers to a dominant gene and the lower-case letter refers to a recessive gene. I think a separate name is justified because it could be equally well argued that homozygous merle is an undesirable recessive for which the merle color is a marker that the dog carries the merle gene.

Many of the standard color genes normally treated as dominant-recessive do in fact have intermediate inheritance, the heterozygote generally much more similar to one homozygote than the other, between at least some alleles in the series. Coat color gene loci with at least some allele pairs leaning toward intermediate inheritance include A (agouti, patterning of black and tan), C (color, intensity of color), and S (white spotting). I suspect the same is true for T (ticking), G (graying) and even D (dilution) if another diluting gene, such as merle, is present. This may be much more generally true than is recognized.

Co-dominant inheritance

The dividing line between intermediate inheritance and co-dominant inheritance is fuzzy. Co-dominance is more likely to be used when biochemistry is concerned, as in blood types. Co-dominance means that both alleles at a locus are expressed. Co-domininance in X-linked genes is a special case that will be treated under sex-linked inheritance.

Sex-limited autosomal inheritance

Please, don't confuse sex-limited inheritance with sex-linked inheritance. They are two totally different things. Sex-linked inheritance is discussed below. I do include sex-influenced traits under the sex-limited heading, though some genetics texts separate sex-influenced and sex-limited traits.

A classic example of a sex-limited trait in dogs is unilateral or bilateral cryptorchidism, in which one or both testicles cannot be found in their usual position in the scrotum. Since a bitch has no testicles, she cannot be a cryptorchid - but she can carry the gene(s) for cryptorchidism, and pass them to her sons. Likewise, genes affecting milk production are not normally expressed in a male. The main problem with sex-limited inheritance is that it is impossible to know even the phenotypes of the unaffected sex in a pedigree, which makes it difficult to determine the mode of inheritance.

In sex-influenced inheritance, the genes behave differently in the two sexes, probably because the sex hormones provide different cellular environments in males and females. A classic example in people is male early-onset pattern baldness. The gene for baldness behaves as a dominant in males but as a recessive in females. Heterozygous males are bald and will pass the gene to about 50% of their offspring of either sex. However, only the males will normally be bald unless the mother also carries the pattern baldness gene without showing it (female heterozygote.) If the mother is affected with baldness (homozygous) but the father is not, all of the sons will be affected and all of the daughters will be non-affected carriers. A bald man may get pattern baldness from either parent; a bald woman must have received the gene from both parents.

Sex-linked inheritance

In order to understand sex-linked traits, we must first understand the genetic determination of sex. Every mammal has a number of paired chromosomes, that are similar in appearance and line up with each other during gamete production (sperm and eggs). In addition, each mammal has two chromosomes that determine sex. These are generally called X and Y in mammals. Normal pairing of chromosomes during the production of gametes will put one or the other in each sperm or ovum.

In mammals, XY develops testicles which secrete male sex hormones and the fetus develops into a male. An XX fetus develops into a female. Thus sperm can be either X or Y; ova are always X. Sex linked inheritance involves genes located on either the X or the Y chromosome. Females can be homozygous or heterozygous for genes carried on the X chromosome; males can only be hemizygous.

X-linked recessive:

The most common type of sex-linked inheritance involves genes on the X chromosome which behave more or less as recessives. Females, having two X chromosomes, have a good chance of having the normal gene on one of the two. Males, however, have only one copy of the X chromosome - and the Y chromosome does not carry many of the same genes as the X, so there is no normal gene to counter the defective X.

An example of this type of inheritance is color blindness in human beings. Using lower case letters for affecteds, we have

  • Affected male: xY Color blind
  • Non-affected males XY Normal color vision
  • Affected female xx Color blind
  • Carrier female xX Normal color vision
  • Clear female XX. Normal color vision

Now the possible matings:

xY to xx (both parents affected) xx females and xY males, all offspring affected.

xY to Xx (affected father, carrier mother) half the females will be xX and carriers, half will be xx and affected. Half the males will be XY and clear, half will be xY and affected.

xY to XX (affected father, clear mother) all male offspring XY clear, all daughters Xx carriers.

Note that the daughters of an affected male are obligate carriers or affected. The unaffected sons of an affected male cannot carry the problem.

XY to xx (father clear, mother affected) xY males (affected) and xX daughters (carriers.)

XY to Xx (father clear, mother carrier) half the males affected (xY) and half clear (XY); half females clear (XX) and half carriers (Xx)

XY to XX (father and mother both genetic clears) all offspring clear.

Note that all female offspring of affected males are obligate carriers (if not affected.) Likewise, any female who has an affected son is a carrier. Non-affected sons of affected fathers are genetically clear.

This type of inheritance may be complicated by the sublethal effect of some X-linked genes. Hemophilia A in many mammals (including dogs and people) is a severe bleeding disorder inherited just like the color-blindness above. Many affected individuals will die before breeding, but for those who are kept alive and bred for other outstanding traits, non-affected sons will not have or produce the disease. All daughters, however, will be carriers.

X-linked dominant:

Here I will use X+ for the dominant gene on the X chromosome, and X for the gene on the normal X chromosome. The actual possibilities are similar to those for an X-linked recessive, except that X+X females are now affected. In X-linked dominant inheritance, more females than males will show the trait. Possible matings are:

Affected to homozygous affected (X+Y to X+X+): All offspring affected.

Affected to heterozygous affected (X+Y to X+X): All daughters affected; half of sons affected.

Affected to homozygous normal (unaffected female): (X+Y to XX): All daughters affected, all sons normal.

Normal to homozygous affected (XY to X+X+): all offspring affected, but daughters are heterozygous affected.

Normal to heterozygous affected: (XY to X+X): Half of offspring affected, regardless of sex. Affected daughters are heterozygous.

Normal to normal (XY to XX) all offspring clear.

X-linked co-dominant:

Mammalian cells, even in females, get along fine with just one X chromosome. In fact, more than one X chromosome within a cell seems to be a problem if both are active. So in female cells, one or the other X chromosome must be inactivated. This occurs more or less at random, so any female mammal has patches of cells with one X chromosome inactivated, and patches with the other not active. If the gene being discussed codes for an enzyme that is spread throughout the body, it may not be obvious that the different patches of cells are behaving differently, and we will get what looks like dominant, recessive, or intermediate inheritance.

However, if the gene is expressed directly within the cell, the mosaic nature of the female may become obvious. The tortoiseshell cat provides an excellent example of this.

In cats, the orange color is on the X chromosome. It is designated as O, and the "wild-type" gene that allows black (eumelanin) to appear in the coat is designated +. Note that a cat homozygous or hemizygous (male) for + may be solid or tabby with the eumelanin pigment showing only in the tabby stripes, ticks and blotches (in extreme cases only on the tips of the hairs) and the "black" may just as well be chocolate or blue. A cat with only O genes will be some shade from cream to deep red., with no black/blue/chocolate pigment in the coat, but usually with tabby markings.

However, a cat with the gene for orange on one X chromosome and the gene for non-orange on the other is neither orange nor non-orange, but has patches of both colors. This color is known as tortoiseshell, and I am going to use the broad definition, including blue/cream or chocolate/yellow tortoiseshells. Most of the time cats with two X chromosomes are female, and since two X-chromosomes are required for tortoiseshell, most tortoiseshell cats are female.

Now and then a cell does not divide properly when it is making a germ cell, and you might, for instance, get an XY sperm cell. This would produce an XXY male, which would look male (he has a Y chromosome) but also have two versions of X and thus could be a tortoiseshell. However, the XXY makeup, corresponding to Klinefelter's syndrome in human beings, is believed to produce sterility. A similar syndrome involving females with only one X chromosome but no Y is called Turner's syndrome in human women, and again appears to produce sterility. We will therefore consider only matings between animals with two sex chromosomes.

Non-orange male to non-orange female (+ to ++): all non-orange offspring.

Non-orange male to tortoiseshell female (+ to +O): Males 50% orange and 50% non-orange; females 50% non-orange and 50% tortoiseshell.

Non-orange male to orange female (+ to OO): all males orange; all females tortoiseshell.

Orange male to non-orange female (O to ++): All males non-orange; all females tortoiseshell.

Orange male to tortoiseshell female (O to O+): males 50% orange and 50% non-orange; females 50% orange and 50% tortoiseshell.

Orange male to orange female (O to OO): All offspring orange.

Y-linked inheritance:

The Y chromosome in most species is very short with very few genes other than those that determine maleness. Y-linked inheritance would show sons the same as their fathers, with no effect from the mother or in daughters. In humans, hairy ears appear to be inherited through the Y chromosome. Padgett does not list any known problem in dogs as being Y-linked.

Test Breedings I

Purpose: to get the genotype of an individual.

Test breedings can be carried out for either of two distinct purposes: to determine the genotype of a specific individual, or to determine the fundamental genetics of a trait. Here we will discuss the first option, looking specifically at the determination of whether a dog carries a recessive gene. Note that as DNA studies advance and the carrier state becomes easier to distinguish via DNA testing, the type of test breeding described here should become less and less relevant.

The primary reason for doing test breedings historically has been to identify dogs carrying a trait that produces a health problem. For simplicity, we will use the black-brown dominant-recessive pair discussed earlier. The problem to be solved is to determine whether a black dog is carrying brown as a recessive. The analysis applies to any case in which a dog with two doses of the recessive is available for breeding, including a number of recessive health problems that are not actually lethal. Note that this type of test breeding is useful only after the mode of transmission (simple recessive) is firmly established.

We already know that if a BB black is bred to a bb brown all of the puppies will be black. If a Bb black is bred to a bb brown, each puppy has a 50% chance of being black and a 50% chance of being brown. So we breed the dog we want to test to a brown. If we get a brown puppy, the dog carries the brown recessive. We can never prove that the dog is pure for black, but we can calculate the probability that the observed number of black puppies would occur by chance if the dog were in fact carrying brown.

Remember each puppy has a 50% chance of being brown. The color of each puppy is independant, so the probility of a specific pair of puppies both being black is 50% x 50% or 25%. In fact, the probability that a Bb x bb mating with n puppies will produce all blacks is given by (.5)n. In tabular form, this is:

Black puppies in litter

Probability that a Bb parent could produce litter

1

50%

2

25%

3

12.5%

4

6.25%

5

3.125%

6

1.5625%

7

0.78125%

8

0.39%

9

0.2%

The exact number of black puppies needed to "prove" that the black does not carry brown depends on how sure you want to be, but the probability that the parent is Bb even though it has produced a number of black puppies and no browns to a brown mate never quite goes to 0.

In our example, we assumed a fertile bb mate was available. What about the case in which the homozygous recessive is not viable or infertile, such as gray-lethal in Collies? Suppose we imagine a locus called L, with alleles L for live and l for lethal. (We assume that the ll lethal can be distinguished at birth or shortly thereafer, not that it is an early embyonic lethal.) We want to determine whether a particular dog is LL or Ll in genetic constitution. We cannot test breed to an ll, because there are no living, fertile ll dogs. The best we can do is observe that any dog of the opposite sex that has produced an ll puppy must itself be Ll in genetic constitution. If we mate our test subject to an known Ll mate, the principle is the same, but this time it takes more puppies to reach the same level of certainty. If the test animal is LL, only LL and Ll puppies will be produced. If it is Ll, the chances of getting the given number of puppies, all healthy is:

Number of non-affected puppies

Probability that an Ll parent could produce litter

2

56.3%

4

31.6%

6

17.8%

8

10%

10

5.6%

12

3.2%

14

1.78%

16

1%

18

0.6%

20

0.3%

A test breeding utilizing a known carrier rather than an affected individual requires over twice as many offspring to get the same degree of certainty that an animal is not a carrier. For obvious reasons bitches were rarely test bred, especially in breeds with small litters - too much of her reproductive life would be lost in demonstrating that she was not a carrier. As the new DNA tests become available, this kind of test breeding will probably become very rare.

The use of test breeding to determine the mode of inheritance, however, may still be needed.

Test Breedings II

Purpose: to determine the genetic basis for a trait.

Suppose we have a list of various types of a particular trait, and we want to know how they are inherited. The first step is to make a guess. It should be an informed guess - for instance, you may know that in other mammals a particular trait is inherited in a particular way, so as a first guess you assume that the inheritance is similar in the animal you are investigating. The point is, this first guess is just that - a guess. In order to elevate that guess to the level of a hypothesis, you need to work out what your guess predicts in terms of what parents can produce what, and then breed (or investigate breeding records) to see if that is really what happens.

Let's take a first guess we know is wrong. Labrador Retrievers come in black, brown and yellow, as explained earlier. Suppose we don't know the genetics of this. We have observed the three colors, and a reasonable initial assumption is that there a locus for color which has three alleles: black, brown and yellow. As we start to look at Stud Book data, we find that;

  1. Black to black can produce any color
  2. Yellow to yellow can produce only yellow
  3. Brown to brown usually produces browns, but can produce yellow
  4. Black to any other color can produce black.

This information adds to our initial guess. If black to black can produce any color then black must be the top dominant in the series. Likewise, if yellow to yellow can produce only yellow, then yellow must be the bottom recessive. Brown looks as if it is recessive to black but dominant to yellow. Our tentative hypothesis, then, is that we have a locus, J, with three alleles:

  • Jblk black
  • jbrn brown
  • jyel yellow.

Now we set up our Punnett squares and work out what each mating will produce. We find that

  1. JblkJblk x JblkJblk gives black to black producing all blacks
  2. JblkJblk x Jblkjbrn gives black to black producing all blacks
  3. Jblkjbrn x Jblkjbrn gives black to black producing black and brown
  4. JblkJblk x Jblkjyel gives black to black producing all black
  5. Jblkjyel x Jblkjyel gives black to black producing black and yellow.
  6. Jblkjbrn x Jblkjyel gives black to black producing black and brown
  7. Jblkjbrn x jbrnjbrn gives black to brown producing black and brown
  8. Jblkjbrn x jbrnjyel gives black to brown producing black and brown
  9. Jblkjbrn x jyeljyel gives black to yellow producing black and brown
  10. Jblkjyel x jbrnjbrn gives black to brown producing black and brown
  11. Jblkjyel x jbrnjyel gives black to brown producing black, brown and yellow
  12. jbrnjbrn x jbrnjbrn gives brown to brown producing all browns
  13. jbrnjbrn x jbrnjyel gives brown to brown producing all browns
  14. jbrnjyel x jbrnjyel gives brown to brown producing brown and yellow
  15. jbrnjyel x jyeljyel gives brown to yellow producing brown and yellow
  16. jyeljyel x jyeljyel gives yellow to yellow producing all yellows

The key point is that none of the black to black or black to yellow matings can, on this hypothesis, give us a litter with all three colors represented. Three colors is only possible if black carrying yellow is mated to an animal which is brown carrying yellow. Blacks always have the potential to produce some blacks, but if a brown is produced than the black must carry brown, and there simply isn't room for the yellow allele at the locus, which can hold only two alleles at once. While the individual matings seem to agree with with our incorrect hypothesis, the hypothesis falls down when it is applied to colors within a single litter.

The problem is that while it's fairly easy to go through a stud book and determine what parent color combinations can give a particular puppy color, it is much harder to pull out a whole litter. In the AKC Stud Books it is almost impossible, as the only dogs listed are those who have produced registered litters. The point is that without determining whether the observed distribution of phenotypes within a litter agrees with the hypothesis, the hypothesis is still little more than a guess.

There are two possible test breeding strategies to expose this problem. The first involves looking at as many litters as possible in which one parent is the top dominant (black) and the other is the bottom recessive (yellow). If such a litter includes both browns and yellows, then our one locus - three allele hypothesis cannot be true.

The second case is a variant - identify blacks with one parent yellow or chocolate, so you "know" that the black is Jblkjyel or Jblkjbrn, and examine litters to yellow and to brown mates. Again, the presence of all three colors in one litter disproves the hypothesis, but it will take fewer litters in total, as the initial selection of the blacks eliminates those that are pure for black.

Note that in most cases, this means a fair number of breedings. This again is a case where there is no way to prove the hypothesis correct. You may have nine litters with black to yellow producing only yellow or brown (with black in each case) but that doesn't prove the hypothesis is correct. Only a few black to yellow litters may even have the right parental genotypes, and especially if the number of puppies is small, one possible color may be missing by pure chance. As usual with scientific hypotheses, the hypothesis cannot be proven, but it can be disproven.

In this particular case, I knew the thypothesis was incorrect. I have friends who breed Labs, and one bred a black to a black and got all three colors in the litter. It's not considered unusual in Labs. I even used the litter in a genetics Science Forum article. There are, however, other loci in dogs where the assignment of one or more genes to the locus is questionable. Probably the most important are the A series and the E series.

Dominant black is a very unlikely top dominant of the A series. This series is known in a number of mammals, and more yellow is almost always dominant over less yellow. The key breeding here would need a breed with dominant black, sable and tan-point. Basenji breedings of this type (black to tan-point) have been reported to include all three colors. The only remaining doubt comes in whether the "reds" from these breedings are sable or ee reds. e is not known to occur in the breed, but without further test breeding of the red offspring, there remains some uncertainty. Still, I am inclined to treat As at this point as belonging to another locus entirely.

There is another possible problem in the A series, this one involving the recessive black seen in Shelties and German Shepherds. If the recessive black is in the A series, with sable dominant to tan-point which in turn is dominant to recessive black, then it shoud not be possible to get a litter with all three colors from a sable to sable or a sable to recessive black breeding - a sable could be black-factored or tanpoint factored but not both. There is some evidence from Shelties that such three-color litters do occur. This suggests that the presence or absence of tan points in the classic tan-point pattern may depend on a different locus.

E is defined to include E, which allows the agouti series to show through, and e which in double dose makes the dog produce only phaeomelanin in the hair coat, effectively hiding what is present at the A locus. The two other proposed members of the E series, Ebr (brindle) and Ema (masked) are still at the hypothesis stage. Even Little, who is often quoted as the source for putting brindle and mask in this locus, prefaced almost everything he said with "if they are at the same locus." In particular, none of the test matings he carried out really clarified the relationship of e to Ema or to his proposed Ebr. Test breeding is definitely needed at this locus. Some work has been done in greyhounds that suggests that the brindle gene might be at the same locus (called "K" bu the researcher) with dominant black, but this is preliminary at this time.

Population Genetics I: Random breeding

Ordinary genetics looks at how one selects breeding stock to produce the best possible offspring. Population genetics looks at the statistical distribution of genes in a particular breeding population, such as a breed of dog, and how different kinds of selection can affect that gene distribution. (Increasingly, population genetics also involves looking at the relationship between species by using gene sequencing as a tool.) You can think of ordinary genetics as predicting the phenotypic makup of the next generation, while population genetics predicts the genetic makeup of the breed as a whole, often several generations away.

This article is based on the assumption that the population is random breeding - an animal is equally likely to mate with any other animal in the population. This is obviously not really true - a dog in California is much more likely to mate with another California dog than with one in New York, a Great Dane is more likely to mate with another Great Dane than with a Papillion, and many breeders of domesticated animals practice deliberate breeding to relatively close relatives. We'll look at possible effects of this later on (if I get around to it). Random breeding with selection based on a single gene is the simplest case, with which other possibilities can be compared.

Unfortunately, I'll have to use a little algebra to do this. I promise I'll try to explain the results in non-mathematical terms.

We need to start by defining a few things.

A gene pool refers to the sum total of genes (and how many of each combination) found in a breeding population. The breeding population may be a single kennel that changes its gene pool every time it breeds to an outside dog, in which case the gene pool can be considered leaky, or at the other extreme may be all of the animals within a pure breed. One can speak of the gene pool of an entire species, but it is simply not true that any member of the species can mate with any other member with equal probabilty. There are species with continuous ranges where a particular gene is very rare at one end of the range and very common at the other - any member of the species can mate with any other, but by far the most likely matings are of relatively near neighbors.

We will deal with a single autosomal locus (no sex-linked genes) with a single pair of alleles, which we will call K and k. Our breeding population is made of of three different types of animals:

KK, which are genetic clears. We will call the fraction of clears in the population n, for normal.

Kk, which are carriers, meaning that they can produce affected animals. We will call the fraction of carriers in the population c, for carrier.

kk, which we will call affected, meaning that they show the effect of the k gene in double dose. We will call the fraction of affecteds in the population a, for affecteds.

Note that n + c + a = 1 = 100%, as every animal in the population is one of the three states.

Note also that "affected" can mean something as innocuous as brown rather than black pigment or something as serious as blindness, bleeding disorders or even prenatal death. I am also making no stipulation at this point as to whether the Kk state can be distinguished from KK. There are a rapidly increasing number of cases in which Kk, once distinguisable from KK only by imperfect breeding tests, can now be identified by genetic testing.

A gene frequency refers to the fraction of the genes in the breeding population that is of a particular type. The gene frequencies of all of the different alleles at a locus must add up to 100%, or 1. We are dealing with a two-allele locus (K and k) so we will define f as the frequency of the k allele and (1-f) as the frequency of the K allele. How does this relate to our clear-carrier-affected numbers?

Each dog has two genes. A fraction n is normal, and has two K genes. They contribute nothing to f. A fraction c are carriers, with one half of their genetic makeup k; they contribute c/2 to f. Finally, the affecteds contribute a to f. This gives

f = c/2 + a.

