What traits are inherited? | Genes and Alleles | Naming Genes | Dominance | Expressivity and Penetrance | Sex Linkage | Determining the Mode of Inheritance | Inbreeding | Notes | References

Expressivity and Penetrance

For a breeder, understanding the inheritance of a trait that is controlled by several genes and influenced by the environment can be a nightmare. Suppose, for example, that you are trying to breed apricot Poodles, but instead of getting only a single shade, your litters always have a variety of shades from pale to dark apricot. You might blame it on variable expressivity, which is just a convenient way of saying that you don't know what other genes or environmental factors are also playing a role in determining the color.

One of the "classic" examples of this in dogs is the variable expression of piebald spotting in beagles shown in Little (1957). The dogs all have the same S^p allele, but the colors range from black-and-tan with white feet to predominantly white with a few black spots.

Penetrance is a similar "term-of-convenience" (euphemism). If you are 99+ % certain that Fido carries the allele for six toes (because both his parents and all his sibs have six toes), but Fido has the normal five toes, you blame it on incomplete penetrance, try to look authoritative, and hope that no one asks additional questions. [Actually, it would probably be safer just to say that the trait is not always expressed and avoid possible embarrassment.]

The difference between expressivity and penetrance is that with the former, the trait is expressed to a variable extent, while with the latter it may or may not be expressed even though the genetic makeup (genotype) of the animal suggests that it should be.

Sex Linkage

In dogs, as in most animals, sex is determined genetically, but not by a single gene. One of the 39 chromosome pairs is used especially for sex determination. The unusual feature of this system is that the "female-determining" chromosome, called the X chromosome, doesn't even look like the male-determining Y chromosome - though they are still considered a "pair", and are referred to as the sex chromosomes. (The other 38 are called autosomes.)

As everyone likely already knows, females have two X chromosomes and males one X and one Y. The male normally produces an equal number of sperm with either the X or the Y chromosome. As his mate will only be producing eggs with X chromosomes, an equal number of female (XX) and male (XY) puppies should be produced. Of course chance plays a major role, and litters often don't have a perfect 1:1 ratio.

Mutations undoubtedly occur in genes that control the development and function of the ovaries, testes and other reproductive organs, but few have been described, probably because disruption of the normal reproductive process results in infertility. However, genes are also found on the sex chromosomes that have nothing to do with sex determination. Those found on the X chromosome have no equivalents on the Y chromosome. As a result, males have only one copy of these genes. (As the terms "homozygous" and "heterozygous" apply only when there are two copies, this situation is given a special name: hemizygous.)

When mutations occur in these X-linked genes, the pattern of transmission of the mutant phenotype differs from that seen for an autosomal gene. If a female carries such a trait, she will not express it (as long as it is recessive), but she will pass the trait to half her sons, and as they receive no X chromosome from their father, it doesn't matter what his genotype is -- half will be affected. Half the daughters will be carriers, but as these are recessive traits, they will not be affected. If the problem does not affect survival and reproduction, an affected male may pass the gene on to his progeny - but only to his daughters, as his sons will get his Y chromosome, and it doesn't have a copy of the gene.

In humans, good examples of sex linkage are red-green color blindness and hemophilia. I have been unable to find an example in the Poodle. Von Willebrands disease, a form of hemophilia, is not equivalent to the human X-linked hemophilia, and follows a normal autosomal pattern of inheritance.

There are also traits that are sex-influenced, which means that their expression is influenced by the individual's sex. This does not imply that the gene is sex-linked. A human example is pattern baldness. The gene's expression is influenced by hormonal levels and only one copy of the baldness allele is sufficient to cause baldness in a man, whereas two copies are needed in a woman. In effect, it behaves as a dominant in males and as a recessive in females. Though 1/2 the sons of a female carrier will be affected, a heterozygous male will also pass the trait to 1/2 his sons.

Thus, any trait that appears more frequently in males than females is suspect as either sex-linked or sex-influenced. If it is passed from the father or the mother to 1/2 the sons, it is likely sex-influenced. If it seems to skip a generation and the pattern is grandfather to grandson, it is likely sex-linked.

Determining the Mode of Inheritance

Suppose that you have a litter in which several of the puppies appear to be less healthy than their litter-mates. Suppose that after a few weeks it is readily apparent that they are growing more slowly and appear less energetic. What do you do? Obviously, the first step is take them to your vet for examination.

Without going into details (as this is a hypothetical example), let us suppose that after appropriate tests, he concludes that they have a hole in the septum between the two sides of the heart that is resulting in a mixing of oxygenated and deoxygenated blood. Quite aside from any considerations about putting down the affected pups, the question remains - what caused the problem? Was it simply a developmental accident, an environmentally-induced condition, or is it genetic? [I have deliberately picked a condition that may arise for any of these reasons.]

As a rule-of-thumb, if only a single pup is affected, the problem has not turned up before in related litters, and the problem does not occur frequently in the breed, it is likely a developmental accident. Nevertheless, given the usual under-reporting of health problems, especially those that may be genetic, a second litter between the same sire and dam might be warranted.

On the other hand, if all, or even the majority of the pups were affected, one might be more inclined to look for something in the environment that could have perturbed the normal developmental process. The majority of genetic abnormalities are recessive and, under normal circumstances, the parents are unlikely to be affected (i.e. homozygous). Therefore, if the problem is a genetic one, it is more likely that the parents will be phenotypically normal carriers (i.e. heterozygous), and the expectation is that 1/4 of the progeny will be affected.

While this is important to keep in mind, obtaining a proportion of affected pups in a litter that is substantially lower or higher than 1/4 is no guarantee that the problem is not genetic. Even the larger breeds only produces litters of about eight, so you would expect only two to be affected. One or three would not be considered unusual, and even getting none is not considered sufficiently improbable to alarm a geneticist. You might well get no affected pups in one litter and four in the next!

Dominant mutations having a significant impact on health will, in most cases, result in death before reproductive age is reached. There are exceptions, such as Huntington's Disease in humans. Any late-onset genetic disease, whether dominant or recessive, represents a potential problem. At least with a dominant you can wait for the progeny to reach an age where the problem would normally have developed, then breed unaffected animals with reasonable assurance that they are not undetected carriers.

For a dominant mutation that is rare, most crosses will be between a heterozygous affected individual (Aa) and a normal one (aa). The expectation is that 1/2 the progeny will be Aa. Should both parents be Aa, 1/4 will be aa (normal) and 3/4 either Aa or AA. Sometimes the AA progeny will be affected more severely, or even die before birth.

Doing the necessary crosses to establish the mode of inheritance can be an expensive and time-consuming task, to which is added the thankless prospect of prospect of putting down sick puppies and finding pet homes for the remainder. Consequently, test matings are seldom done on a scale sufficient to produce numbers that can be subjected to statistical analysis. [One notable exception is the monumental study by Bourns on Dayblindness