As a general rule, we do not know the value of c, as not all carriers are identified. But if we assume random breeding, the probabilities of the nine types of breedings possible (normal male to normal female, normal male to carrier female, normal male to affected female, carrier male to normal female, carrier male to carrier female, carrier male to affected female, affected male to normal female, affected male to carrier female, and affected male to affected female) can be calculated if we know c, a and n. specifically, we get these fractions:

  1. Normal to normal: n x n.
  2. Carrier to carrier: c x c.
  3. Affected to affected a x a
  4. Normal to carrier (combining the cases where the male or female is the carrier): 2 x n x c
  5. Normal to affected: 2 x n x a.
  6. Carrier to affected: 2 x c x a.

We also know the expected results of each kind of breeding:

  1. Normal to normal all normal.
  2. Carrier to carrier 25% normal, 50% carrier, 25% affected.
  3. Affected to affected all affected.
  4. Normal to carrier 50% normal, 50% carrier.
  5. Normal to affected all carrier.
  6. Carrier to affected 50% carrier, 50% affected.

If we multiply the types of offspring by the fraction of the breedings in each category, and then group the offspring by their genetic makeup, we get some surprisingly simple numbers:

  1. n (fraction of normals) = (1-f) x (1 - f)
  2. c (fraction of carriers) = 2 x f x (1-f)
  3. a (fraction of affecteds) = f x f.
Chart.  Equations available on request.
Figure 1. Percents of normal, carrier and affected individuals for a random-breeding population with a given gene frequency.

If we recalculate f from these values of n, c and a, it will be the same as the f we started with. Completely random breeding without selection does not change gene frequencies, unless the breeding population is so small that the assumption of a predictable distribution of types within litters of the same type or types of matings within a gene pool breaks down.

Until now we have assumed that there is no differential breeding based on whether the animal is a normal, a carrier, or an affected. Now let us assume that the kk genotype is undesirable. It does not matter whether the kk animal is a color the breeder does not like or has a lethal defect that results in its death before it reaches breeding age. For breeding purposes it is a lethal gene, i.e., all kk (affected) animals are removed from the breeding pool in each generation. For the moment we will also assume that Kk (carriers) cannot be distinguished from KK (normals.) What does this do to the frequency of the gene? (If you can't stand algebra and want to go straight to Figure 2 you can.)

We will use subscripts (numbers below and to the right of the symbol) to indicate the generation. Thus f0 is the gene frequency in our starting generation, f1 is the gene frequency in the first generation after all affected animals in the initial generation are removed, f2 is the gene frequency in the next generation after the affecteds are removed, and so on. For illustrative purposes, suppose that f0 is so large that the population is effectively made up only of affecteds and carriers. After all of the affecteds are removed, however, the remaining gene pool is made up almost entirely of carriers, which by definition have a gene frequency of 50%. When these dogs are interbred, they produce 25% genetic normals, 50% carriers, and 25% affecteds, which again are discarded from the breeding pool. Our new gene pool is 2/3 carriers (f=50%) and 1/3 normals (f = 0), so f2 = 1/3. Breeding these dogs gives 1/9 affecteds, and when these are removed we have a population with equal numbers of carriers and normals, for a gene frequency of 1/4. Note that while selection solely by removing affecteds is very fast if the original percent of affecteds is high, the continued reduction after the 4th or 5th generaltion is slow.

Chart. Equations available on request.
Percent of normals, carriers and affected in each generation of a program of removing all affected animals, assuming affected condition is autosomal recessive. It doesn't show on the graph, but generation 20 would still have a quarter of a percent - one puppy in 400 - affected.

Can anything be done beyond this? Yes, provided the mode of inheritance (autosomal recessive) is known. Assume at first the carrier state cannot be distinguished from the affected state, i.e, that Kk cannot be distinguished from KK except through breeding results. (This has historically been the case with most recessive problems.) Use the breeding results to identify the carriers, and limit (not necessarily avoid at this stage) the breeding of carriers. In other words, if an animal produces affected offspring, it is a carrier and should be bred again only if it has other traits that are truly outstanding and hard to get. Full siblings of an affected animal have two chances in three of being carriers, and one in three of being normal, and these animals are less likely than the parent to produce the problem. Removing animals from the breeding pool that have produced affected animals is the next step in lowering the gene frequency.

Between test breeding and DNA sequencing, the number of conditions in which the carrier state can be unambiguously identified is increasing rapidly, and the obvious answer is not to breed carriers. However, I hesitate to recommend any breeding strategy which would remove over 10% of the gene pool due to a single gene. This could easily happen if the carrier state is identified, and has resulted in health problems in the past when the few genetic clears for one problem turned out to carry a different problem. However, there are a couple of intermediate strategies which will lower the gene frequency to the point that carriers can be eliminated safely, while at the same time minimizing the number of affecteds produced.

First, breed carriers only to tested normals. This will eliminate the production of affected offspring, but it does nothing in itself to reduce the gene frequency of the unwanted gene.

Second, treat carrier status as a fairly serious fault. The idea is to reduce the use of carriers while not eliminating them entirely until the carrier frequency drops below 5 to 10%. The figure below is based on how the carrier frequency would change with time if various percents of the carrier-normal breedings that would take place on a random basis were not made.

The point of this figure is not to select heavily against carriers, as that will result in too much loss in genetic diversity if the carrier frequency is high. Rather, it is that not making carrier to carrier breedings, while cutting down on the total number of offspring produced by carriers, is an effective means both of eliminating the production of affected animals and of reducing the gene frequency in the population. The type and severity of selection used at any given point in time should depend on both the gene frequency and the severity of the problem.

Note that the figures all relate to a population that starts with 50% gene frequency. In practice this means that even the mildest selection, that of removing affecteds, will start out by removing more than 10% of the breeding population due to a single gene. In cases where the breeding pool has a high incidence of affecteds, a different kind of selection becomes important - aimed not so much as reducing the number of affected and carrier animals as of increasing the frequency of the normal gene. Only after the gene frequency of k has been reduced by these earlier steps can the stonger selection suggested here be applied.

Population Genetics II: Reducing High Gene Frequencies

 

Suppose you have an undesirable recessive gene that is affecting most of a population. This gene is clearly not lethal in the normal sense, as there is no way that a naturally lethal gene can exceed a gene frequency of 50% (every animal in the breed a carrier, and that is unlikely unless there is strong selection against both homozygotes.) But it can easily be a gene which affects health (e.g., deafness, blindness, bleeding tendencies, metabolic disorders) but does not appear obvious to the eye of the breeder without tests. It is possible for such an undesirable recessive to affect an entire breed; and once this happens it is not possible to eliminate the condition without crossing to another breed. For breeds which have not quite reached this 100% frequency, then, it is of extreme importance to preserve the normal gene.

Suppose we start with a breed gene frequency of 95%. We will again assume random breeding, modified only by the breeding strategy of the breeders. With a 95% gene frequency, we would expect 90.25% affected, 0.25% genetic clears, and about 9.5% carriers, for an unaffected rate of slightly less than 10%. (In practice, some breeders will normally have been testing and removing carriers, so the fractions of affecteds and clears will increase at the expense of carriers.) We assume that in any generation we want to remove no more than 10% of the gene pool due to this single gene. The exact value of 10% can be argued - it should depend on the severity of the unwanted gene - but removing much more than 10% in a single generation due to a single gene can have dangerous effects on the overall genetic diversity of the breed.

In the first few generations, you forget about selection against the undesirable gene and concentrate - hard - on selection for the normal gene. In effect, unaffected status - be it carrier or simply non-affected - is treated as an extremely positive virtue and bred for. Almost all unaffected dogs should be bred, and they should be bred to the best mates available. This means that owners of top quality dogs must be willing to mate them to bitches which are of poor quality by show standards if these bitches are non-affected. Affected, poor-quality offspring of such matings can and should be removed from the breeding pool; non-affected offspring, like their non-affected parent, should be kept in the gene pool. A more difficult goal is to get owners of top quality bitches to mate them at least once in their lives to the best non-affected male available. The goal at this point is to increase the number of carriers at the expense of affecteds. Unfortunately the show ring provides no reward for this kind of long-range thinking.

How fast will this have an effect? It depends on how strong the selection for non-affecteds is, and how rare non-affecteds are to start with. I'll be adding a figure here once I fight my way through the algebra.

It is clear, however, that it will take some time to get a reasonable spread of K genes in the breed (remember most of the breed starts out kk) especially if we want those K genes to come from as wide a range of individuals as possible. Note that at this time we are distinguishing only between affected (kk) and non-affected Kk and KK) individuals. To a first approximation, the percent of affected individuals is the square of the gene frequency. (This is exact only for random breeding.) The gene frequency is then the square root of the percent of affected individuals in the breed. This is an easy calculation on a $10 pocket calculator - punch in the fraction of affecteds as a decimal (e.g., 70% is put in as 0.70) and hit the square root key. (In this case the gene frequency is about 0.84 = 84% - the gene frequency will always be greater than the percent of affecteds.)

By the time the gene frequency has dropped to around 80% (64% affecteds) some mild selection against affecteds should be added to the mix. Affected to affected breedings should be looked on with an increasingly critical eye - not actually banned yet, but limited. Affected dogs (both sexes) without any great virtues to offer should be removed from the gene pool.

As the gene frequency continues to drop, the selection against affecteds should grow stronger. Actual removal of all affecteds should wait until the observed frequency of affecteds drops below the critical value of 10% (gene frequency about 32%), but affected to affected breedings should be eliminated and non-affected to non-affected breedings encouraged as far as possible. At this stage it is premature to worry about carriers, but an affected dog should have really great virtues to offer if it is kept in the breeding pool. Once the gene frequency drops below about 30%, it is safe to start removing all affected individuals from the breeding pool. By this time, 90% of the animals in the breed will be non-affected, and there should be no problem in finding good non-affected mates.

Until now, we have assumed that we cannot differentiate KK from Kk - both are simply non-affected. In most cases, however, there are ways of identifying carriers. The simplest is simply to continue to test for the condition, and pay attention to normal breeding results. If a breeding produces any affected individuals, both parents are carriers and non-affected littermates have 2 chances out of three of being carriers. One in three of the littermates, however, are genotypic normals. Thus the littermates of affected pups, if of exceptional type otherwise, should be tested for carrier status. If such an animal tests as a genetic normal, it cannot pass on the gene for the problem, even though a littermate was affected.

Testing for carrier status beyond what comes out of normal breeding has changed sharply in the last few years. The old method (still needed for some genes) is to breed the questionable dog to an affected one. Some affecteds will still be produced at this stage, and some should be retained for test breeding if that is necessary. This type of test breeding, however, has considerable uncertainty and required several known carrier offspring to be produced (around 10) before a dog could be pronounced to be a non-carrier with a reasonably high degree of confidence. In fact, a dog could never be proven to be a non-carrier; it could only be demonstrated that he could not be proved to be a carrier.

Increasingly, gene sequencing is offering an alternative in determining carrier status. This has great advantages over test breeding: no carriers or affected dogs need be produced to determine the status of the dog, and the production of affected individuals can be entirely avoided if the carrier status of all individuals in the breeding population is known. It does produce problems as well: the temptation is to say that no carriers should be bred right from the start, when a large number of dogs, could be removed due to a single gene. Suppose that the test becomes available when the fraction of affected individuals in the breed is on the order of 4%. This corresponds to a gene frequency of 20% and a carrier frequency of 32%. Even with an affected frequency of 1% we can expect a carrier frequency of 18%. Yet we do not want to elminate more than 10% of the breed due to this single gene. How do we prodeed?

We can avoid producing affecteds by breeding carriers only to dogs genetically tested as non-carriers - genetic normals. This in itself, however, does nothing to reduce the gene frequency. For the best benefit of the breed as a whole, the avoidance of carrier to carrier matings should be accompanied by some selection against carriers, but not by actual elimination of carriers from the gene pool when such elimination would lead to too rapid a restriction of the gene pool A limitation on the number of litters produced by carriers would be appropriate, as would removal of those carriers whose virtues could be found in non-carriers. Figure 3 in part I of this series shows how rapidly selection will reduce the gene frequency using this strategy. Probably the initial approach would be to allow carriers to reproduce at around 90% of their expected rate, then reduce the reproductive rate with each generation until the carriers make up less than 10% of the population. At that point the remaining carriers could be removed from the breeding pool.

How long should testing continue? Certainly as long as occasional affecteds are being produced. More practically, offspring from normal to normal breedings should all be normal. Until the test is throroughly established, breeding stock from normal to normal breedings should still be checked, but carrier status for these dogs is not expected. Once the test is fully validated, all pups from matings involving a carrier as a parent should be tested. Once all carriers are removed, in theory no more testing is needed - but to catch any new mutations, it is still a good idea to check widely used animals - any dog bred to produce more than two litters a year, I would say. Also all relatives of any affected pups that show up after the gene is apparently eradicated.

Inbreeding and linebreeding

What are inbreeding and linebreeding, and what effect do they have?

In genetic terminology, inbreeding is the breeding of two animals who are related to each other. In its opposite, outcrossing, the two parents are totally unrelated. Since all pure breeds of animal trace back to a relatively limited number of foundation dogs, all pure breeding is by this definition inbreeding, although the term is not generally used to refer to matings where a common ancestor does not occur behind sire and dam in a four or five generation pedigree.

Breeders of purebred livestock have introduced a term, linebreeding, to cover the milder forms of inbreeding. Exactly what the difference is between linebreeding and inbreeding tends to be defined differently for each species and often for each breed within the species. On this definition, inbreeding at its most restrictive applies to what would be considered unquestioned incest in human beings - parent to offspring or a mating between full siblings. Uncle-niece, aunt-nephew, half sibling matings, and first cousin matings are called inbreeding by some people and linebreeding by others.

What does inbreeding (in the genetic sense) do? Basically, it increase the probability that the two copies of any given gene will be identical and derived from the same ancestor. Technically, the animal is homozygous for that gene. The heterozygous animal has some differences in the two copies of the gene Remember that each animal (or plant, for that matter) has two copies of any given gene (two alleles at each locus, if you want to get technical), one derived from the father and one from the mother. If the father and mother are related, there is a chance that the two genes in the offspring are both identical copies contributed by the common ancestor. This is neither good nor bad in itself. Consider, for instance, the gene for PRA (progressive retinal atrophy), which causes progressive blindness. Carriers have normal vision, but if one is mated to another carrier, one in four of the puppies will have PRA and go blind. Inbreeding will increase both the number of affected dogs (bad) and the number of genetically normal dogs (good) at the expense of carriers. Inbreeding can thus bring these undesirable recessive genes to the surface, where they can be removed from the breeding pool.

Unfortunately, we cannot breed animals based on a single gene - the genes come as a package. We may inbreed and rigorously remove pups with PRA or even their parents and littermates from the breeding pool. But remember inbreeding tends to make all genes more homozygous. In at least one breed, an effort to remove the PRA-causing gene resulted in the surfacing of a completely different and previously unsuspected health problem. It is easier and faster to lose genes (sometimes very desirable genes) from the breeding pool when inbreeding is practiced than when a more open breeding system is used. In other words, inbreeding will tend to produce more nearly homozygous animals, but generally some of the homozygous pairs will be "good" and others will be "bad".

Furthermore, there may be genes where heterozygosity is an advantage. There are several variant hemoglobin types in human beings, for instance, where one homozygote suffers from some type of illness, the other homozygote is vulnerable to malaria, and the heterozygote is generally malaria-resistant with little or no negative health impacts from a single copy of the non-standard hemoglobin gene. A more widespread case is the so-called major histocompatibility complex (MHC), a group of genes where heterozygosity seems to improve disease resistance.

Is there a way of measuring inbreeding? Wright developed what is called the inbreeding coefficient. This is related to the probability that both copies of any given gene are derived from the same ancestor. A cold outcross (in dogs, probably a first-generation cross between two purebreds of different, unrelated breeds would be the best approximation) would have an inbreeding coefficient of 0. Note that this dog would not be heterozygous at every locus. There are genes shared with every multicellular organism, genes shared with all animals, genes shared with all animals with backbones, genes shared with all four-limbed animals (including most fish and all amphibians, reptiles, birds and mammals) and with all mammals. Although the DNA might differ slightly, the proteins produced would be functionally the same. Further, the chances are that our dogs with inbreeding coefficient = 0 would still be homozygous for some genes shared by all dogs. The inbreeding coefficient thus specifically refers to those genes that are variable (more than one possible form) in the species and even the breed being considered.

An inbreeding coefficient of 1 (rare in mammals) would result if the only matings practiced over many generations were between full brother and full sister.

The figure shows how the inbreeding coefficient chages with generations of brother-sister matings. As a general rule, this type of mating in domestic animals cannot be kept up beyond 8-10 generations, as by that time the rate of breeding success is very low. However, the rare survivors may go on to found genetically uniform populations.

This has been done in laboratory rodents, producing inbred strains of mice and rats so similar genetically that they easily tolerate skin or organ grafts from other animals from the same inbred strain. However, the process of inbreeding used to create these strains generally results in loss of fertility (first seen in these mammals as a reduction in litter size) which actually kills off the majority of the strains between 8 and 12 generations of this extent of inbreeding. A handful of the initial strains survive this bottleneck, and these are the inbred laboratory strains. However, very little selection other than for viability and fertility is possible during this process. You wind up with animals homozygous for a more or less random selection of whatever genes happened to be in the strains that survived, all of which derive from the parents of the initial pair.

Note that two very inbred parents can produce offspring that have very low inbreeding coefficients if the inbred parents do not have ancestors in common. This, however, assumes that mates are available who are not strongly inbred on a common ancestor. If the parents are related to each other, their own inbreeding coefficients will indeed increase the inbreeding coefficients of their offspring. The critical factor is the coefficient of kinship, which is the inbreeding coefficient of a hypothetical offspring of the two individuals.

Inbreeding has become an important consideration for wildlife conservationists. Many wild populations are in danger of extinction due to some combination of habitat destruction and hunting of the animals, either to protect humans or because the animal parts are considered valuable. (Examples are ivory, rhinorcerus horn, and infant apes for the pet trade, as well as meat hunting.) For some of these animals the only real hope of survival is captive breeding programs. But the number of animals available in such captive breeding programs, especially at a single zoo, is often limited. Biologists are concerned that the resulting inbred populations would not have all of the genes found in the wild populations, and thus lose some flexibility in responding to change. In reaction to this threat they have developed networks such that animals can be exchanged among captive breeding poplulations in such a way as to minimize the overall inbreeding of the captive population. The idea is to select pairs in such a way that the inbreeding coefficient of the offspring is kept as low as possible.

Most elementary genetics books have instructions for calculating the inbreeding coefficient from the pedigree. (For more information, see Dr. Armstrong's site, Significant Relationships.) However, these procedures have two major limitations. First, they are not really designed for cases where there are multiple common ancestors, though they can be used separately for each common ancestor and the results added. Second, they become impossibly complex as the length of the pedigree increases. It is by no means uncommon in dogs, for instance, to have pedigrees which can be researched in the AKC stud book and the KC Gazette and which go back to foundation dogs born around the turn of the century - perhaps 30 or even 40 generations earlier. With this type of long pedigree, foundation animals may appear a million times or more in the pedigree.

With this in mind, a computer program called GENES was developed by Dr. Robert Lacy for the calculation of the inbreeding coefficient, kinship coefficients among animals in the breeding pool, percent contributions of varying founding ancestors, and related output, assuming full pedigrees to the foundation stock were available for all animals currently in the breeding population. For captive breeding populations, the less inbreeding the better, and this is the way the program is used.

In purebred livestock the situtation is a little different - we want homozygosity for those genes which create a desirable similarity to the breed standard. Wright's defense of inbreeding was based on this fact. However, inbreeding tends to remove those heterozygotes which are beneficial (e.g., the MHC) as well as increasing undesirable as well as desirable homozygotes. The practice is most dangerous in the potential increase of homozygous health problems which are not obvious on inspection, but which shorten the life span or decrease the quality of life for the animal.

I do not at the present time have other dog breeds for comparison, but I recently submitted a Shetland Sheepdog pedigree database to Dr. Armstrong for calculation of true inbreeding coefficients. This database was based on full pedigrees of all AKC Shetland Sheepdogs that had sired 10 or more breed champions (males) or produced 5 or more (females.) These top producing animals were set up as the current living population (a somewhat artifial assumption, as the dogs involved where whelped from 1930 to after 1990.) I would love to see some comparisons with other breeds.


Finding the Genes that Determine Canine Behavior

The following is an explanation of how scientists working on the Dog Genome Initiative are going about trying to identify genes that determine behavior or inherited diseases in dogs. It was written for non-scientists by Dr. Polly Matzinger, an immunologist, and originally posted on the email list BC-Forum.


Start by thinking of GENES as pearls on a string (made of DNA instead of oyster saliva).


O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-0-O-O-

Dogs, like people, have lots of these strings, a bit like a multi-strand pearl necklace. The strings are called chromosomes. Now suppose that you wanted to know how many of these genes it takes to control something as complicated as the behavioural trait we call "eye" and you wanted to know which particular ones, on which particular strings, do the job. If you look at the chromosome strings in a microscope, they all look pretty much the same, though some are longer than others.


O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-0-O-O
O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O
O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O

Suppose that the third gene on the first chromosome string has something to do with the INTENSITY with which an animal pays attention to an object, the 11th gene on the second chromosome controls whether it pays attention by LOOKING rather than listening or smelling, the 7th gene on the third chromosome controls HOW LONG it will continue to pay attention, and the 22nd gene on the 4th chromosome controls whether it pays attention to STATIONARY or only moving objects.

1	  O-O-(I)-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-0-O-O-O-O-O-O-O-O
2 O-O-O-O-O-O-O-O-O-O-(L)-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O
3 O-O-O-O-O-O-(HL)-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O
4 O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-(S/m)-O

How would you ever be able to find this out? remember, the chromosomes all look the same.

This is NOT an easy task and for years we didn't have the technology to do it, but recently several interesting and odd quirks of nature have been discovered that open the way.

One of the odd quirks is a type of DNA called 'micro-satellite'. These are funny little areas where the DNA string can stretch and contract. They are a little like the leaves of a dining table that can be used to make it longer. The micro-satellite extensions are always made of the same stuff but sometimes they are very long (a boardroom table, lots of extensions added) and sometimes short (a card table). There are about 4,000 of these in most species that have been studied and they are scattered all around the genome (another word for the total number of strings that make up the pearl necklace). So our picture of the DNA pearl necklace begins to get a bit more detailed:


1 O-O-(I)-mmmmmmmmmm-O-O-O-O-mmmmm-O-O-O-O-O-O-O-mmmmmmm-O-O-O-O-0-O-O-O-
2 O-O-O-O-O-O-O-O-O-mmmm-O-(L)-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmmm-O-O-O-O-
3 O-O-O-O-O-O-(HL)-O-O-O-O-O-O-mm-O-O-O-O-O-O-mmmmmm-O-O-O-O-O-O-O-O-O
4 O-O-mmmmmmmmmmmm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmm-O-O-O-(S)-O

No one really knows why the micro-satellites exist, but the current view is that they are due to slippage mistakes made during the repair of the strings, which, being very delicate, periodically break and need repair. The micro-satellites have three properties that make them incredibly useful to researchers who want to find the genes that control particular traits.

First, because the micro-satellites are always made of the same stuff, they can be located and mapped. For example, chromosome number one in dogs (the chromosomes were originally numbered in order of length, since there was no other useful way to tell them apart: number one is the longest) might contain a micro-satellite 1,000 units in from the left end, and another one that is 450,000 units further down to the right and so on. People have been working on the micro-satellite maps of the chromosomes of different species for a couple of decades and some of the maps are getting very close to complete.

Second, their lengths will vary randomly, so the one that is 1000 units in from the left end might be 92 units long, whereas the next one down might only be 31 units long and so on. Each micro-satellite therefore has two properties that identify it; its position and its length (like mapping the co-ordinates of a city and also knowing its size)

Third, the more distantly related two individuals are, the more different their micro-satellites will be. Breaks in dog strings, for example, will be randomly repaired differently from those in human strings, not because there's anything inherently different about dog DNA but simply because the breaks are random. So, although both humans and dogs carry genes for blue and brown eyes, and red and black hair (and probably for behavioral things like attention spans and ability to see and hear), the years of breaks and repairs that have gone on between us will lead to differences in the positions and lengths of the micro-satellites

Border collies and newfoundlands, though not as different as humans and dogs, have been separated for long enough that many of their micro-satellites are different. So people like the Dog Genome researchers can look at the micro-satellite map of, say, chromosome two and know whether the chromosome came from a border collie,

2b O-O-O-O-O-O-O-O-O-mmmm-O-(Lo)-O-O-O-O-O-O-O-O-O-O-O-O-mmmmm-O-O-O-O-O-O

or a newf,


2n O-O-O-O-O-O-O-O-O-mmmmmmmm-O-(li)-O-O-mmmm-O-O-O-O-O-O-O-O-O-O-O-mm-O-O

just by looking at the micro-satellites.

I'm making a couple of assumptions here. In the position where the border collie has the gene for paying attention by looking (Lo), I'm assuming that the newf has a gene for paying attention by listening (li). This may not be true, of course, but let's use it for illustration. The same sort of thing holds for chromosome four, where sits the gene for paying attention to stationary things or to moving things. Lets say that the border collie has a gene that induces it to pay attention to things regardless of whether they are moving or stationary (a scared sheep? The sheep that's been backed into a corner?), while the newf mostly pays attention to things that are moving (drowning people rather than the rocks their boat crashed on). So at position 22, the border collie chromosome has the stationary/moving gene (Sm) and the newf has the moving gene (m). The two chromosomes will also have different micro-satellites.


border collie
4b O-O-mmmmmmmmmmmm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmm-O-O-O-(Sm)-O

newfoundland
4n O-O-mm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmmmmmmm-O-O-O-(m)-mmm-O-

Now remember that nobody knows where the behavior genes are (or even how many exist, or which types of behavior are influenced by genes). They only know the positions and lengths of the micro-satellites. How can they use this information to find the behavior genes?

They start by mating a newfoundland to a border collie. Now, in every individual, each one of the chromosome strings is actually paired up. There are two copies of each chromosome, one received from the mother and one from the father. So the border collie and the newf each has a pair of chromosome 2s and a pair of chromosome 4s. In the process of making eggs and sperm, they split these pairs up and donate one half (a complete set of singles) to all their progeny. All the puppies will thus have one set of chromosome strings from their mother (the newf, in this case) and one from their father. So their sets of chromosomes 2 and 4 will look like this.


2b O-O-O-O-O-O-O-O-O-mmmm-O-(Lo)-O-O-O-O-O-O-O-O-O-O-O-O-mmmmm-O-O-O-O-O-O
2n O-O-O-O-O-O-O-O-O-mmmmmmmm-O-(li)-O-O-mmmm-O-O-O-O-O-O-O-O-O-O-O-mm-O-O

4b O-O-mmmmmmmmmmmm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmm-O-O-O-(Sm)-O
4n O-O-mm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmmmmmmm-O-O-O-(m)-mmm-O-

By analyzing the behavior of this first cross, the scientists can make some guesses about the relative strengths of the different behavior genes, (though they won't yet be able to say how many there are or where they sit on the chromosomes). For example, if the puppies tend to look rather than listen, then looking (Lo) would be said to be DOMINANT over listening (li). If they tend to do both, paying attention with both their ears and their eyes, the genes would be said to be CO-DOMINANT. For the sake of this example, let's say that they are co-dominant. Lets also say that the Moving vs. Stationary genes on chromosome 4 are not co-dominant, but that paying attention only to moving things is dominant over paying attention to both moving and stationary things. So the puppies of a newf by border collie cross would pay attention only to moving things and they would do it by both listening and looking.

Good. This means that the first generation has taught us something, but not a whole lot. To learn more, we need to do some more breeding. We do this by breeding the puppies to each other (brothers to sisters) to make the second generation (called the F2 generation). Each parent will split its pairs of chromosmes, sending one copy (either the border collie copy or the newf copy) into the sperm or egg. The splits happen randomly so that a border collie type of chromosome 2 might end up going into the same egg as a newfoundland type of 4 etc. The puppies will therefore get all sorts of combinations of pairs of chromosomes. (Just like the progeny of a tri-color, prick eared bitch and a black, drop eared dog will come out in all the combinations of tri-color-drop eared, black-prick eared etc). Now things begin to get really interesting. We wait for the new puppies to grow up and then test them for the looking vs listening type of attention as well as for moving vs stationary attention. (The tests haven't really been worked out yet. In fact, I think this is the most problematic part of the whole project, but that's another story. Let's pretend that good tests have been devised and let's get back to the genetics, because the genetics will work for any trait, including many of the diseases for which good tests already exist).

Suppose that we find an F2 puppy that Looks (and doesn't listen) at both stationary and moving things. This is a dog that has copies of the border collie genes for LOOKING and STATIONARY/MOVING and doesn't have copies of the newfoundland genes. We don't know where these genes are yet, all we know is that we have found a dog that has them. So we take a little bit of blood, isolate the DNA from the white blood cells and look at the micro-satellite map. We find that both copies of chromosome 4 have a border collie type of micro-satellite pattern. We also find that both chromosome 2s are border collie type.


2b O-O-O-O-O-O-O-O-O-mmmm-O-(Lo)-O-O-O-O-O-O-O-O-O-O-O-O-mmmmm-O-O-O-O-O-O
2b O-O-O-O-O-O-O-O-O-mmmm-O-(Lo)-O-O-O-O-O-O-O-O-O-O-O-O-mmmmm-O-O-O-O-O-O

4b O-O-mmmmmmmmmmmm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmm-O-O-O-(Sm)-O
4b O-O-mmmmmmmmmmmm-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-mmmm-O-O-O-(Sm)-O

But we can't yet conclude that the Looking and Stationary/Moving genes are on chromosomes 2 and 4 because this dog also has two sets of border collie chromosomes 7, 9 and 13. Though these chromosomes don't carry any genes that we're interested in, we don't know that yet. All we know is that chromosome sets 2,4,7,9 and 13 are pure border collie. Let's say that sets 5,6 11 and 14 are pure newfoundland and all the rest are mixed pairs, where one comes from the border collie and the other from the newf. We can therefore guess that the LOOKING gene (Lo) and the gene for STATIONARY/MOVING attention (Sm) are somewhere on chromosomes 2,4,7 9 or 13.

To pin point it a bit closer, we need to find other dogs that have the border collie trait. Suppose that we now find one that looks (and doesn't listen) but only to moving things. We know therefore that it has the border collie Looking gene (Lo) and the newfoundland moving gene (m). When we analyse the DNA from its white blood cells, we find that chromosomes 1,2 and 7 are pure border collie, 4, 8, 9 and 15 are pure newf and the rest are mixes. We're now down to two choices for the Looking gene!! It must be either on chromosome 2 or 7 because these are the only two that are pure border collie in BOTH dogs. We haven't learned anything more about the Stationary/moving gene because this dog has the dominant trait (looking at only moving things) that can result from having either two pure copies of newf genes (m) or one copy each of the border collie (Sm) and the newfoundland (m) gene.

So we look at more dogs, hoping to find some more that have the Looking trait. We test them, find the ones that have the Looking trait rather than the Listening trait, bleed them, look at their DNA and . . . eventually . . . after a LOT of work, we pinpoint the Looking (and the Listening) genes to chromosome 2.

We've now accomplished the first step. We have mapped a behavior gene. We have learned a LOT from this. First, that there really is a gene involved in controlling this behavior, in the same way that there are genes governing ear prick and coat color. We've learned that a single gene is at work (not always true) and that it is co-dominant with its partner, the Listening gene. This means that, if we want dogs that will both look and listen, we'll need to keep making hybrids (like tomatoes) because this is a trait that needs both genes and therefore will never breed 'true'. Every time we breed two looking/listening dogs together, we will get some puppies that look (about one fourth of them), some that listen (another fourth) and about half that do both.

Now, please remember that this is a concocted fantasy example. I don't think that anything is known yet about the number, position, dominance, co-dominance or recessiveness of genes for behavior. I have just given an account of how the search is being done.

I think we can pretty well say that genes for behavior do exist. Anyone who has worked with different breeds of dogs can't help but know this. And hopefully, if these amazingly dedicated people get enough funding to do the work, we'll know the answers to some of our questions some day.



Inbreeding coefficients for ROM Shetland Sheepdogs

American Shetland Sheepdogs, at least as indicated by those Shelties that have earned the Register of Merit or ROM (sire of at least 10 Champions or dam of at least 5) have 160 ancestors of unknown pedigree. These ancestors, however, contribute very unevenly to the modern Shetland Sheepdog. When to this is added the fact that the modern American Sheltie is bred from a relatively small number of imported dogs, many closely related to each other, it is hardly surprising that inbreeding coefficients for the Register of Merit Shelties are high, and have increased steadily since the initial importations, which took place during the 1920's. Each dot on the figure below represents one ROM Sheltie. Note that the average value for a recent ROM Sheltie is probably in excess of 40% - equivalent to between two and three generations of brother-sister matings. Individual inbreeding coefficients are available for the ROM Shelties.


.Note that the highest values on the left side of the plot are incorrect, due to the fact that two early suspected Collie crosses (Jean of Anahassitt and Ch Kim o'Page's Hill) were placed in the database with their paper (purebred Sheltie) pedigrees. We now have the inbreeding coefficients for the ROM Shelties with the assumption that Jean of Anahassitt and Ch Kim o'Page's Hill were sired by unrelated Collies. Although some of the high early values are lowered considerably, the effect on modern ROM dogs is a reduction of the inbreeding coefficient of only about .03. The plot below is thought to be closer to the truth.


The concept of the inbreeding coefficient can be extended to the kinship coefficient, where instead of calculating the inbreeding coefficient for an individual, one calculates the inbreeding coefficient for the hypothetical offspring of two individuals. This is called the kinship coefficient. The kinship coefficient between two full siblings (assuming their parents have no common ancestors) is 25%, which is the same as the kinship coefficient between an outcrossed parent and its offspring. A reasonably high degree of inbreeding in an individual is not an overwhelming problem, as mating between two individuals, both with high inbreeding coefficients but with few ancestors in common, will produce animals with quite low inbreeding coefficients. But what happens when the kinship coefficient of a dog with every possible mate is high?

In the case of Shelties, the kinship coefficient between any two ROM Shelties whelped since 1980 averages 33%, with a highest value of 62% (A/C Ch Alfenloch Ryan o'Neill ROM x Ch Mainstay Cemeo Farms Model ROM) and a lowest value of 25% - the equivalent of full siblings. In other words, every Register of Merit Sheltie is as closely related to any other ROM Sheltie as if they were littermates from unrelated parents. We clearly do not have a large gene pool, at least not in the top show lines, although we do have a large number of individual dogs.

One interesting point is that Shelties are notorious for not breeding "true" - multiple champion litters are rare, with particular problems in getting a litter which is all in size and all have correct ears. Is it possible that some of the traits selected for via the show ring are in fact dependant on heterozygosity at some loci?

Canine Color Genetics

Dogs have a wide variety of genes that influence color. Further, the same genes may give a very different effect on different types and lengths of coats. While this site is primarily concerned with Shetland Sheepdog colors and a long, working-type (double) coat, I will use comparisons from other breeds and even other species whenever it seems useful. References, including other mammalian color genetics, are on a separate page.

One of the biggest problems people have with genetics is the assumption that a defined trait - size, ear type, color, yappiness - is due to a single gene. In fact, genes code for two types of things. One, which is relatively well understood, is the structure of a particular protein. The normal equivalent of the albino gene, for instance, codes for tyrosinase, an enzyme which breaks up the amino acid tyrosine as a first step in producing melanin, the major pigment in mammalian skin and hair. In an albino, this enzyme cannot be produced, and as a result melanin cannot be produced. A second type of gene controls when and where other genes are turned on or off. These genes are the subject of vigorous ongoing study, and probably have a major impact on such things on the number of vertebrae in the spine or the age at which growth is complete. I've included a page which defines some of the terms used in genetics, as well as explaining dominant, recessive and incompletely dominant genes. Right now, let's look at some of the gene series (loci) known to influence canine color, and try to get a feel for what they do.

Before starting our list, we need to know that mammals have two forms of melanin in their coats. One, eumelanin, is dark, though it can vary somewhat in color due to variations in the protein that forms the framework of the pigment granule. The base form of melanin is black. Melanin can also appear brown (often called liver in dogs) or blue-gray. The second pigment, which varies from pale cream through shades of yellow, tan and red to mahogany (as in the Irish Setter), is called phaeomelanin. There are at least two and possibly as many as four gene series that determine where, on the dog and along the length of the hair, eumelanin and phaeomelanin appear.

The generally recognised color series (loci) in dogs are called A (agouti), B (brown), C (albino series), D (blue dilution) E (extension), G (graying), M (merle), R (roaning), S (white spotting) and T (ticking.) There may be more, unrecognised gene series, and in a given breed modifying factors may drastically affect the actual appearance. Thus one school of thought holds that the round spots on a Dalmation are due to the same gene that produces the roaned areas on a German Shorthair Pointer, but with vastly different modifiers.

A, the agouti series. The standard assumption, based on Little's research, is that this series contains four alleles (different forms of the gene). A fifth allele may exist in Shetland Sheepdogs, and a sixth in certain "saddle-tan" breeds.

  • As produces black without any tan on the dog. White markings are due to a different gene, and there are other genes that can modify the black to liver (chocolate Lab) or blue dilute (blue Great Dane.) If As is present, in most cases the dog will be able to produce only eumelanin pigment (but see the E series). Note that the agouti series is known in a number of mammals, and dominant black is almost always found in a different series, so there is a strong possibility that dominant black is not really in the agouti series.
  • ay in the absense of As produces a dog which is predominantly tan (phaeomelanin) sometimes with black tipped hairs or interspersed black hairs. The usual term for this color is "sable." In examining dogs from ay breeds, I have generally found that even if there is no other black on the coat, the whiskers (the course, stiff vibrissae, not the "beard" seen with some terrier coats) are black if they originate in a pigmented area. Examples of ay dogs include Collies, fawn Boxers and Great Danes, and some reds (Basenji red is thought to be ay, for instance.) ay is recessive to As, but incompletely dominant to at. That is, an ayat dog is on average darker (more black hairs) than an ayay dog, but the difference is generally within the range of color for ayay within the breed.
  • at, present in double dose, produces a dog which is predominantly black, with tan markings on the muzzle, over the eyes, on the chest, legs, and under the tail. A Dobermann or Rottweiler is a good example of the classic black and tan pattern. The Bernese Mountain Dog shows the effect of black and tan combined with white markings, often called tricolor.
  • aw is the fourth allele considered by Little. This is the wild "wolf-color" seen in Norwegian Elkhounds and possibly in some salt-and pepper breeds. It differs from sable in two ways. First, the tan is replaced by a pale cream to pale gray color. Second, the hairs are normally banded - not just the scattering of black-tipped hairs sometimes seen in a sable, but several bands of alternating light and black pigment along the length of the hair. Little was unable to determine the dominance relationship of this gene, or even to say with certainty that the banding and the reduction of tan pigment were due to the same gene.

Although Little did not make any distinction between the Dobermann black and tan and the "saddle tan" seen in many terrier breeds (black "saddle" but extensive tan on legs and head), it seems likely that a fifth gene exists in the a series. For the moment I'll call it "saddle tan," asa. It seems recessive to ay sable, but other dominance relationships in the series need more investigation.

Finally, at least two breeds (Shetland Sheepdog and German Shepherd) have a fully recessive black. Since black is the bottom recessive of the A series in many other mammals, it seems logical to assign this color to recessive black, a, and state that recessive black is caused by aa at the agouti locus. There is an alternative theory in Shelties which suggests the existence of a recessive gene that removes tan points from a genetic black and tan or a dominant, widespread gene that forms tan points on all colors but dominant black.

Little's assignment of dominant black in dogs to the A locus (As) is totally against experience with this locus in other species, where more yellow is generally dominant to more black. There may be a third locus controlling dominant black, in which case Ay would be the top dominant in the A series.

B, the brown series. This series is relatively simple. B, in single or double dose, allows the production of black pigment. A bb dog produces brown pigment wherever the dog would otherwise have produced black. The gene apparently codes for one of the proteins that makes up the eumelanin pigment granule, so the bb granules are smaller and rounder in shape as well as appearing a lighter color than those of a dog carrying B. This gene is responsible for a number of liver and chocolate colors, especially in the sporting breeds. The same gene produces some "reds" (in Australian Shepherds, Border Collies, and Dobermanns, for example), and probably the bronze Newfoundland. It has some effect on the iris of the eye and on the skin color, including the eye rims and the nose leather. Phaeomelanin (tan) is very little affected, so the color of the tan points on a red Dobermann (atatbb), for instance, is little affected. I have seen little discussion of the effect of brown on a sable dog, but I would expect a brown nose leather and eye rims, with the coat shaded brown rather than black. Probably the dog would closely resemble a sable, perhaps with an orangey cast and a light nose. Note that some shades of liver, though a eumelanin pigment, overlap some shades of tan, a phaeomelanin pigment. In particular the deadgrass color (bbcchcch) can overlap recessive yellow (ee)

C, the albino series. This again is a fairly complex locus, especially in other mammals. The top dominant, C, allows full color to develop, and is probably the structural gene for tyrosinase. The bottom recessive, c, does not appear to occur in dogs, but in other mammals it completely prevents the formation of any melenin in the coat or the irises of the eyes, giving a pink-eyed or red-eyed white. It is worth pointing out that human albinos from dark-skinned parents often show some yellowish or reddish hair and even skin color, but it seems this is not due to granular melenin. c, therefore, is a form of tyrosinase which cannot act as it is intended to in the formation of melanin. Since c is simply a non-working form, there may be more than one form of c gene (lots of ways to get something not to work), and there is some evidence that when two different forms are mated, colored offspring may result.

There are a number of intermediate genes where the mutation apparently produces a partly active form of tyrosinase. Some C alleles known in other mammals are:

  • C full color, allows full expression of whatever pigment is prescribed by other genes. Most dogs are CC.
  • cch, chinchilla or silver, when present in double dose removes most or all of the phaeomelanin pigment with only a slight effect on black pigment. This is named after a small fur-bearing South American rodent called the chinchilla. Black and silver replacing black and tan, or a wolf-like color without the extra banding (see aw, above) may also be due to a cchcch genotype. Dogs with very light tan probably are cchcch or something similar. Liver dogs show lightening even of eumelanin pigment, and the "deadgrass" color of the Chesapeake Bay Retriever is thought to be due to a bbcchcch genetic makeup. The possibility of other, rufous modifiers affecting the shade of phaeomelanin pigment needs to be kept in mind, as does the possibility of more than one form of chinchilla in the dog - rabbits are thought to have three.
  • ce, extreme dilution, has also been proposed for the dog. This gene may be part of the makeup of some "white" dog breeds where the white color is due to extreme dilution of tan. The West Highland White Terrier may be ceceee. A cross to a black and tan breed would be interesting from the point of view of color genetics. Eyes may be lightened in some species, but this is doubtful in dogs.
  • ch, Himalyan, is not known to occur in the dog. In homozygous form, it makes the formation of eumelanin dependant on the temperature of the skin. Thus a genetically solid black animal will have reduced black on the extremities (seal brown) and an almost white color on the body. The effect on tan/orange pigment is confusing - the tan in agouti hairs is removed, but that resulting from the orange gene in cats (not in dogs) remains intense on the extremities. There is reason to suspect that this gene, as well as some forms of chinchilla, also affects the organization of the brain, particularly in the neural pathways from the eyes to the brain. There may be a reason for Siamese cats to be cross-eyed. Eyes are normally blue or pink.
  • cp, platinum, is optically similar to albino but retains very slight tysonase activity and in the mouse is described as retaining some luster in the coat as opposed to the pure white seen in albino. Although there is a total absense of proof one way or the other, I would hypothesize that the white Doberman, with pale blue eyes and pink nose, is due to a homologous gene.
  • c, albino, is not known to occur in the dog as a regular part of any breed color, though possible candidates for mutations to c have been recorded. As mentioned above, the c gene cannot produce working tyrosinase, and a cc individual cannot produce melanin pigment.

As seen from the above, C is known to have a number of different forms and effects. The usual assumption is that dogs have at least one mutant allele, cch which when homozygous lightens phaeomelanin (yellow) pigment to cream and more weakly affects liver and longhaired black. A second proposed allele, ce may be responsible for further reduction of cream to white in some breeds, or modifying alleles may be responsible for the further lightening in these cases. While some forms of C modify eye pigment (e.g., blue eyes in Siamese cats) there is little evidence for this in dogs unless "white" Dobermans are indeed due to a C-locus mutation. Although C appears to be fully dominant over any of the other alleles, the dominance relationship between the others generally goes in the direction of more color incompletely dominant over less color, the heterozygote generally resembling but not necessarily identical to the homozygote with more pigment

D, the dilution series. This, again, is a relatively simple series, containing D (dominant, full pigmentation) and d (recessive, dilute pigment). In contrast to C, which has its strongest effect on phaeomelanin, or B, which effects only eumelanin, D affects both eumelanin and phaeomelanin pigment. It is thought to act by causing the clumping of pigment granules in the hair. Like B, it often affects skin and eye color, and in some breeds dd has been associated with skin problems. "Maltese blue" is a term often used to describe dd blacks. If a solid liver dog also is dd, the result is the silvery color seen in Weimararners and known as "fawn" in Dobermans. (In most breeds, fawn refers to ay yellows.)

While dd acting on black or liver is a part of the genotype of several breeds, dd acting on sable is relatively rare. For one thing, the action of dd on phaeomelanin has been described as a flattening or dulling of color. The cinnamon color in Chows is probably due to an ayaydd genotype, but otherwise the combination of dd with phaeomelanin coat color seems limited to breeds in which color is of little importance (e.g., blue brindle in Whippets.)

Although D is usually described as completely dominant to d, I have seen one blue merle Sheltie bitch who suggested that this may not always be the case. The black merling patches in this bitch were actually an extremely dark blue-gray. Other than this she was an excellently colored blue merle. The owner insisted that she was not a maltese blue, but that she had relatives who were. I suspect that this bitch may have been Dd, with the additional diluting effect of the merle gene allowing the normally hidden effect of a single dose of d to show through.

E, the extension series. This series is probably the least satisfactory of those generally assumed to exist in the dog. In most mammals, the E series includes Ed (dominant black), E (normal extension) and e (recessive red or yellow, and sometimes some intermediate alleles called Japanese brindles. In dogs, this is clearly not the case; breeding experiments have conclusively proven that dominant black and recessive red are not in the same series. This has led to dominant black being thrust into the A series, which as already mentioned conflicts with results in other mammals.

In this summary, I will give the genes as postulated by Little, followed by a brief discussion of other possible explanations and a suggestion for matings that might clarify the situation. Note that the question is not in whether the genes occur, but whether they are in fact alleles in the same gene series. With regard to e and E, recent sequencing of the e and E genes in dogs show definite homology with those in other species.

  • Em, mask factor. This gene replaces phaeomelanin (tan) with eumelanin (black) over part of the dog. There is considerable variation in the area of replacement, probably affected by modifiers but possibly involving more than one form of Em. At its weakest the mask factor may produce black hair fringing the mouth, or a slightly smutty muzzle. At its strongest (Belgian Tervuren) most of the head is black, and there is considerable blackening of chest and legs. The effect of Em shows to its fullest extent on clear sable dogs (ayay), but is visible on the tan points of black and tan dogs (atat) as well. In its strongest version, it can change a black and tan to a pseudo-black, with tan so restricted in its distribution that it may not be immediately apparent that the dog is not black. The occasional "black" puppy produced by two Tervuren parents is probably this type of black, with two ayatEmEm parents producing an atatEmEm puppy. A similar but not quite as strong blackening of the head of a genetic black and tan occurs in German Shepherds.
  • Ebr, brindle. This gene probably got into the E series by mistaken homology with Japanese brindle, which behaves quite differently from brindle in the dog. In Japanese brindle, the patchy color is believed to be due to two alleles of the E series side by side on the same chromosome. Only one can be expressed, and different parts of the animal will show the expression of different genes. The result is a coat made up of random small patches of tan and black pigment, rather like a tortoiseshell cat. If a Japanese brindle animal also has the genes for extensive white spotting, the tan and black pigmented areas tend to become larger and more compact, similar to what one sees in a calico cat (genetically, a tortoiseshell with white markings.) There is a canid which might be Japanese brindle with white spotting, the Cape hunting dog, Lycaon pictus. This animal has a coat which is a rather random patchwork of black, yellow and white. The color has very little similarity to brindle in the dog.
    Brindle in dogs consists of black, vertical stripes on a sable/fawn background, usually rather soft-edged, but much more regular that a typical Japanese brindle, and showing no tendency for the tan and black patches to become more distinct in the presense of white spotting genes. Genes that affect eumelanin will affect the dark stripes, so a bb brindle, for instance, will have brown rather than black stripes. Brindle on a black and tan will show only in the tan areas, while brindle on a black cannot be distinguished at all. If in fact recessive red (ee) is in the same series with brindle, it is not possible for brindle (or mask) to occur on an ee dog as one of the E genes would have to be Ebr (or Em), leaving no room for ee. Little implies that brindle and mask were co-dominant, with masked brindles being EbrEm, in which case masked brindle could not breed true.
  • E, normal extension of black, allows the A-series alleles to show through with no masking or brindling. It is apparently recessive to both Em and Ebr.
  • e, recessive red, overrides whatever gene is present at the A locus to produce a dog which shows only phaeomelanin pigment in the coat. Skin and eye color show apparently normal eumelanin, although some ee dogs appear to show reduced pigment on the nose, especially in winter (snow nose.) A number of breeds show recessive red as a normal or even breed-wide characteristic - Irish Setters, Golden Retrievers, yellow Labradors. In a few breeds such as the Cocker Spaniel "reds" may be either ayay or ee, and crossing the two can produce unexpected blacks. I believe there may be a key in the color of the whiskers, which on my observations seem to be black in ayay breeds and straw to cream (dilute red) in ee breeds, always assuming the whisker base sprouts from a pigmented area. Little hypothesized that dogs with both forms of red (ay-ee) were not viable and would be lost before birth.

The dominance relationships in the Little proposal are not simple. He assumes that Em and Ebr are co-dominant. In an ayay dog, then, brindle without a mask could be EbrEbr, EbrE, or Ebre. A masked dog without brindling would be EmEm, EmE or Eme. A masked brindle would have to have the genotype EmEbr. This assumption makes some predictions which should be readily testable:

  1. Two masked brindles, mated together, should produce appoximately a 1:2:1 ratio of masked fawn to masked brindle to brindle without masking. In other words, masked brindle should not breed true.
  2. A masked brindle could not carry E or e. Thus a masked brindle, bred to sable ayayE- would pass either mask or brindle. The expectation would be a litter of brindles without masks and masked sables (fawns) without brindling, but no sables without either mask or brindle and no masked brindles.
  3. If a masked brindle is bred to an ee red, the results would depend on the A series genes in the ee red, but there would be neither ee nor ayay reds with neither masking nor brindling. Some blacks might occur, but if the puppy had areas of tan pigment, the tan would be either masked or brindled, but never both and never tan without either mask or brindle.

My impression in talking to breeders of masked brindles is that these predictions are not fulfilled. Possible revisions of the E series include:

  1. Remove Ebr from the E series, instead recognising that in many ways it is closer to tabby (Ta) in the cat family. This is the gene series responsible for the various stripes, ticking, spots and rosettes seen in both wild and domestic cats. Granted, the pattern is not the same (striped cats normally have stripes ringing the legs), but brindle is also a black striping gene which is visible primarily on an ay background. This would leave Em, E and e in the E series, giving a prediction that Em- bred to ee could produce either 100% masks if the mask is EmEm, half masks and half sables without masks if the mask is EmE, or half masks and half recessive reds if the mask is Eme. The one outcome that would be missing is that a masked to recessive red breeding could produce unmasked sables and unmasked recessive reds in the same litter. Given the difficulty in distinguishing sables from recessive reds, this might prove difficult.
  2. Remove Ebr from the E series, possibly putting it in the same series with dominant black (currently in the A series.) The new series (here called K - the last letter of black - for convenience) would have three genes, Kd dominant black, Kbr producing eumelanin stripes on any phaeomelanin (tan) pigment on the dog. The assumption is that Kd is dominant over Kbr which in turn is dominant over k (more black dominant over less black.) The prediction would be that a dominant black (Kd-) bred to a clear sable would produce either all dominant blacks if the black is KdKd, a fifty fifty mix of dominant black and brindle if the black is KdKbr, or a fifty fifty mix of dominant black and clear unmasked sable if the black is Kdk, but never a litter with all three colors. Unpublished studies on racing greyhound litters agree with this prediction.
  3. Em might still be in the E series, but this should be tested. The test breeding would be difficult, because of the difficulty in being sure whether a "red" dog is ee or ayay, but the test is whether a masked dog, bred to another mask or to a recessive red ee, produces both ee red and fully expressed, unmasked tan-point or sable in the same litter. Probably some cross breeding would be required to be sure of the genotypes of parents and offspring.
  4. If both removals hold up, this would leave the E series with just two alleles, normal expression of the A series (E -dominant) and recessive red (e - recessive.) It has now been reported in the scientific literature (Newton et al, 2000) that the genetic sequence of canine e/E correponds to the E-locus (specifically recessive red) in several other species (fox, cow, human and mouse.)

G, the graying series. Although only two genes were recognised in this series by Little, this may be a more complex locus, or genes that affect graying may reside at more than one locus. The effect of G, in single or double dose, is the replacement of colored by uncolored hairs as the animal ages, very much like premature graying in human beings. This gene should be suspected in any breed where a dark puppy pales and washes out with age, and the paling is due to interspersed white hairs. The gene is almost certainly present in some Poodles, Old English Sheepdogs, and terriers. The fading may start immediately after birth or after a period of weeks to months has elapsed, and may go as far as it is going to by the first adult coat or may continue through the animal's lifetime. G may or may not be the gene involved in the graying of muzzle and over the eyes in aged dogs, or in the lightening of black to steel blue without interspersed white hairs. This is a series that definitely needs more work.

M, merle. This is another dilution gene, but instead of diluting the whole coat it causes a patchy dilution, with a black coat becoming gray patched with black. Liver becomes dilute red patched with liver, while sable merles can be distinguished from sables with varying amounts of difficulty. The merling is reportedly clearly visible at birth, but may fade to little more than a possible slight mottling of ear tips as an adult. Merling on the tan points of a merled black and tan is not immediately obvious, either, though it does show if mask factor is present, and may be discernable under a microscope. Eyes of an Mm dog are sometimes blue or merled (brown and blue segments in the eye.)

Although merle is generally treated as a dominant gene, it is in fact an incomplete dominant or a gene with intermediate expression. An mm dog is normal color (no merling). A Mm dog is merled. But an MM dog has much more white than is normal for the breed (almost all white in Shelties) and may have hearing loss, vision problems including small or missing eyes, and possible infertility (Little). The health effects seem worse if a gene for white markings is also present. Thus the dachsund, which is normally lacking white markings, has dapples (Mm) and double dapples (MM) the latter often having considerable white, but according to Little other effects are limited to smaller than normal eyes. In Shelties, Collies, Border Collies, and Australian Shepherds, all of which normally have fairly extensive white markings, the MM white has a strong probability of being deaf or blind. The same is probably true with double merle Foxhounds and double merles from Harlequin Great Danes with the desired white chest. A few double merles of good quality have been kept and bred from, as a MM double merle to mm black breeding is the only one that will produce 100% merles.

It is possible that merle is a "fragile" gene, with M having a relatively high probability of mutating back to m. The observed pattern would then be the result of some clones of melanocytes having suffered such a back mutaion to mm while they are migrating to their final site in the skin, producing the black patches, while others remained Mm. This hypothesis also explains why a double merle to black breeding occasionally produces a black puppy, the proposed back mutation in this case occurring in a germ cell. On the other hand, the observed blacks from this ype of breeding may actually be cryptic merles - genetically Mm, but with the random black patches covering virtually all of the coat.

Merle is a part of the pattern of ragged black spots seen in the harlequin Great Dane. There appears to be an additional gene which removes the dilute pigment, leaving the "blue" area clear white. The fact that harlequins continue to produce merles argues that animals pure for this proposed extra factor may not exist, and one possibility is that a homozygote for this whitening factor is an embryonic lethal. Interestingly, there are recent reports of Shelties born with a harlequin pattern, but in this case the "blue" area actually develops color with time, winding up a light silvery blue. These dogs appear to have larger than normal black areas, at the extreme being so-called cryptic merles, that is, no blue is visible without an extensive search. Other shelties born harlequin or "domino" retain the white body color.

Although Danes are usually solid color, the harlequin color description includes a preference for a white neck and front. Since the black patching is as apt to be on neck and front as anywhere else, this requires incorporation of a gene for white spotting (probably irish spotting, si si). Given that SS double merles seem to fare better than their si si counterparts, I would expect that double merles from harlequin Danes with patched fronts and necks might be healthier than from those that fit the standard better. The harlequin description also faults black hairs in the white area. The harlequin - silver blue pattern in Shelties could be an extreme case of black hairs in the white area. Both harlequins and the silver-blue merle Shelties have occasional patches of gray (merle?) as well as black, though this is not considered desirable.

R, roan. This may or may not be a true series. Both Little and Searle suggest that roan may simply be a very fine ticking, with dark hairs growing in an initially white area of the coat. A second type of roan, in which white hairs develop in an initially dark coat, could be due to gray or could be a type of roaning different from the progressive development of dark hair in a light area. In any event, roan (R) appears to be dominant to non-roan (rr). It is not clear whether this is full dominance or incomplete dominance. I will here treat roan as being at the ticking locus.

S, white spotting. This is another somewhat unsatisfactory series, and one in which modifying genes appear to have a very large effect. Certainly there are genes for solid color, for a more regular white spotting, and for basically white with some colored markings. But the variability within each type makes it unclear how many alleles actually occur at this locus. In general dominance is incomplete, with more color being dominant over less color. Heterozygotes commonly resemble the more-pigmented homozygote, but with somewhat more white.

  • S, solid color. This is the normal gene in breeds without white markings. An SS dog can completely lack white, but it can also express very minor white markings - white toes, white tail tip, or a star or streak on the chest. SS breeds generally fault these markings.
  • si, irish spotting. Irish spotting is generally confined to the neck, the chest, the underbody, the legs and the tail tip. White does not cross the back between the withers and the tail, though it may appear on the back of the neck. Breeds with "Collie markings" which breed true for the markings are generally si si.
  • sp, piebald. This is a more difficult gene to identify. Certainly some breeds, such as parti-color Cockers, seem to breed true for piebald. Crosses of parti-color and solid in Cockers, however, often have minor white marking. Piebald and irish spotting seem to overlap in phenotype in one direction, while piebald and extreme white overlap in the other. In general, it seems a piebald has more than 50% white, white often crosses the back, and the pattern gives the impression of fairly large colored spots on a white ground.
  • sw, extreme white piebald. Extreme white piebalds range from the color-headed whites (Collies, Shelties) which may also have a few colored spots on the body, especially near the tail, through dogs with color confined to the area around the ear or eye (Sealyham, White Bull Terrier, Great Pynenees) to some pure whites (Dalmation ideal). There is some anecdotal evidence that swsw dogs without color on or near the ear have a higher probability of deafness than dogs with color on the ears, but this varies with breed and it is not known whether a separate allele of S might be involved. In Boxers, some whites are produced from show-marked parents. Little believed that the Boxer lacked the gene for si, the irish-type spotting desired in the show ring being produced by heterozygosity for S and sw. Since the Boxer club is adamantly opposed to any breeding of whites, even test breeding, this has not been independantly confirmed.

All of the spotting genes are assumed to be affected by the action of modifiers, with + (plus) modifiers being generally understood to increase the amount of pigment (decrease white) while - (minus) modifiers being assumed to decrease the amount of pigment (increase white.) Merle appears to act as a minus modifier, in addition to its effects on coat color.

It is not clear to what extent the S series affects head pigment. Color-headed white shelties, for instance (swsw), can have completely colored heads - not even a forehead star or white nose. On the other hand, relatively conservatively marked dogs can appear with half white or all white heads. There is probably at least one other gene series that affects head markings. It is at least possible that the plus and minus modifiers affect head and body markings simultaneously.

T, ticking. Some dogs develop flecks of color in areas left white by genes in the S series. The clearest and most obvious ticking is seen in Dalmations, where additional modifier genes have enlarged and rounded the ticks. A large number of irish, piebald and extreme white breeds also have variable ticking, though not often as obvious as the Dalmation. The color of the ticking seems to be the color the coat would be in that area if the white spotting genes were not present. Thus a genetically black and tan Dalmation (a fault) will have tan spots where a black and tan would have tan markings. A ticked sable, ayayTT or ayayTt, may not have obvious ticking, becasue there is not much contrast between the tan and the white. Careful examination, however, will often show tan flecks on the legs. Ticking on a long-haired dog is also difficult to discern. The Border Collie on the front page of my site is ticked and probably sisw, as well as having the gene(?) for half white head. The tick marks in her ruff are not visible in the photo, but they are present (if difficult to find) on the living dog.

The usual dominance relationship given is that T (ticking) is dominant over t (lack of ticking.) Some breed-specific sources suggest that ticking acts as a recessive. I am inclined to suspect incomplete dominance of T. In Border Collies, for instance, a color called blue mottle is in fact a very heavily ticked piebald. The dam of the Border Collie mentioned above was such a blue mottle, presumably TT, while Dot is apparently Tt.

Ticking is also very much affected by genes which modify the size, shape and density of tick marks. In fact roan, which can develop by the gradual growth of pigmented hair in white areas of the coat, may simply be a form of ticking.

Chromosomes are made up of protein and DNA, deoxyribonucleic acid, which carries instructions for the inheritance of characteristics within organisms. Almost all cells of an individual organism have the same amount and type of DNA. The DNA is found mostly in the nucleus in tightly coiled threads, which are the chromosomes. Depending on the cell type, different parts of the chromosomes are used to make different substances, which determine the cell’s function.

The instructions for an organism’s characteristics are actually located within the genes. Genes are sections of DNA, so many genes can be found along the lengths of DNA making up the chromosomes. All genes have more than one version, so when chromosomes are inherited from parent cells, the version of the gene, or allele, is not always the same. Although homologous chromosomes have the same genes, they do not have to have the same allele for each gene.

If each chromosome of the homologous chromosomes pair has the same allele for a particular gene, it is said to be homozygous. If the alleles are different, then the cell is referred to as heterozygous. The way in which the alleles interact determines the characteristics of the offspring. Alleles can be dominant or recessive and, if different alleles are present, the dominant allele will determine the characteristic of the offspring.

Within the somatic, non-reproductive, cells of each organism, there are two copies of each chromosome. Cells that have two copies of each chromosome are called diploid cells and those that have only a single copy are called haploid cells. Reproductive cells, or gametes, only have one copy of each chromosome, so they are haploid. This ensures that the cells that are formed through the fusion of two gamete cells have the correct number of chromosomes after fertilization. 

Wait! Don't leave yet. I know that for many breeders any article with the word genetics in the title causes an immediate negative reaction. Either they quickly turn the page and pretend they didn't see it, or they drop the magazine and flee from the room in terror. But this article is written especially for those people. It is for you - the one who always thought that genetics was too complicated, too full of big words and funny symbols for the average person to understand. Anyone who is serious about breeding a better cat needs a basic knowledge of genetics. The key word, though, is basic. It may be interesting to know all of the ins and outs of genetics and to be able to rattle off a whole page of symbols to describe your cat. But unless you are going to work on developing a new breed it really isn't necessary. The purpose of this article, then, is to present the fundamentals of genetics in layman language without any more of the big words and symbols than are absolutely necessary. Ready? Take a deep breath and let's begin.

Every living body, including a cat's, is made up of a bunch of cells. Each one of those cells contains the chemical code for all of the characteristics in the whole body - every characteristic from eye color to liver size to number of toes. Inside of each cell are some long wormy looking things called chromosomes. At certain times you can see these chromosomes inside of the cell by using a microscope. All individuals of a particular group of animals have the same number of chromosomes in their cells. All humans have 46 chromosomes; all crayfish have 200; all domestic cats have 38. Each characteristic which an individual possesses has its own chemical code which is contained in a unit called a gene. There is a gene for coat color, a gene for tail length, a gene for intestine length, a gene for every one of the thousands of intricate characteristics which make up an individual animal. The genes are located on the chromosomes. A chromosome carries many different genes on it and a particular gene is always located in the same place on the same chromosome.

All of the chromosomes in a cell are arranged in pairs. The two chromosomes in a pair have genes on them for the same characteristics. Therefore, every cat has two genes for every characteristic that he possesses. For example, a cat has two genes which each control hair length. One of these genes may be a chemical code which makes the hair long; the other may be a code which makes the hair short. Or, they could both be for long hair or both be for short hair. Obviously, both genes cannot operate and control a characteristic if they are different. One of them must be stronger than the other and produce the characteristic according to its code. In the majority of cases this is exactly what happens. The strongest gene is called dominant; the weaker gene is called recessive. In cats, the gene for short hair is dominant over the gene for long hair. Therefore, a cat which has one gene on the chromosome pair for long hair and the other gene for short hair will have short hair. In order for a cat to have long hair it must possess both genes for long hair. There must be two recessive genes present for a recessive characteristic to show. A great many genes with which we have to deal in cat breeding are either dominant or recessive to the other gene in the pair. Occasionally, however, we run into something called incomplete dominance. In this case, neither gene in the pair is strong enough to be completely dominant over the other. When this happens the characteristic appears as something different than either gene would have made it alone. For example, in cattle, a cow may have one gene for white coat color and one gene for red coat color. Neither of these genes is completely dominant and the cow will have red and white hairs mixed in the coat. An example of this in cats is the mink color in Tonkinese and other breeds. Mink color is produced when the cat has one gene for siamese pattern and one gene for burmese pattern. Neither gene is dominant and an in between color appears.

Now then. You are probably wondering about the characteristics which have more than two different ways of appearing, and many characteristics do. We have learned that a gene for a particular characteristic is always located in the same place on the same chromosome. And we have learned that, because of the fact of chromosome pairs, there are always two genes present for each characteristic - no more and no less. All of the genes which produce alternate forms of the same characteristic are called alleles. If there are more than two gene alleles for one characteristic it is called an allele series. However, no matter how many alleles there are in an allele series, only two of them can be present at the same time. Let's take an example. There is an allele series which controls the distribution of color pigment in a hair of the cat. The genes in this series are as follows: full color, burmese, siamese, albino. It is only possible for a cat to have two of these alleles at one time. If the full color gene is present it will be dominant over any of the others. If the albino gene is present it will be recessive to any of the other alleles. If, however, the siamese gene is present it will be recessive to the full color gene but dominant over the albino. Remember, of these four genes, no more than two can be present in one cat because they are all located in the same place on the same chromosome pair.

How do you know whether a gene is dominant or recessive to another gene? How do you know how many gene there are in an allele series? All of this is found out by doing experimental breedings. It takes a long time and a whole lot of breedings to find out for sure about a gene. If you flip a coin five times it may come up heads every time and you may be tempted to say that the coin has two heads. But if you flip it one hundred times you will get very close to fifty per cent heads and fifty per cent tails. The same is true in cats. It takes a lot of kittens to make a definite statement about a gene. Most breeders are content to get their information from books or from more experienced breeders.

Now you know a little about genes and chromosomes and how they determine which characteristics a certain cat will possess. But in cat breeding we are concerned with the characteristics that a cat passes on to its offspring.

All of the cells in a cat's body are capable of reproducing themselves. When an ordinary cell, say one in the cat's ear, is ready to reproduce itself each one of the chromosomes in the cell makes an exact copy of itself. For a short time the cell contains two complete sets of chromosomes. Then the cell splits in half and one complete set of chromosomes goes into each half. When the split is finished you have two identical cells. However, the cells which make the sperm in the male and the egg in the female do not reproduce in this manner.(See figure I) When a cell which will eventually be a sperm or an egg is ready to divide to make two cells it does not duplicate its chromosomes first. Instead, one chromosome from each pair stays in the old cell. The two cells produced from this division each have only one half of a complete set of chromosomes. Remember that this happens with both the sperm cells and the egg cells. When a sperm joins with an egg to make the first cell in a new kitten embryo, the half set of chromosomes from the egg and the half set of chromosomes from the sperm make a complete set again. The new cell will have a complete set of chromosomes, half obtained from its mother and half obtained from its father, which it will duplicate to make the billions of cells necessary to produce a living kitten. The chemical code carried by the genes on those chromosomes will be what determines the characteristics possessed by the new kitten.

genetics.gif (4518 bytes)

We have learned, in talking about dominant and recessive genes, that a cat may have a gene in its genetic makeup which does not show in its physical makeup. A short hair cat can have a recessive gene on the other chromosome in the pair for long hair. Therefore, a cat can pass on a characteristic to its offspring which in itself does not physically possess. Let us suppose, for example, that we have a male short hair cat who carries the recessive gene for long hair. When a cell from his body splits to make two sperm, one of these sperm will have the gene for short hair and the other sperm will have the gene for long hair. If the sperm with the long hair gene should join with an egg that also carries long hair then a long hair kitten will be produced. Which sperm gets which gene and which sperm joins with which egg is strictly a matter of chance. If a sperm carrying short hair joins with an egg carrying short hair then a short hair kitten will result which will never have a long hair offspring, since it carries no gene for long hair. A cat cannot pass on a characteristic which it does not possess in its genetic makeup. Bear in mind, however, that a recessive gene can be passed along for many generations and until it meets another recessive like it that characteristic will not show up physically. In order for you to be certain that a particular cat does not carry a particular recessive gene you must mate it to a cat which you know does carry that recessive gene. If, after several litters, that characteristic has not shown up, you can assume that the cat does not carry it.

The kitten pictured in figure 2 is the result of a cross between a Siamese and a Cornish Rex. This kitten carries the gene for the Siamese pattern and a gene for the Rex coat. However, since both of these genes are recessive, neither characteristic is visible. With the proper breeding this kitten will produce both Siamese patterned and Rex coated    kittens.


It was said before that the two chromosomes in a chromosome pair are identical to each other. There is exception to this rule - the chromosome pair which determines the sex of an individual. In this pair there can be different types of chromosomes. One chromosome is normal in appearance and is designated as the X chromosome. The other Is short and crooked and is designated as the Y chromosome. If an individual has two X chromosomes it will be a female. If it has one X and one Y it will be a male. It is obviously impossible for an individual to have two Y chromosomes since one chromosome comes from each parent and the mother can only give an X.

The sex chromosomes carry genes for determining various body characteristics just as the other chromosomes do. However, since the Y chromosome is abnormal in shape, its genes do not completely match those on the X chromosome.

Characteristics which are controlled by genes located on the X and Y chromosomes are called sex linked. In cats, color is sex linked. The gene for red or black pigment is located on the X chromosome and there is no color gene on the Y chromosome. If a cat has one X with the gene for black pigment and one X with the gene for red pigment she will be a tortoiseshell. A special mechanism controls which color each cell will produce when both are present. A male cannot be tortoiseshell because his X chromosome will carry either the red or the black gene, not both, and the other allele is not present on the Y chromosome.

Occasionally a tortoiseshell cat with male characteristics is reported. These cats usually have an extra X chromosome in addition to the usual X and Y. This extra chromosome could carry the other color; it also would almost always make the cat sterile.

Obviously, then, things do sometimes happen with genetics which don't follow the rules. Even though you may know all that is possible about your line, a kitten may suddenly appear with a new characteristic, or with a characteristic in combination with another that has not occurred before. There are a number of causes for this. Sometimes a piece of a chromosome breaks off and is lost or attaches itself to another chromosome. Sometimes there is a mistake when the cell splits and the chromosomes don't all go in the proper place. Sometimes the chemical code in a gene changes spontaneously. This last occurrence is called a mutation and is the most well known of genetic changes. An example of a mutation in cats is the Rex. Mutations are permanent and breed true. Most mutations, however, do not produce results as dramatic as that of the Rex mutation.

It should be kept in mind that a great many characteristics are produced by several genes working together. A blue smoke cat, for example, must have one gene to make black pigment, another gene to change the black pigment to make it appear as blue, and another gene to make the pigment occur only in the upper part of the hair. If any one of these genes is not present the cat will not be a blue smoke.

Genetics is not yet an exact science and there is still much to learn about it, even though geneticists are learning more each day. The areas covered here, however, have been long tested and proven reliable. By studying basic genetics and using it in your breeding program you should be able to develop the characteristic you want in your cats

 

GENETICS GLOSSARY

Allele: One of a series of genes which are alternative to each other because they are situated at the same locus. Each chromosome normally carries only one allele of the series.

Autosome: Any chromosome other than a sex chromosome (X or Y).

Crossing over: The exchange of parts between homologous chromosomes leading to the separation of linked genes. Causes unexpected results in the offspring.

Dominant: Having a visible effect in single dose (i.e. when heterozygous)

Epistatic: A gene is epistatic over another non-allelic gene when it masks its visible effects.

F1: The offspring resulting from crossing members of the parental generation.

F2: The offspring resulting from intercrossing members of the F1 generation.

Feral: Referring especially to wild forms of domesticated species.

Genome: Sets of chromosomes, with respect particularly to genetic information contained therein.

Genotype: The genetic makeup of an organism .

Heterozygous: The two alleles at a particular locus are different.(ex Aa)

Homozygous: The two alleles at a particular locus are the same.(ex. AA)

Linkage: Genes are on the same chromosome and therefore stay together during cell division unless separated by crossing over.

Locus: The place on a particular chromosome where the gene under consideration is located.

Monogenic: Under the control of a single gene.

Phenotype: The appearance of an organism with respect to the characteristics under consideration. Animals of the same phenotype may have different genotypes.

Polygenic: Many genes, each producing a small effect, work together to produce a characteristic.

Recessive: Without a visible effect unless homozygous.

Wild type: The normal form of an organism or gene, typical of the species in the wild. The wild type allele at any locus can be denoted by +.

Zygote: A fertilized egg.



 

Introduction

For our purposes the genes we're interested in can be divided into the following groups:

  • Color Genes: genes that affect the pigment color of hairs.
  • Pattern Genes: genes that affect the distribution of a particular color.

Breed vs Genetic Terminology

Different terms are sometimes used for the same genetic colors, depending on breed and sometimes country too. This can really confuse matters. E.g. a dog that is genetically 'recessive red' (ee) is known as yellow in some breeds. In this article we are going to try to stick to the 'genetic' color descriptions.

Melanin, Agouti, and Red

This is quite a complex topic but its understanding is fundamental to understanding the basic color genetics of the dog. Many of the other genes are simple recessives that have easy-to-understand effects.

Melanin is the substance or pigment that gives a dog's hair its color.

There are two distinct types of melanin in the dog - as in many mammals - eumelanin and phaeomelanin. Eumelanin is, in the absence of other modifying genes (see below), black or dark brown. Phaeomelanin is, in its unmodified form, a yellowish color.

Melanin is produced by cells called melanocytes. These are found in the skin, hair bulbs (from which the hairs grow) and other places.

Melanocytes in the skin are sensitive to UV radiation and normally produce eumelanin. They are responsible e.g. for tanning in humans, and for darker exposed skin e.g. nose leather in furred mammals.

Melanocytes within the hair follicles cause melanin to be added to the hair as it grows. However, melanin is not added at a constant 'rate'. At the very tip of the hair, (eu)melanin production is usually most intense, resulting in the darker tip thats frequently seen.

A protein called the Agouti protein has a major effect on the 'injection' of melanin into the growing hair. This is widespread in many mammals, though not in humans. The Agouti protein causes a banding effect on the hair: it causes a fairly sudden change from the production of eumelanin (black/brown pigment) to phaeomelanin (red/yellow pigment). The result is the agouti appearance as typified by the wild rabbit. The term 'Agouti' actually refers to a South American rodent that exemplifies this type of hair.

NOTE: It is worth mentioning at this point that there remain areas of considerable doubt about the exact genes/alleles that affect certain aspects of coat color in dogs. The main ones surround the proposed 'dominant black' (As) at the top of the Agouti series, and in the E series there are questionmarks over Em (black mask) and Ebr (brindle).

In the past it was thought that with the A and E series, you had:
Agouti Series (A): As, ay, aw, as, at, a
Extension Series (E): Em, E, Ebr, e

But newer research indicates that 'dominant black' As may not belong in the Agouti series at all - and this would be consistent with other mammals that also share the Agouti series, none of which has a dominant phaeomelanin suppressor like As at the top of the series. Research also indicates that brindle (Ebr in the older system) and 'dominant black' form a separate series of at least 3 alleles, which can be called the K series (for blacK); this includes both dominant black and brindle.

We have chosen to adopt this later model.

The Agouti Locus - A

The Agouti locus controls the formation of the Agouti protein, that in turn is one of the mechanisms that controls the replacement of eumelanin with phaeomelanin in the growing hair. The alleles of the Agouti locus can affect not just whether or not the eumelanin->phaeomelanin shift occurs, but also where on the dog's body this happens.

The probable alleles at the Agouti locus, in order of decreasing dominance, are: Ay, aw, as, at and a.

Dominant Black. Dogs certainly do have a dominant form of black that is indeed very dominant: completely obliterating all formation of phaeomelanin pigment. Traditionally, dominant black has been placed at the head of the Agouti series (symbol As). It is now believed to be part of a separate series (the K series - see below) and not at the Agouti locus at all. This is in keeping with the operation of the Agouti locus in all other mammals that have it: increasing dominance of Agouti locus alleles results in increasing production of phaeomelanin without exception. We mention it here simply because it has long been thought, mistakenly, to be part of the Agouti locus.

So at the top of the Agouti series then we have Ay, Sable - also known as 'dominant yellow' or 'golden sable'. This results in an essentially phaeomelanic phenotype, but the hair tips are eumelanin (black). The extent of the eumelanin tip varies considerably from lighter sables (where just the ear tips are black) to darker sables - where much of the body is dark. It is possible that Ay is not completely dominant over the lower Agouti series alleles, with an Ay heterozygote e.g. Ayat having a darker body. AyAy may be called 'clear red' whereas Ayat can be 'sabled red'. Sable is a very common color in many breeds of dog, e.g. German Shepherd.

Next we have aw, 'wolf' color. This is like Ay but the tan is replaced with a pale gray/cream color and the hairs usually have several bands of light and dark color, not just the black tip of sable. Seen in the Keeshond, Siberian and Norwegian Elkhound.

Moving down the series we next come to as, 'saddle tan'. This is somewhat like the black+tan allele (below), except that eumelanin is restricted to the back and side regions, hence the name 'saddle'. It is also possible that this is due to another gene interacting with at/at genotypes.

Allele at, 'black+tan' is next. This is a primarily black dog but with tan (phaeomelanin) markings around the eyes, muzzle, chest, stomach and lower legs. Commonly seen in hounds, Doberman's and Rottweilers.

Finally, at the bottom of the Agouti series is recessive black, symbol a. When a dog is homozygous for recessive black (aa), it will have no phaeomelanin in its coat (unless it is also ee, which is epistatic to the Agouti series - see below). Examples of breeds that exhibit recessive black are German Shepherd and Shetland Sheepdog. Whilst some breeders discount the presence of a recessive black at the bottom of the Agouti series is is consistent with the behaviour of this locus in many other mammals.

The existence of all these alleles in the Agouti series is not certain, nor is the precise order of dominance of the intermediate alleles aw as and at.

The Extension Locus - E

This refers to the extension of eumelanin over the dog's body. The dominant form, E, is known as normal extension. The recessive form, e, is called non-extension. When a dog is homozygous for non-extension (ee), its coat will be entirely phaeomelanin based - i.e. red/yellow. For this reason this is sometimes termed recessive red or recessive yellow, to distinguish it from the sable reds/yellows generated by the Ay allele at the Agouti locus.

The extension locus is shared by many mammals, e.g. horses, and operates in a very similar way to this description. In the past it had been proposed that there were additional alleles present at the E locus for black mask and brindle, but this is not borne out by breeding data.

The (Dominant) Black Locus - K

This relative newcomer to the traditional models of dog color genetics codes for both dominant black and brindle in decreasing order of dominance: K=dominant blacK, kbr=brindle, k='normal'. So a dog that is KK or Kkbr is dominant black, kbrkbr or kbrk is brindled, and kk is 'normal'.

Brindling is the presence of 'stripes' of eumelanin-based hairs in areas that are otherwise phaeomelanin based. When a dog is brindled the color of the eumelanin stripes may be modified by the normal genes that affect eumelanin (B and D, see below).

Dominant black (K) is epistatic to whatever is found at the Agouti locus, however it in turn is overridden by ee at the E locus.

Bringing it Together

It appears that the three loci E, K and A act together as follows:

  1. If a dog is ee at the E locus, its coat will be entirely phaeomelanin based (red/yellow);
  2. Otherwise (it is Ee or EE at the E locus), if it is K- at the K locus its coat will be entirely eumelanin based (dominant black);
  3. Otherwise (it is Ee or EE at the E locus), if it is kbrkbr or kbrk at the K locus it will be brindled with the color of the phaeomelanin part of the brindling in turn affected by the Agouti alleles present;
  4. Otherwise (it is Ee or EE at the E locus, and it is kk at the K locus), the distribution of eumelanin and phaeomelanin will be determined solely by the Agouti alleles present.

With this topic under our belt we can now move on the describing the genes one by one.

Other Genes

Chocolate - B gene

This gene has a lightening effect on eumelanin only. I.e, it has no effect on red-based colors.

In the dog there are two alleles for this gene, with symbols B and b respectively. When B is present (BB or Bb) the brown/black eumelanin is its normal, unlightened, color. But when a dog is bb the brown is lightened to Chocolate.

Blue Dilution - D gene

This recessive gene has a diluting effect on both eumelanin and phaeomelanin. When present in the homozygous recessive form (dd) it dilutes brown eumelanin to blue, and red to cream.

Combinations of B and D in Eumelanistic Coats

The effects of these 2 genes combine to form a range of 4 eumelanistic ('black-based') colors:

Choc Dilute Eumelanistic Color
B- D- Black
B- dd Blue
bb D- Liver/Chocolate
bb dd Faded Liver/Chocolate

Albino - C gene

This gene affects the intensity of melanin production in the coat hairs. The normal or dominant form, C, is what might be termed 'full color'. There are however various incompletely dominant mutant alleles postulated for this locus, with varying effects on color intensity. These mutant forms are temperature sensitive - the higher the temperature, the more effective they are (i.e, the lighter the color).

Almost all dogs are CC at this locus - full color.

The lower series alleles that have been suggested include, in order of decreasing dominance, cch, ce, cb and c.

The first, cch, is chinchilla. This lightens most or all of the phaemelanin with little or no effect on eumelanin. E.g. it turns black+tan to black+silver.

The next allele, ce, is 'extreme dilution'. Causes tan to become almost white. It is thought that the white labrador might be ce with another, lower, C series allele. The ce allele may be responsible for producing white hair in other breeds of dogs, like the West Highland White Terrier, while allowing full expression of dark nose and eye pigment

Moving on down we have cb, or blue-eyed albino. This is an entirely white coat but with a very small amount of residual pigment in the eyes, giving pale blue eyes. This is known as ca in cats. Can be called platinum or silver.

Finally we have c, true pink-eyed albino. This doesn't seem to occur in dogs.

Graying - G gene

This is a dominant mutant gene that causes the dog to gray with age - pigmented hairs are progressively replaced with unpigmented hairs.

Super-Extension - Se

This dominant gene controls the expression of a black mask.

Traditional models of dog color genetics placed black mask in the Extension (E) series. However it seems that a more accurate model is to place it at a separate locus. Alternate literature has used the symbol Ma for this.

Most breeds do not exhibit black mask, and are therefore sese for this locus. Breeds that have black mask (Se-) include the Mastiff, Pug and Belgian sheepdog.

White Spotting - S

The piebalding or 'white spotting' gene is common to many mammals e.g. cats, not just dogs. And, as in cats, it is not really fully understood.

In dogs it is thought there are four alleles, in decreasing order of dominance: S, si, sp and sw. The S series alleles appear to be incompletely dominant, further complicating matters. E.g. Ssw will be similar to sisi in appearance. The degree of white spotting is also affected by modifiers. E.g when merle (M) is also present, the white spotting has a greater effect (more white).

The most dominant allele, S, means 'solid color'. Most dogs that are homozygous for S (i.e. SS) have no white hair at all, or possible a tiny amount e.g. a white tail tip, though this can be considered a fault in breeds that are normally SS.

The next allele, si, mean 'irish spotting'. This involves white spotting on most parts of the coat, but not crossing the back.

Moving on down we next come to sp, 'piebald'. The white is more extensive than irish spotting, and often crosses the back.

The most recessive allele in the series is sw, or 'extreme white piebald'. A dog that is homozygous for sw will be almost entirely white, e.g. the Dalmatian.

Breeds that exhibit white spotting use varying terminology for the differing degrees of white. E.g. in herding dogs the terms 'normal white pattern' (sisi), 'white-factored' (sisw) and 'color headed' (swsw) are seen. In Boxers there is the term 'flashy white' (Ssw - si is not thought to exist in the Boxer). The term 'Mantle' is applied to a Great Dane that is sisw.

Dogs exhibiting extensive white spotting are more likely to suffer from deafness than non-white dogs, e.g. Dalmatians.

Ticked - T

This dominant mutation causes the presence of color in those areas that have been made white by the effect of alleles in the white spotting (S) series. An extreme example of ticking is the Dalmatian.

Merle - M

This is an incomplete dominant that causes 'merling' - patchy dilution e.g. black becoming patched with gray ('blue merled') or sable becoming sable merle. Merling has little or no effect on phaeomelanin. The M allele is not found in all breeds; in fact most don't have it. Examples of breeds that display merling include the Australian Shepherd and Dachshund (where it is called 'dapple'). Merling also affects the eye color.

Most merled dogs are actually the heterozygote, Mm. There is good reason for this; there are serious health problems associated with the homoygote MM, including tiny eyes (microopthalmic) or even entirely missing eyes (anopthamlic). The homozygote is also known as a 'double merle'. They are often predominantly white, hence their alternate name 'defective white'.

When breeding merles, many reputable breeders avoid breeding Mm to Mm; they generally go for Mm X mm and get 50% single merles (Mm) and 50% not.

A Comparison With Cats

It is perhaps interesting to compare dog color/pattern genetics with cat color genetics. For there are many similarities, and yet also some interesting differences.

The most striking difference is that cats do not have the Extension (E) gene. But they do have a fascinating alternative - the so-called Red gene (O). The effect of the O allele is to cause eumelanin to be replaced with phaeomelanin. But what makes O particularly interesting is that it is sex-linked. Males can be O or o, but females can be OO, Oo or oo. And the heterozygote, Oo is also a fascinating case because it is this that causes the Tortoiseshell pattern - where the cat's coat is made up of a patchwork of eumelanistic areas (black based) and phaeomelanistic areas (red based).

Cats also do not seem to have a dominant form of black, nor do they exhibit brindling.

Cats do have the Agouti series - though there is thought to be just 2 alleles present which correspond roughly to Ay and a in the dog.

Eumelanistic colors are affected by blue dilution (D gene) and chocolate (B) just as they are in the dog, but with some additions. The B gene in the cat has a third, more recessive allele, symbol bl, which gives rises to a lighter phase of chocolate (called cinnamon). Secondly, there is a dominant modifier to the blue dilution gene that causes a brownish tinge to cats that are homozygous for blue dilution (dd). Blue dilution has the same effect on phaeomelanin in cats as it does in dogs.

Piebaldism (white spotting) - the S gene - is also present in cats, and as with dogs aspects of the operation of this gene are not understood. It likewise is associated with deafness in cats just as it is in dogs. Cat breeders generally consider there to be 2 alleles (S and s) in the series, with S being incompletely dominant over s.

Merle (M), Graying (G), Ticking (T) and Super-Extension (Se) are not recorded as existing in the cat.

Canine Genetics Software

We provide a free Windows program that simulates the interaction of many of the genes described in this article, and many others not mentioned such as many canine congenital defects where the mode of inheritance is known.


Canine Genetics Software

With this program:

  • You can select from various genetic configurations tailored to any of the major breeds; these differ both in the assumptions that are made for genes you don't explicitly enter (e.g. with the Dalmatian configuration the program will assume swsw and T-) and also in the terminology used to describe given colors.
  • You can enter male and female genotypes and the program will compute the expressed phenotype.
  • You can get it to compute a prediction of the genotypes and phenotypes that would result from a given mating, and the probabilities of each.

To download this software, click here:

Please note, this software may not be distributed to others in any form whatsoever - you must download it from this web page. You may not copy it to any web site, FTP server or any other download service.

If you find this software useful and have a web site, please consider linking to this page using the instructions below.

First dog cloned

[18 August 2005]


South Korean team overcomes challenges of canine cloning to create Snuppy

Move over, Fluffy; cloning isn't just for cats anymore. The South Korean researchers who announced earlier this year that they had successfully derived stem cells from a cloned human embryo have now created the first-ever dog clone, a male Afghan hound, they report in Nature this week.

The puppy–named Snuppy for the researchers' Seoul National University–was born by cesarean section on April 24 to a yellow Labrador surrogate mother and turned 100 days old yesterday (August 2). A second cloned dog lived just 22 days before succumbing to aspiration pneumonia. A postmortem analysis showed no signs of "any congenital defect due to cloning," said Woo Suk Hwang, the leader of the Korean team. A third pregnancy resulted in a miscarriage.

Until now, somatic cell cloning in dogs has been hampered by limited success in maturing canine oocytes in vitro, said Hwang. Such maturation is necessary because unlike those of other domestic animals, canine oocytes aren't mature at ovulation. They're ovulated at prophase of the first meiotic division and undergo maturation in the distal part of the oviduct for at least 48 to 72 hours. The dog's opaque ova also make manipulation difficult.

Hwang attributed his team's success to their ability to produce a nuclear transfer construct using in vivo matured oocytes, to transfer it into a surrogate mother at an early stage of development without in vitro embryo culture, and to optimize the conditions for transfer "through trial and error."

"We were able to determine the exact ovulation and embryo transfer time," Hwang told The Scientist via E-mail. "Through hormonal and cellular analysis of vaginal smears, we made a database for prediction of ovulation time and for estrus synchronization. Thus, our team could obtain a good number of in vivo matured oocytes with good quality and find good surrogate mothers with an appropriate estrous cycle."

Altogether, the researchers collected an average of 12 oocytes from 123 donor females to create nearly 1,500 successfully reconstructed embryos. Of those, 1,095 were transferred back into the same 123 surrogates. The researchers used "naturally collected eggs" rather than the hormone stimulation typical of in vitro fertilization, coauthor Gerald Schatten, of the University of Pittsburgh, noted.

The team chose an Afghan hound because the dog was known to have a "gentle and docile pedigree," Hwang said. They also had access to a good collection of photos of the dog, which had unique fur color and appearance, when it was a puppy, he said, making it easier to distinguish whether the clone was identical. Microsatellite analysis of genomic DNA from the donor, the cloned dogs, and the surrogates confirmed that the clones were genetically identical to the donor.

Other animal cloning researchers hailed the report, but noted the low efficiency of transfer–2 live births out of 123 transfers, or 1.6%–and the greater availability of canine surrogates and ova in South Korea than in the United States.

"The efficiency is still pretty dismal," said Jorge Piedrahita, who studies animal cloning at North Carolina State University. Cattle embryonic transfer efficiency is about 10%, while pig efficiency is as high as 8% to 9%. "The statistic they cite is somewhat misleading," Piedrahita told The Scientist. "It is not 1.6%; it should be 1 out of 1,095. It's an important advance, but I doubt the utility at that efficiency."

Phil Damiani, chief scientific officer of Genetic Savings & Clone, which announced in December 2004 that it made the world's first sale of a cloned cat, said the efficiency was "probably one of the lower ones ever done for cloned animals." The company had hoped to be the first to produce a cloned dog and a few years ago had a clone that nearly came to term, Damiani told The Scientist. The fetus was alive on ultrasound, but stopped breathing by the time it was delivered by cesarean section. The Korean team has "jumped ahead," he said.

Damiani said that his company remained convinced that their technology–which relies on chromatin transfer, rather than nuclear transfer, and egg and embryo assessment prior to cloning and transfer–would eventually make it possible to clone dogs commercially.

The company expects to be able to produce a cloned dog in the next few months, said Genetic Savings & Clone spokesperson Ben Carlson. "People have been asking us, does this mean that tomorrow you'll be able to start offering this service commercially? We wouldn't be able to make a successful business out of using the technique the South Koreans used," Carlson said. The low efficiency rate, combined with stricter animal welfare rules in the United States that limit the number of times eggs can be harvested and that transfers can be made, would make it impossible. But "it certainly validates our contention that dogs can be cloned," he said. "It doesn't mean we're quite there yet."

Schatten, who traveled to Seoul this past weekend, was quick to note that the team does not support the cloning of pets "or any other members of our family. Nuclear transfer should be restricted to medical research," he told The Scientist via E-mail. "This is not to make dogs by this unnatural method, but to advance stem cell science and medicine."




Links within this article


I. Oransky, "The cat's meow," The Scientist, October 25, 2004 (second story).
http://www.the-scientist.com/2004/10/25/12/1


W.S. Hwang et al., "Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst," Science, 303:1669-74, 2004
[Read the abstract on PubMed]


B.C. Lee et al., "Dogs cloned from adult somatic cells," Nature, 436:641 August 4, 2005.
http://www.nature.com


Gerald Schatten
http://www.pdc.magee.edu/faculty/schatten.html


Jorge Piedrahita
http://www.cvm.ncsu.edu/cbs/piedrahita_jorge.htm


Genetic Savings & Clone
http://www.savingsandclone.com/


E.J. Sullivan et al., "Cloned calves from chromatin remodeled in vitro," Biol. Reprod, 70(1):146-53, January 2004. Epub September 17, 2003.
[Read the abstract on PubMed]


I. Oransky, "Cloning for profit," The Scientist, 19:41, January 31, 2005.
http://www.the-scientist.com/2005/1/31/41/1


I. Oransky, "USDA: no pet cloning regulation," The Scientist, July 19, 2005.
http://www.the-scientist.com/news/20050719/02

The canine genome

  1. Elaine A. Ostrander1,3 and
  2. Robert K. Wayne2

+ Author Affiliations

  1. 1Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  2. 2Department of Ecology and Evolutionary Biology, University of California at Los Angeles, Los Angeles, California 90095, USA

Abstract

The dog has emerged as a premier species for the study of morphology, behavior, and disease. The recent availability of a high-quality draft sequence lifts the dog system to a new threshold. We provide a primer to use the dog genome by first focusing on its evolutionary history. We overview the relationship of dogs to wild canids and discuss their origin and domestication. Dogs clearly originated from a substantial number of gray wolves and dog breeds define distinct genetic units that can be divided into at least four hierarchical groupings. We review evidence showing that dogs have high levels of linkage disequilibrium. Consequently, given that dog breeds express specific phenotypic traits and vary in behavior and the incidence of genetic disease, genomic-wide scans for linkage disequilibrium may allow the discovery of genes influencing breed-specific characteristics. Finally, we review studies that have utilized the dog to understand the genetic underpinning of several traits, and we summarize genomic resources that can be used to advance such studies. We suggest that given these resources and the unique characteristics of breeds, that the dog is a uniquely valuable resource for studying the genetic basis of complex traits.

As one of the premier journals in genome biology celebrates its' 10th anniversary, the scientific community studying dogs also enjoys a year of major advances and milestones, particularly with regard to canine genomics and comparative genetics. In July of 2004, the first high-quality draft (7.5×) sequence of the Boxer dog was made publicly available (Lindblad-Toh et al. 2005). This advance followed on the heels of other major milestones in the past several months, including the availability of a 1.5× Poodle sequence (Kirkness et al. 2003), a dense high quality radiation hybrid (RH) map (Breen et al. 2004), a detailed comparative map (Hitte et al. 2005), the localization and cloning of several disease genes, the successful application of dogs for gene therapy studies (Howell et al. 1997; Acland et al. 2001; Mount et al. 2002; Ponder et al. 2002), and new insights into the evolution of dogs and dog breeds (Parker et al. 2004).

As a result, the genome community is well poised to take advantage of the canine system and begin to fulfill some of the expectations advanced nearly 15 yr ago. First, with the development of appropriate molecular resources, the canine system was proposed to hold the power to map and clone disease genes that had proven intractable through studies of human families. Second, the variation in size and skeletal proportions that are segregated into distinct breeds of dog was hypothesized to provide a unique resource for dissecting genetic pathways underlying skeletal development. Finally, the range of behavioral traits that appeared strongly associated with individual breeds suggested a mechanism to decipher the basic genetic vocabulary of behavior (Patterson et al. 1982; Ostrander et al. 1993, 2000; Galibert et al. 1998; Patterson 2000). At the heart of these questions lies a fundamental conundrum. Why has the wolf genome, from which the dog is recently evolved, retained alleles controlling such a large amount of genetic variability, particularly as regards morphology? Is the dog genome somehow unique from other genomes? Or would strong selective pressures applied to any mammalian genome result in a range of species with a level of phenotypic variation that rivals the dog? Research done to date cannot readily answer these questions. However, we are beginning to understand how to localize the genes that regulate morphology (Chase et al. 2002). In so doing, we can begin to understand how genetic variation leads to major phenotypic changes. With the sequencing of the dog genome, it may be within our grasp to localize genes that cause the difference between Giant Mastiffs and Pekingese, Pointer and Terrier, and sight and scent hounds.

In this celebratory review, we first discuss the evolutionary framework and domestication of dogs. We then consider the recent accomplishments of the canine genome community. Finally, we highlight ongoing studies aimed at addressing some of the questions above.

The evolutionary framework

The domestic dog is the most recently evolved species in the dog family Canidae, a group that has a long history spanning the last 50 million years (Myr). This history can be portrayed as a succession of phylogenetic hierarchies defined by DNA sequence information (Fig. 1) and is a necessary structure for understanding molecular data. Of note is that dogs are the earliest divergence in the superfamily Canoidae that includes bears, weasels, skunks, raccoons, and the pinnipeds (seals, sea lions, and walruses) (Fig. 1A). This kinship predicts dogs will share more molecular similarities with these taxa than with cats, mongooses, civets, or hyenas. However, because of the early divergence of dogs from all other carnivores, only slowly evolving regions will show substantial sequence similarities. A second important point is that the 35 species of extant canids are genetically very similar, having radiated from a common ancestor less than about 10 Mya. The recent radiation in a family that otherwise has a long evolutionary history suggests that genetic comparisons among extant canids will highlight rapidly evolving sequences and that they all may share uniquely evolved molecular structures such as SINE elements inherited from their recent common ancestor (Fanning et al. 1988; Kirkness et al. 2003) or rapidly evolving genes such as olfactory receptors, immune related genes, or reproductive proteins (e.g., Clark et al. 2003). In fact, although the dog family has a diverse chromosome complement ranging from 36 to 78 chromosomes, they all can be reconstructed through simple chromosome rearrangement from a common ancestral karyotype (Nash et al. 2001).

Figure 1.

Evolutionary relationships of the dog. (A) The evolutionary relationships of carnivores based on DNA hybridization data. (Wayne et al. 1989). (B) A neighbor-joining tree of canids based on 2001 bp of mitochondrial DNA sequence (cytochrome b, cytochrome c oxidaes I, and cytochrome c oxidase II) (Wayne et al. 1997a). (C) A neighbor-joining tree of wolf (W) and dog (D) haplotypes based on 261 bp of control region I sequences (Vila et al. 1997). Dog haplotypes are grouped in four sequence clades, numbered I to IV.

Within the Canidae, three distinct phylogenetic groupings are apparent (Fig. 1B) (Wayne et al. 1987a,b, 1997b) as follows: (1) the fox-like canids, which include species closely related to the red fox (genus Vulpes), as well as the arctic and fennec fox (genus Alopex and Fennecus, respectively); (2) the wolf-like canids including dog, wolf, coyote, Ethiopian wolf or Simien jackal, and three other species of jackals (genus Canis), as well as the African hunting dog (genus Lycaon) and the dhole (genus Cuon); and (3) the South American canids including fox-sized canids such as the pampus fox, crab-eating fox, and small-eared dog (genus Pseudolopex, Lycolopex, Atelocynus) and the maned wolf (genus Chrysocyon) and bushdog (genus Speothos). Additionally, there are several canids that have no close living relatives and define distinct evolutionary lineages such as the gray fox (genus Urocyon), the bat-eared fox (genus Otocyon), and the raccoon dog (genus Nyctereutes).

These phylogenetic relationships imply that the dog has several close relatives within its genus, in fact, all members of Canis can produce fertile hybrids and several species may have genomes that reflect hybridization in the wild (Wayne and Jenks 1991; Gottelli et al. 1994; Roy et al. 1996; Wilson et al. 2000; Adams et al. 2003). Furthermore, the wolf-like canids are grouped more closely with the South American canids and the red and gray fox are very distinct groups whose common ancestry with dogs extends to the beginning of the modern radiation. Consequently, molecular tools developed from the dog genome sequencing project are likely to be most applicable to the wolf-like canids. For instance, fewer than half of microsatellite primers developed in the dog amplify DNA in the gray fox (Goldstein et al. 1999).

The domestication of the dog

The essential questions about dog domestication concern the species from which the dog originated and the location, number, and timing of domestication or interbreeding events. Molecular data has shed some light on all of these questions. First, with regard to species origins, Charles Darwin and others such as Konard Lorenz, the renowned behavioral biologist, speculated that given the great diversity in form and behavior of dogs, they might share ancestry with wolves and other canids, such as any one of the three species of jackals. However, extensive genetic analyses of the dog and other wolf-like canids clearly show that the dog is derived from gray wolves only, rather than jackals, coyotes, or Ethiopian wolves (Fig. 1C; Wayne et al. 1987a,b; Vila et al. 1997, 2005; Leonard et al. 2002; Savolainen et al. 2002). Consequently, the immense phenotypic diversity in the dog owes its origin to primarily the standing genetic variation existing in the ancestral population of gray wolves and any subsequent mutations that occurred during the brief history of domestication. At least for structural genes, such mutations are expected to be few since their mutation rate is so low, on the order of 10-5 mutations per gene per generation (Hartl and Clark 1997).

Mitochondrial DNA (mtDNA) sequence analysis has shed some light on the location of dog domestication as well as the number of founding matralines. MtDNA analysis offers a unique perspective on evolutionary history because the mitochondrial genome is maternally inherited, and hence, only females leave a genetic legacy. Moreover, because the mitochondrial genome does not recombine, phylogenetic analysis of mtDNA sequence data defines a uniquely bifurcating haplotype tree (Fig. 1A,B,C). Phylogenetic analysis of dog and gray wolf mitochondrial sequences clearly show that dog sequences are found in at least four distinct clades, implying a single origination event and at least three other origination or interbreeding events. The latter are difficult to distinguish once the first domestication had occurred, although extensive marker analysis of the nuclear genome might be able to discriminate the two alternatives. A striking finding of the mtDNA analysis is that one sequence clade (clade I, Fig. 1C) contains the majority of dog sequences and that the nucleotide diversity of this clade is high, implying an origin of the clade from 40 to 135 thousand years ago (Vila et al. 1997; Savolainen et al. 2002). This date exceeds the 15,000-yr-old archeological record of dogs and suggests that dogs may have had a long prehistory when they were not phenotypically distinct from wolf progenitors. These early dogs may not have been recognized as domesticated by study of the archeological record before 15,000 yr ago because of their physical similarity to gray wolves. The initial change to the diagnostic phenotype of domestic dogs beginning about 15,000 yr ago may have instead indicated a change in the selection pressures associated with the transition from hunter gatherer to more sedentary lifestyles (Wayne et al. 2006).

Conceivably, a more recent date can be made consistent with the archeological record if it is assumed that dogs were founded from multiple matralines in clade one (Savolainen et al. 2002). To determine whether such a diverse founding is likely, analysis of nuclear genes sequence data is needed (e.g., Parker et al. 2004). In fact, recent analysis of major histocompatability (MHC) genes in dogs and wolves suggest that the origin of dogs involved several populations and hundreds of individuals (Vila et al. 2005). Consequently, the model emerging from mitochondrial DNA, MHC analysis, and microsatellite loci is that the dogs had a diverse origin in East Asia that likely involved multiple contributions from several populations, and thereafter, there may have been other origins of domestication and backcrossing (Vila et al. 1997, 2005; Leonard et al. 2002; Savolainen et al. 2002; Parker et al. 2004). A multiple and diverse origin model describes domestication in other domestic animals such as cattle, sheep, and goats (Bruford et al. 2003). Furthermore, once domesticated, dogs rapidly spread around the earth and as a result, genetically divergent populations and breeds are found in Africa, Asia, the Arctic, Australia, the Middle East, and historically, the New World (Leonard et al. 2002; Parker et al. 2004; Savolainen et al. 2004).

Breed diversity and genetic structure

The explosion of dog breeds over the past two centuries represents perhaps one of the greatest genetic experiments ever conducted by humans. Distilled from the genome of the wild wolf are animals that differ by more than 40-fold in size with the ability to herd, guard, hunt, and guide (American Kennel Club 1998). Behavioral variation is surpassed by morphologic variation, with individual breeds represented by dogs of every imaginable size and proportion. Coats alone can be described by color, texture, length, thickness, and curl. Tails can be described as plumed, curled, double curled, gay (upright), sickled (arching), otter (down and flat), whipped, ringed, screwed, or snapped (American Kennel Club 1998). The diversity in skeletal size and proportion of dogs is greater than any mammalian species and even exceeds that of the entire canid family (Wayne 1986a,1986c). Such variation may reflect simple modifications of post-natal development (Wayne 1986a,1986c), but the specific genetic mechanisms are not well known (see below).

Much of the morphologic variation in dogs is partitioned into over 350 distinct breeds worldwide as a result of the development of breed standards and controlled breeding. In general, in order to register a dog in the American Kennel Club at least both parents must have been registered in the same breed. Consequently, purebred dogs are members of closed breeding populations, which receive little genetic variation beyond that existing in the original founders (Ostrander and Giniger 1997; Galibert et al. 1998; Ostrander et al. 2000; Sutter and Ostrander 2004).

Common to the origin and development of many breeds is a founder event involving only a few dogs and, thereafter, reproductive dominance by popular sires that conform most closely to the breed standard. These restrictive breeding practices reduce effective population size and increase genetic drift, resulting in the loss of genetic diversity within breeds and allele frequency divergence among them. For example, in a genetic study of 85 breeds, Parker et al. (2004) showed that humans and dogs have similar levels of overall nucleotide diversity, 8 × 10-4, which represent the overall number of nucleotide substitutions per base/pair. However, the variation between dog breeds is much greater than the variation between human populations (27.5% versus 5.4%). Conversely, the degree of genetic homogeneity is much greater within individual dog breeds than within distinct human populations (94.6% versus 72.5%). Furthermore, in some breeds, genetic variation has been additionally reduced by bottlenecks associated with catastrophic events such as war and economic depression, making them analogous to human populations of limited genetic variation used for disease-mapping studies such as the Finns, Icelanders, and Bedouins. As a result, the unique pattern of LD in dogs provides an exceptional opportunity to study complex traits that are relevant to human biology using robust approaches that would not be possible in human populations.

Because many breeds represent closed gene pools, they may define distinct genetic clusters. Analysis of microsatellie loci have strongly supported this notion (Koskinen 2003). For example, in the Parker et al. (2004) study, 96 microsatellite markers were genotyped that spanned all dog autosomes at approximately a 30-Mb resolution (Parker et al. 2004). Excluding data from the highly related Belgian Sheepdog and Belgian Tervuren breeds, they observed that 99% of 414 dogs were correctly assigned to breed. Consequently, a “breed” can be defined at the molecular level and dogs can be correctly assigned to their breed with small amounts of data. These results strongly imply that breeds are distinct genetic units and even closely related breeds do not represent genetic replicates.

Breed origin and relationship

Mitochondrial DNA studies have not been useful for the reconstruction of breed origins or relationships because the origin of the vast majority of sequence polymorphisms found in dogs preceded the development of modern breeds. Therefore, phylogenetic hierarchies based on DNA sequences reveal the history of mutations that occurred before dogs were domesticated (e.g., Fig. 1C). However, many breeds contain several mitochondrial DNA haplotypes, suggesting that multiple matralines were involved in the founding of a dog breed. To assess the recent evolution and relationships of breeds, microsatellite loci provide a better tool, as their high variability insures allele frequency divergence through drift. Genetic distance trees based on the microsatellite dataset from Parker et al. (2004) revealed several distinct breed clusters. The most divergent grouping presumably contained the most ancient breeds, but none of these nine ancient breeds were of European origin. The ancient breeds included dogs from a wide geographic area including the Arctic, Asia, Africa, and the Middle East. By comparison, the majority of breeds, including European breeds, appeared to stem from a single node without significant phylogenetic structure, which has been termed a “hedge,” indicating a recent origin and extensive hybridization between the breeds (Parker et al. 2004; Fig. 2). The focus on breeds belonging to this hedge in past studies probably explains the observed lack of phylogenetic resolution (Zajc et al. 1997; Koskinen and Bredbacka 2000; Irion et al. 2003).

Figure 2.

Structure analysis of 85 dog breeds. Cluster results from a structure analysis of 414 dogs from 69 breeds and based on 96 microsatellite markers. Each breed was usually represented by five dogs, and all dogs were unrelated to one another at the grandparent level. Structure implements a Bayesian model-based clustering algorithm that attempts to identify genetically distinct subpopulations based on patterns of allele frequencies (Pritchard et al. 2000). Each genotyped dog is represented by a single vertical line divided into K colors, where K is the number of clusters assumed in each structure analysis. The length of the colored segment represents the individual's estimated proportion of membership in that cluster (Parker et al. 2004). At K = 4, four clusters are clearly defined representing genetically distinct breed grouping within the domestic dog (see text).

This evolutionary hierarchy suggests breeds should cluster genetically into groups sharing recent common ancestry. A genetic clustering algorithm, deployed in the computer program “structure” was used to explore the possible groupings within dogs (Pritchard et al. 2000). Structure assigned 335 dogs correctly to 69 unique breed specific clusters that represented either single breeds or sets of very closely related breeds. However, the program could not easily distinguish a half-dozen obviously related pairs such as the Bernese Mountain Dog and Greater Swiss Mountain Dog or Mastiff and Bullmastiff. This lack of resolution in these few breeds is predicted based on breed history. For instance, the Bullmastiff is reported to be 60% Mastiff and 40% Bulldog and was created by crossing the two breeds in the mid-1800s (Rogers and Brace 1995).

Individual breeds represented the smallest definable cluster; however, higher order clusters are expected given the origins of many dogs breeds. Consequently, the number of groups (K) was set to two, three, and finally, four. The first distinct cluster to be defined at K = 2 included nearly all breeds of Asian origin (Akita, Shiba Inu, Shar Pei, Lhasa Apso, etc.), some sled dogs, and some known ancient hounds such as the Saluki (Fig. 2). When added to the analysis, gray wolves from eight countries all grouped in the first cluster as well. The early divergence of the Asian breeds on the phylogenetic tree and their association with the wolves in clustering analysis (Fig. 2) supports the conclusions of mitochondrial DNA analysis that domestication first took place in East Asia (Savolainen et al. 2002). The next cluster to be defined at K = 3 was comprised of mastiff-type dogs including the Mastiff, Bull-mastiff, Bulldog, Boxer, etc. Finally, at K = 4, the third cluster to be defined included working dogs such as the Collie and Shetland Sheepdog, together with a subset of the sight hounds, such as the Greyhound. The final cluster comprised mostly modern breeds used in hunting and included gun dogs, hounds, and terriers. On-going analysis is focusing on defining clusters within this hedge group, using more highly mutable tetranucleotide-based microsatellite markers (Francisco et al. 1996) and less mutable markers based on single nucleotide polymorphisms (SNPs). However, the structure analysis for the first time defined groups based on common ancestry and genetic similarity rather than function (e.g., hunting or herding breeds) and provides a genetic guide to the design of whole-genomic scans (see below).

Another promising approach toward reconstructing breed history utilizes single gene histories. For example, study of the multidrug resistance gene (MDR1) and four closely linked microsatellite markers was used to reconstruct the history of a group of related breeds (Neff et al. 2004). A single MDR1 mutation was found to segregate in nine breeds that included seven herding breeds and two sight hound subgroups, which were likely related to at least one of the herding breeds. Haplotype analysis confirmed this relationship by revealing that the region around MDR1 was identical by descent in all nine breeds, suggesting that they inherited this haplotype from an exclusive common ancestor. Additional study of single gene mutations in dogs will help dissect the branching structure of “twigs” in the phylogenetic tree of dogs.

Mapping and sequencing the dog genome

The success of disease-mapping studies and those unraveling the mysteries of canine evolution were clearly dependent on the prior development of key resources. Meiotic linkage maps and RH maps based on family studies (Mellersh et al. 1997) and a 5000 rad panel (Vignaux et al. 1999) were first made available in the late 1990s and were essential to subsequent map-building efforts (Mellersh et al. 1997, 2000; Priat et al. 1998; Neff et al. 1999). The first comparative maps and later dense RH maps that followed allowed researchers to take full advantage of the much more well-developed human and mouse genome mapping resources (Breen et al. 2001; Guyon et al. 2003, 2004). A recent integrated RH map of the dog, including microsatellites, genes, and BAC ends (Breen et al. 2004), has proven invaluable in allowing investigators to do positional cloning experiments following initial findings of linkage. Most recent mapping efforts focused on developing a high-resolution 9000 rad comparative map (Hitte et al. 2004), which includes 10,348 canine markers, 9850 corresponding to canine orthologs of human genes derived from a 1.5× poodle shotgun sequence (Kirkness et al. 2003). For online information, see http://sun-recomgen.med.univ-rennes1.fr/Dogs/ and http://research.nhgri.nih.gov/dog_genome/.

Very recently, the landscape for canine genome studies has been changed by the availability of a 7.5× assembled sequence of the Boxer genome (http://www.genome.ucsc.edu), completed by investigators at the Broad Institute (CanFam1.0 and CanFam2.0) (Lindblad-Toh et al. 2005). These data suggest that the euchromatic portion of the dog genome is ∼18% smaller than the human genome and 6% smaller than the mouse genome. The size difference is explained by a lower rate of repeat insertions in the dog genome relative to both human and mouse, while the deletion rate of ancestral bases has been approximately equal between the dog and human lineages. The relatively low level of recent repeats in the dog genome contributes, together with high quality data and improved assembly algorithms, to the high connectivity and quality of the dog genome assembly. This is well supported by the above-mentioned RH gene map of the dog, which shows high concordance with the assembled sequence as well as a set of several hundred BAC ends previously localized by FISH (Hitte et al. 2005).

The assembled sequence demonstrates that ∼94% of the dog genome is contained in clear segments of conserved synteny relative to the human and mouse genomes. The gene count of ∼19,000 canine genes is slightly lower than that currently considered for human, which is somewhat surprising. The accuracy of these data, however, is high; of the 19,000 reported canine genes, 14,200 represent 1-1-1 orthologs between dog, human, and mouse. Approximately 5.4% of the orthologous nucleotides between human and dog appears to be under purifying selection. The purifying selection acting on conserved orthologous genes appears significantly higher in the lineage leading to dog than in that leading to human, but lower than in the lineage leading to mouse. However, the relative constraints between orthologs with different functions have been highly correlated between the three lineages. Only genes involved in nervous system function have diverged faster in both dog and human relative to mouse, but not relative to each other, consistent with similar selection pressures, and possibly, convergent evolution. Finally, gene family expansions are less common in dog than in human, suggesting that the dog has the most primitive gene content of the currently sequenced placental mammals.

Linkage disequilibrium across and between dog breeds

To fully exploit the unique genetic characteristics of the dog, the architecture of linkage disequilibrium (LD) in the canine genome needs to be understood. This knowledge would facilitate the mapping and cloning of genes important to canine health, as well as the discovery of loci regulating phenotypic traits. The importance of this knowledge is demonstrated in human studies where LD mapping in well-defined populations has simplified locus heterogeneity problems associated with complex traits (Kruglyak 1999a; Sundin et al. 2000; Ophoff et al. 2002; Friedrichsen et al. 2004). Three fundamental questions have been addressed. First, how does the extent of LD compare to that which has been reported in humans? Second, how does LD differ between breeds, and finally, how well does breed history predict the extent of LD?

These issues have been addressed in two major studies (Sutter et al. 2004; Wade et al. 2005). Sutter et al. (2004) examined 189 SNPs from five unlinked loci in five breeds using 20 unrelated dogs from each breed (Fig. 3). They found that in the Golden Retriever, LD falls to half of its maximum value at about 0.48 Mb. However, in the other breeds, LD is more extensive, increasing to about 0.9 in the Pekingese and Labrador Retriever and to 2.2 Mb in the Bernese Mountain Dog. Finally, at 3.8 Mb, LD in the Akita is nearly 10× greater than that observed in the Golden Retriever. In some cases, these observations agree well with recorded breed history (Fogel 1995; Wilcox and Walkowicz 1995; American Kennel Club 1998;). For instance, the Golden and Labrador Retriever are among the most popular breeds and neither breed has experienced significant population bottlenecks (Fogel 1995; Wilcox and Walkowicz 1995). By comparison, LD is expected to be greater in the Pekingese, as these dogs are derived from a small number of founders that came to the U.S. from China (Fogel 1995; Wilcox and Walkowicz 1995). LD is predicted to be most extreme in the Akita, a relatively rare breed with a restricted gene pool.

Figure 3.

LD in five breeds of dog. LD in 20 unrelated dogs from each of the five breeds scanned for a total of 51 Kb in five unlinked regions on chromosomes 1, 2, 3, 34, and 37. The scan revealed 189 SNPs and those with a minor allele frequency greater then 0.2 in each breed were used on LD calculations. Data were averaged across the five sites and the D' statistic used to indicate the level of linkage disequilibrium. D'0.5 indicates the point at which the D' statistic decays by 50%. Data are given in Mb for dog and Kb for human.

These results suggest two important considerations for the design of mapping and cloning studies. First, as there is at least a 10-fold difference in the extent of LD between dog breeds, breed selection deserves careful consideration. Second, LD in dogs is 20–50 times more extensive than that found in humans, where LD is typically reported to be about 0.28 Mb (Reich et al. 2001; Weiss and Clark 2002). More than 500,000 SNPs must be genotyped for whole-genome association studies in humans (Kruglyak 1999b; The International HapMap Consortium 2003). In contrast, only about 10,000 SNPs are hypothesized to be needed for the comparable dog study (Sutter et al. 2004). Thus, the mapping of common and complex diseases such as epilepsy, cancer, autoimmune disease, deafness, and heart disease in dogs may be more economical than similar efforts in humans.

The canine genome sequencing effort has made 2.1 million SNPs publicly available (http://www.broad.mit.edu/mammals/dog/snp/) (Lindblad-Toh et al. 2005) To determine how to best use this resource, Sutter et al. (2004) examined the extent of haplotype sharing for the five breeds described above. For any one breed, 80% of chromosomes examined had, on average, just 2.7 haplotypes. For all 100 dogs examined, 80% of chromosomes carried just 4.5 haplotypes. The overall degree of haplotype sharing, measured as the proportion of a breed's chromosomes carrying haplotypes shared with another breed, ranged from 46% to 84%. These findings of low haplotype diversity and high haplotype sharing, albeit with great variability, suggest that a universal SNP set of modest size will be sufficient to successfully accomplish whole-genome association studies in most breeds.

A more in-depth analysis of the same general questions, as well as issues regarding the overall haplotype structure of the dog were examined using ∼1300 SNPs plus resequencing data drawn from 10 random regions covering 6% of the genome. The study was undertaken as part of the canine genome sequencing effort (Lindblad-Toh et al. 2005) and the conclusions largely agree with those of Sutter et al. (2004). In addition to the 7.5× Boxer sequence, the genome sequencing effort generated 100,000 sequence reads from each of nine diverse breeds representing all seven AKC groups, and 20,000 reads from each of five wild canids (four wolves and one coyote). The resulting SNP frequencies of 1/900 bp between breeds, 1/580 bp between dogs and wolves, and 1/420 bp between dogs and coyote, emphasizes that all three species are more closely related than human and chimpanzee. The resulting set of 2.1 million SNPs have a polymorphism rate across breeds of ∼72% within any given breed, suggesting that most SNPs discovered as part of the sequencing effort will be useful for mapping in any breed.

Comparison of the two boxer haplotypes, as well as extensive resequencing and genotyping in 10 breeds by the sequencing group has been illustrative for understanding the detailed haplotype structure of the dog. Such analyses demonstrate megabase sized portions of the genome that are alternatively homozygous and heterozygous exist both for the sequenced boxer, as well as for 24 dogs from different breeds and 20 dogs from each of 10 breeds. Thus, megabase-sized haplotypes will be common within virtually any purebred dog.

Lindblad-Toh and collaborators conclude that LD within any breed is actually dependent on the intensity and duration of two bottlenecks. The first is an ancient bottleneck occurring at the time of canine domestication that is common to all dogs. The second likely occurred during breed formation. In combination, these bottlenecks resulted in LD that extends for megabases in most breeds and limited haplotype diversity. Indeed, across the dog population as a whole, ancestral haplotype blocks are roughly 5–10 kb long with approximately five alleles in each block. Thus, when LD is examined carefully across many breeds, typically, five haplotypes are observed across each 10–500-kb window, with one or two being common and the rest rare. The recent ancestry of these haplotypes supports the idea that a modest number of SNPs, perhaps as few as 5000, will be sufficient for genome-wide association mapping. However, the underlying ancestral haplotype block structure implies that the false-positive rate will be high if only single SNP association is used. Consequently, haplotype-based association should be used instead for most mapping studies.

Canine disease gene mapping

Billions of dollars are spent on canine health in the United States each year (Association 2002) and much of it is focused on a limited number of diseases including cancer, epilepsy, blindness, cataracts, autoimmune disease, and heart disease. Over 360 genetic disorders found in humans have also been described in the dog (Patterson 2000; Sargan 2004), and about 46% of these genetic diseases occur predominantly or exclusively in one or a few breeds. A detailed listing of over 1000 canine diseases, and descriptions of each, appears in the database of inherited diseases in dogs (IDID, http://www.vet.cam.ac.uk/idid) (Sargan 2004).

To date, the location of many canine disease loci has been determined, and in some cases the underlying gene has been cloned (for review, see Patterson et al. 1982; Ostrander and Giniger 1997; Galibert et al. 1998; Ostrander et al. 2000; Sutter and Ostrander 2004; Switonski et al. 2004).

In some cases, identification of canine disease genes has opened new avenues of research for human biologists. For instance, the identification of a mutation in the hypocretin 2 receptor gene (Lin et al. 1999) in Doberman Pinschers with inherited narcolepsy has proven key to understanding the molecular mechanisms which regulate sleep (Nishino et al. 2000; Thannickal et al. 2000). In humans, the disease is associated with a progressive loss of hypocretin-expressing neurons and is a non-Mendelian trait mediated by a unique mechanism different from that causing the disease in Dobermans. However, study of the simpler etiology in dogs provided the requisite tools for understanding the more complex disease in humans.

In other cases, study of canine disease genes has increased our understanding of the interaction between genes and how such interactions affect disease. Such interactions have proven difficult to study in human populations, where the size of even the largest case-control studies is simply too small to identify anything but major effects. The identification of the MURR1 gene associated with copper toxicosis in Bedlington Terriers (van De Sluis et al. 2002) provides an excellent example. Contrary to expectation, this disease did not map to the portion of the canine genome analogous to the Wilson's disease locus in humans (Yuzbasiyan-Gurkan et al. 1997; van de Sluis et al. 1999). Analysis of the human homolog of MURR1 in Wilson's disease patients has subsequently proven provocative, as those who carry particular sequence variants appear to present with earlier onset disease (Stuehler et al. 2004), suggesting that the two genes or their products interact to accelerate disease.

Another significant advance concerns the identification of novel disease mechanisms through the study of dog genetics. Lohi et al. (2005) recently identified a gene for progressive myoclonic epilepsy (PME) in a population of purebred miniature wirehaired dachshunds. About 5% of the breed suffers from this autosomal recessive disease, which was shown to be analogous to the human disorder, Lafora disease. As in the human disease, affected individuals carry mutations in the NHLRC1 gene. However, in contrast to the human disease, the disease in dogs is due exclusively to bi-allelic expansion of a dodecamer repeat found within the 5′ end of the genes' single large exon. Affected individuals carry 19 to 26 copies of the repeat sequence rather than the expected two copies. This is the first example of a dodecamer repeat expansion associated with disease in any mammalian system and suggests a potential novel mechanism for human disorders.

Currently, perhaps the greatest concentrated collaborative efforts are focused on the study of canine cancer (Chun and de Lorimier 2003; Ettinger 2003; Fan 2003; London and Seguin 2003; Porrello et al. 2004; Modiano et al. 2005). Dogs develop cancer about twice as frequently as humans and the disease presentation and pathology of canine cancers is similar to analogous human tumors. Genetic studies are ongoing to find susceptibility genes for canine osteosarcoma, lymphoma, mast cell tumors, malignant histiocytosis, and kidney cancer, and a BAC CGH array resource is in development to better understand somatic events leading to tumor growth and metastasis (Thomas et al. 2003a,b). Of primary interest is determining whether different types of tumors have unique or shared origins. If a common origin of a particular canine cancer is established, then considering data from several breeds simultaneously can facilitate the localization of the susceptibility gene. Breeds of similar appearance and sharing common ancestry as suggested by historical record may often share variants for disease phenotypes (e.g., Neff et al. 2004). However, in most cases, rigorous studies such as those described below are needed to address the issue.

Genetics of morphology

The genetic basis for differences in size and proportion among dogs has yet to be revealed. However, both candidate gene and association studies are beginning to provide insight into the complexity underlying morphological differentiation. For example, two potential candidate genes, MSX2 and TCOF1, which are expressed during cranial facial development, were sequenced in 10 different dog breeds that varied in cranial and face shape (Haworth et al. 2001a,b). However, only a single amino acid change in the TCOF1 protein showed an association with short and broad skulls. Nonetheless, greatly expanded surveys of candidate genes may prove more fruitful; for example, variation in the production of insulin-like growth factor 1 (IGF-1) was shown to correlate with differences in the body size of poodles, suggesting it may be a candidate gene for size variation in dogs (Eigenmann et al. 1984).

More definitive associations have been demonstrated through quantitative analysis of morphologic measurements combined with genome marker scans. For example, Chase et al. (2002) analyzed data from nearly 700 Portuguese Water Dogs genotyped with ∼500 markers and http://www.georgieproject.com/. For 460 dogs, they recorded 91 measurements from a set of five x-rays taken on each dog. The data were analyzed using principal component analysis, which defines independent component axes based on linear combinations of variables. Each axis is ordered by a decreasing fraction of the total variation in the data set. The first four axes explained 61% of the variation in the data set and represented different components of size and shape. For example, the first principal component axis reflected overall size variation of the skeleton, whereas the second reflected the relationship between the pelvis, head, and neck, such that the size and strength of the pelvis and head–neck musculoskeletal systems are inversely related. Quantitative Trait Loci (QTLs) have been localized that are related to variation on each of the above four principal components. Moreover, using a data set of 286 phenotyped dogs, Chase et al. (2004) defined two loci on chromosome one spaced 95 Mb apart that appear to account for a modest percentage of hip dysplasia, as defined by Norberg angle in the Portuguese Water Dog.

Nonclassical genetic variation may also be an important source of phenotypic variation in dogs. Fondon III and Garner (2004) suggested that highly mutable simple tandem repeats imbedded in genes may be the source of new variation in recent developed lines and may explain their high rate of morphologic change. To test this hypothesis, these investigators analyzed three-dimensional models of dog skulls from 20 breeds and seven mongrels. In representatives of 92 different breeds, they also sequenced 37 repeat-containing regions from 17 genes known or thought to be involved in craniofacial development. In general, they found that dogs had more perfect repeats than humans and may be changing faster in length. Additionally, they found that the size and the ratio of lengths of two tandem repeats in the Runx-2 gene correlated with the degree of dorsoventral nose bend (clinorhynchy) and mid-face length in a variety of breeds. Although this evidence is suggestive, clearly more detailed studies are needed associating repeat change with specific phenotypic traits (Pennisi 2000). If such genetic mechanisms are unique to the dog, they may explain, in part, the apparent phenotypic plasticity of dogs. However, dogs also have a unique skeletal development whose alterations may more readily result in novel phenotypes (Wayne 1986a,b,c; Morey 1992, 1994).

One area of morphology we do not discuss in detail is that of canine coat color, which has been written about extensively in the past. More recently, progress on dissecting coat color genetics in the dog has been done by two groups (Kerns et al. 2003; Berryere et al. 2005). Particular progress has been made in understanding the interactions between the Agouti protein and the Melanocortin 1 receptor, which control the type of pigment synthesized in mammalian hair (Berryere et al. 2005). Additional recent work has focused on black color in dogs, which appears to be independent of the above interactions (Schmutz et al. 2002; Kerns et al. 2003). Very interesting work that is just beginning focuses on the role of polymorphisms in coat color affecting genes, such as the melanophilin gene (Philipp et al. 2005). With the availability of the canine genome sequence, this is an area that will surely expand in the coming years.

Genetics of behavior

Dog breeds have distinct behaviors, and dogs as a whole have unique behaviors not found in gray wolves (Hare et al. 2002). However, the genetic basis of behavior is less well understood than morphology. In general, the greatest need remains the development of assays to reproducibly score specific behaviors. However, some understanding is likely to come from the study of pedigrees of dogs displaying aberrant behaviors. For example, Moon-Fanelli et al. (1998) have characterized pedigrees of Bull Terriers displaying obsessive compulsive disease (OCD) phenotypes, such as tail chasing, which in other respects is similar to human OCD. As genome scans of affected pedigrees are completed, they may shed light on both the human and canine disease conditions.

Expression patterns may also provide clues to the genetic basis of behavior. Saetre et al. (2004) surveyed the expression pattern of 7762 genes in three different regions in the brains of domestic dogs and in gray wolves and coyotes. They found that the pattern of gene expression in the hypothalamus of domestic dogs was different from that in gray wolves and coyotes, whereas patterns of gene expression in the amygdala and frontal cortex were less differentiated. The hypothalamus controls specific emotional, endocrinological, and autonomic responses of dogs and is highly conserved throughout mammals. The results of Saetre et al. (2004) suggest that behavioral selection in dogs may have affected this central part of the brain, initiating a cascade of effects that result in some of the unique behaviors found in dogs.

Conclusions

The domestic dog has long fascinated evolutionary biologists and geneticists because of the extreme phenotypic diversity exhibited by the species and the short time frame over which this diversity has evolved. Molecular genetic evidence suggests that dogs are indeed the oldest domesticated species and their origin may have even well preceded their first appearance in the archeological record about 15,000 yr ago. The dog has a diverse genetic origin that likely involved multiple gray wolf populations and subsequently was enriched by backcrossing with wolves throughout their history. This substantial input of variation from wild ancestors has provided the raw material for phenotypic change, but unique development and genetic mechanisms may also have assisted the course of artificial selection. Dogs clearly have behaviors, phenotypes, and diseases that are not evident in their wild progenitors. Finally, in the more recent evolution of dog breeds, limited interbreeding has imposed a remarkable genetic structure such that nearly all breeds represent distinct genetic pools that can be divided into at least four distinct genetic groupings.

Understanding the genetic mechanisms that have given rise to the unique attributes of domestic dogs may finally be within reach. A complete and a partial genome sequence are available from a boxer and a poodle, respectively, and mapping resources are well developed and increasing in sophistication. The dog genome in general has high levels of LD, such that whole-genome association studies will be facilitated and genomic scans of specific breeds segregating traits of interest may readily be found through patterns of LD or reductions in heterozygosity due to selective sweeps (Weiss and Clark 2002; Bamshad and Wooding 2003; Luikart et al. 2003; Pollinger et al. 2005). In this review, we have provided the evolutionary and empirical framework for understanding the molecular diversity of dogs with the aim of taking the first step toward answering the questions posed in the introduction. The primary intent of this article was to help generate the enthusiasm that will lead to realizing the promise of the dog genome for solving significant problems in evolution, genetics, and human health.

Acknowledgments

We thank two anonymous reviewers, Kerstin Lindblad-Toh, Heidi Parker, Nate Sutter, Ed Giniger, and Francis Galibert for thoughtful comments and helpful suggestions on this manuscript. We also thank Kerstin Lindblad-Toh for sharing data in advance of publication. Finally, we thank the many colleagues, dog owners, and breeders who have generously shared samples and made much of the work reviewed here possible.

http://www.cvm.missouri.edu/demo/K9genomics/player.html
A Glossary Of Genetic terms......
 
Autosomal
Phenotypic trait or gene NOT associated with either the X or Y sex chromosome; i.e., not sex-linked.

Congenital
Existing at or before birth resulting from hereditary or environmental influences.

Genome
Complete set of chromosomes carried in a cell.

Gibbs sampling
Method of calculating the genetic merit of dogs that takes advantage of fast computers. The process itself is just a computer-based method for integrating a function without having to find the antiderivative.
 
Idiopathic
Arising spontaneously with no obvious external cause (e.g., genetic as opposed to trauma-induced).
 
Locus (plural - loci)
Site or position on a chromosome where a particular gene or DNA sequence resides. Often used interchangeably with the term 'gene', but locus is more generic.
 
Microsatellite
As used here, a region of the DNA that can be consistently identified, using a laboratory procedure, across all individuals in a single breed. Microsatellites themselves are repetitive DNA sequences that are randomly distributed throughout the mammalian genome, tend to be highly polymorphic, and are short DNA segments.
 
Polygenic
Phenotypic trait whose expression is controlled by, or associated with, more than one gene.
 
Polymorphic
Presence of several common, alternate forms of a genetic characteristic in a population.
 
Recessive
Trait that requires two mutant copies of the gene (i.e., alleles) in order for the disorder to be expressed; must be homozygous for the mutant allele.

Participating Studies needing samples............
 
Research Area: Black Hair Folllicular Dysplasia/Color Dilution Alopecia
Breeds: All Breeds

Researchers at the University of Saskatchewan are seeking cheek swab DNA samples from dogs with these diseases, as well as a photo and description of symptoms.

Contact:

Sheila M. Schmutz, PhD
Department of Animal and Poultry Science
University of Saskatchewan
51 Campus Drive
Saskatoon, SK S7N 5A8
Canada
[email protected]
Http://skyway.usask.ca/~schmutz


Researchers in the Oncology Research Group at the Animal Health Trust are collecting DNA samples from as many dogs as possible belonging to the breeds listed above. They would like to collect samples (cheek swab, or whole blood sample in EDTA) from dogs that are either currently affected with lymphoma, or have previously had lymphoma.

Anyone who is interested in taking part in these research studies and would be willing to submit cheek swabs, or have their veterinary surgeon collect a blood sample from their dog(s), is invited to contact Dr Mike Starkey [+44 (0)8700 509188; [email protected] The AHT Fedex Account number, 2439-2185-6 (quoting reference name: Mike Starkey), can be used to finance the sending of samples to the AHT. Blood samples sent from countries that do not belong to the European Union should be sent in a package labelled "Animal Pathogen - importation authorised by licence number AHZ/2026A/2004/2 issued under the Importation of Animal Pathogens Order 1980".
Research Area: Histocompatibility alleles conferring susceptibility to canine diabetes, immune-mediated thyroiditis and immune-mediated hemolytic anemia
Breeds: All Breeds

Autoimmune diseases cause significant amounts of mortality and debilitating disease in dogs. In humans many autoimmune diseases occur only in individuals expressing one of the few predisposing histocompatibility genes. For example, all cases of type I diabetes in humans are associated with only a few of the many allelic forms of class II histocompatibility genes. Consequently, if the frequencies of these few alleles were reduced by half, the incidence of diabetes would be reduced by half. Here we propose to characterize histocompatibility susceptibility alleles for three major, heritable canine autoimmune diseases - diabetes, immune-mediated thyroiditis and immune-mediated hemolytic anemia. If any of these three debilitating (or lethal) autoimmune diseases have a restricted number of susceptibility alleles it will allow: (1) development of diagnostic tests for identifying individuals at risk for prophylactic therapy and research and (2) reducing the incidence of the disease by reducing the breeding of individuals carrying the predisposing histocompatibility alleles. For each of the three autoimmune diseases, we propose to collect DNA samples from approximately 100 purebred dogs diagnosed with the disease. Histocompatibility genes will be cloned and sequenced for each dog for a total of approximately 1100 sequences. Histocompatibility alleles will be tested for significant associations with each of the autoimmune diseases.

We need samples from purebred dogs that have confirmed diagnosis of one of these three autoimmune diseases: diabetes, immune-mediated thyroiditis or immune-mediated hemolytic anemia. If your dog has been diagnosed with one of these three diseases please take a consent/diagnosis form (or print one from our website: http://stormy.biology.utah.edu). Fill it out completely, including the diagnosis criteria signed by your veterinarian and return to us. We will then send you a DNA collection kit, which only requires cheek swabbing your dog and returning the swabs to us in a pre-stamped envelope.

Dogs May Provide an Excellent Model for Understanding Human Complex Diseases

ScienceDaily (Feb. 2, 2010) — Researchers at Uppsala University and the Swedish University of Agricultural Sciences (SLU) have found several genes that lead to increased risk for an SLE-like autoimmune disorder in dogs. This is the first time scientists have found genes behind such a complex disease.



The study is being published in the journal Nature Genetics.

"It's extremely interesting and feels fantastic that we can so readily find genes even for complex diseases in dogs. The study also provides entirely new avenues for studying SLE in humans," says Professor Kerstin Lindblad-Toh, who directed the study, which was carried out in collaboration with scientists at SLU and colleagues in Finland and the US.

To find genes for human common diseases, thousands of blood samples are needed from both patients and healthy controls. The structure provided by dog breeding, and the refinement of various properties within the breeds, make it much easier to find pathogenic genes with a smaller number of samples.

Veterinarian Helene Hamlin at SLU has previously described an autoimmune disease complex in the breed Nova Scotia duck tolling retriever, which is characterized by a rheumatic SLE-like disorder (Systemic Lupus Erythematosus), where the dog develops joint complaints and inflammatory symptoms in various inner organs. In these, the body has often formed antibodies against the nuclei of the body's own cells, a characteristic found in SLE in humans as well. The other variant of the disease complex is non-bacterial meningitis, so-called steroid-responsive meningitis-arthritis (SRMA).

The researchers sifted through the DNA of 81 diseased dogs and 57 healthy dogs and identified five regions in the genome that each , greatly increase the risk of developing the disease. Three of the regions greatly increase the risk of developing the SLE-like variant of the disease, while the other two regions increase the risk for both SLE and meningitis.

"We know that SLE in humans is caused by many genes and were therefore not surprised to find several risk factors that contribute to the disease in dogs," says Maria Wilbe, a doctoral candidate at SLU and lead author of the article.

"It's worth pointing out that the canine risk factors are very strong," says Kerstin Lindblad-Toh. "The risk factors that have been found thus far in humans with SLE may double the risk, but in dogs, each disease gene increases the risk about five times."

One can even hypothesize as to why Nova Scotia duck tolling retrievers develop this disorder to such a great extent. The breed was decimated by canine distemper virus in the early 20th century. The dogs that survived may have been the dogs with the strongest immune system, and this strong immune response is now also resulting in an autoimmune disorder. The scientists have examined what the genes are in the risk regions and note that several of these genes govern the activation of T cells, the white blood cells that deal with viruses in our immune system.

"The genes that have thus far been found in humans with SLE do not primarily regulate T cells, but a major share of the genetic risk factors are still unknown in humans. It will therefore be interesting to move on and look at various subtypes of SLE and see whether genes that regulate T cells cause any of them," says Kerstin Lindblad-Toh.


Canine Health May Parallel Community Health

ScienceDaily (Mar. 7, 2010) — The family dog may not only be a friendly companion but also a reflection of community health.



Students at The University of Findlay are helping Michael Edelbrock, Ph.D., associate professor of biology, study canine cells using a process originally developed using human cells and perfected by Alexander Vaglenov, M.D., Ph.D., associate professor of pharmaceutical sciences.

According to Edelbrock, dogs respond to toxicity much like humans. When humans are exposed to environmental pollution, the genome can be affected, which causes mutations that can lead to diseases such as cancer. Edelbrock's research is looking at the possibility of studying the canine population in a defined geographical area to determine how the same environment may affect humans.

Edelbrock plans to compare cells from pets and strays, and build depth from there. "The questions are endless," said Edelbrock. "We could look at environmental differences such as smoking versus non-smoking homes, rural versus urban animals, and eventually compare results from different cities."

If consistencies are found in the dogs' cells, canines could be used in studying an overall city's health and environment.

Students and faculty members at the University conduct research in $450,000 state-of-the-art science laboratories, which were completed prior to the 2007-2008 academic year.


Small Dogs Originated in the Middle East, Genetic Study Finds

ScienceDaily (Mar. 13, 2010) — A genetic study has found that small domestic dogs probably originated in the Middle East more than 12,000 years ago. Researchers writing in the open access journal BMC Biology traced the evolutionary history of the IGF1 gene, finding that the version of the gene that is a major determinant of small size probably originated as a result of the domestication of the Middle Eastern gray wolf.



Melissa Gray and Robert Wayne, from the University of California, Los Angeles, led a team of researchers who surveyed a large sample of gray wolf populations. She said, "The mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess this variant of IGF1, it probably arose early in their history. Our results show that the version of the IGF1 gene found in small dogs is closely related to that found in Middle Eastern wolves and is consistent with an ancient origin in this region of small domestic dogs."

Previous archeological work in the Middle East has unearthed the remains of small domestic dogs dating to 12,000 years ago. Sites in Belgium, Germany and Western Russia contain older remains (13,000-31,000 years ago), but these are of larger dogs. These findings support the hypothesis put forward by Gray and colleagues that small body size evolved in the Middle East.

Reduction in body size is a common feature of domestication and has been seen in other domesticated animals including cattle, pigs and goats. According to Gray, "Small size could have been more desirable in more densely packed agricultural societies, in which dogs may have lived partly indoors or in confined outdoor spaces."



Search ScienceDaily

SCIENCE DAILY DOG NEWS

For more science articles, visit 
ScienceDaily.
ScienceDaily: Dog News
Updated : Sun, 14 Mar 2010 17:05:01 EDT

Small dogs originated in the Middle East, genetic study finds
A genetic study has found that small domestic dogs probably originated in the Middle East more than 12,000 years ago. Researchers have traced the evolutionary history of the IGF1 gene, finding that the version of the gene that is a major determinant of small size probably originated as a result of the domestication of the Middle Eastern gray wolf.
Publ.Date : Sat, 13 Mar 2010 11:00:00 EST

Canine health may parallel community health
The family dog may not only be a friendly companion but also a reflection of community health.
Publ.Date : Sun, 07 Mar 2010 17:00:00 EST

Canine morphology: Hunting for genes and tracking mutations
Why do domestic dogs vary so much in size, shape, coat texture, color and patterning? Study of the dog genome has reached a point where the molecular mechanisms governing such variation across mammalian species are becoming understood.
Publ.Date : Wed, 03 Mar 2010 14:00:00 EST

Choking is a leading cause of injury and death among children
Choking is a leading cause of injury and death among children, especially those younger than 4 years of age. The majority of choking-related incidents among children are associated with food, coins and toys.
Publ.Date : Sun, 28 Feb 2010 05:00:00 EST

Managed wolf populations could restore ecosystems
Wildlife researchers argue that advances in animal control techniques mean it should be feasible and acceptable to introduce small, managed populations of wolves into a variety of parks and other sites for the purpose of ecosystem restoration. This practice could also increase the public's appreciation of wolves and boost ecotourism.
Publ.Date : Tue, 02 Feb 2010 11:00:00 EST

Dogs may provide an excellent model for understanding human complex diseases
Researchers in Sweden and Finland have found several genes that lead to increased risk for a systemic lupus erythematosus (SLE)-like autoimmune disorder in dogs. This is the first time scientists have found genes behind such a complex disease. The study indicates that the homogeneity of strong genetic risk factors within dog breeds make dogs an excellent model in which to identify pathways involved in human complex diseases. The results of the study also open the door for further studies of specific T-cell activation pathways in human populations.
Publ.Date : Tue, 02 Feb 2010 08:00:00 EST

Wide variation in calorie content among 'low calorie' pet foods
Dog and cat owners buying weight-control diets for their overweight pets are faced with a confusing two-fold variation in calorie density, recommended intake, and wide range cost of low-calorie pet foods, according to a study.
Publ.Date : Thu, 28 Jan 2010 05:00:00 EST

'Survival of the cutest' proves Darwin right
Domestic dogs have followed their own evolutionary path, twisting Darwin's directive "survival of the fittest" to their own needs -- and have proved him right in the process, according to a new study.
Publ.Date : Thu, 21 Jan 2010 14:00:00 EST

Dog genome researchers track paw prints of selective breeding
Researchers gave identified 155 regions on the dog genome that appear to have been influenced by selective breeding. Although dogs have been domesticated for 14,000 years, their spectacular diversity originated over the past several centuries through intense artificial selection.
Publ.Date : Tue, 19 Jan 2010 02:00:00 EST

Canine compulsive disorder gene identified in dogs; shares family with recently targeted gene for autism in humans
A canine chromosome 7 locus that confers a high risk of compulsive disorder susceptibility has been identified.
Publ.Date : Thu, 07 Jan 2010 08:00:00 EST

Dominant Chemical That Attracts Mosquitoes To Humans Identified
Scientists have identified the dominant odor naturally produced in humans and birds that attracts the blood-feeding Culex mosquitoes, which transmits West Nile virus and other life-threatening diseases. The groundbreaking research explains why mosquitoes shifted hosts from birds to humans and paves the way for key developments in mosquito and disease control.
Publ.Date : Wed, 30 Dec 2009 11:00:00 EST

Nearly 100 new species described by California Academy of Sciences in 2009
In 2009, researchers at the California Academy of Sciences added 94 new relatives to our family tree. The new species include 65 arthropods, 14 plants, eight fishes, five sea slugs, one coral and one fossil mammal.
Publ.Date : Wed, 16 Dec 2009 23:00:00 EST

Pet therapy: Recovering with four-legged friends requires less pain medication
Adults who use pet therapy while recovering from total joint-replacement surgery require 50 percent less pain medication than those who do not, according to new research.
Publ.Date : Tue, 17 Nov 2009 11:00:00 EST

Domestic Horse Genome Sequenced
Scientists have decoded the genome of the domestic horse, revealing a genome structure with remarkable similarities to humans and more than one million genetic differences across a variety of horse breeds. In addition to shedding light on a key part of the mammalian branch of the evolutionary tree, the work also provides a critical starting point for mapping disease genes in horses.
Publ.Date : Thu, 05 Nov 2009 20:00:00 EST

New Clues To Extinct Falklands Wolf Mystery
Ever since the Falklands wolf was described by Darwin himself, the origin of this now-extinct canid found only on the Falkland Islands far off the east coast of Argentina has remained a mystery. Now, researchers who have compared DNA from four of the world's dozen or so known Falklands wolf museum specimens to that of living canids offer new insight into the evolutionary ancestry of these enigmatic carnivores.
Publ.Date : Tue, 03 Nov 2009 17:00:00 EST

Wolves, Moose And Biodiversity: An Unexpected Connection
Moose eat plants; wolves kill moose. What difference does this classic predator-prey interaction make to biodiversity? A large and unexpected one, say wildlife biologists.
Publ.Date : Tue, 03 Nov 2009 11:00:00 EST

American Physiological Society Endorses Report On Random Source Dogs And Cats
The American Physiological Society announced that it has endorsed the recommendation of a National Academy of Sciences report calling for the identification of new suppliers to replace Class B dealers as providers of random source dogs and cats for medical research.
Publ.Date : Thu, 29 Oct 2009 00:00:00 EDT

Wolves Lose Their Predatory Edge In Mid-life, Study Shows
Although most wolves in Yellowstone National Park live to be nearly six years old, their ability to kill prey peaks when they are two to three, according to a new study.
Publ.Date : Tue, 27 Oct 2009 11:00:00 EDT

Iberian Wolves Prefer Wild Roe Deer To Domestic Animals
A Spanish researcher has analyzed the preferences of wolves from the north east of the Iberian Peninsula to demonstrate that, in reality, their favorite prey are roe deer, deer and wild boar, ahead of domestic ruminants (sheep, goats, cows and horses).
Publ.Date : Fri, 23 Oct 2009 20:00:00 EDT

Studying Cancer In Pet Dogs To Find New Treatments For Human Patients
Scientists say that studying pet dogs with cancer could yield valuable information on how to diagnose and treat human cancers.
Publ.Date : Tue, 20 Oct 2009 08:00:00 EDT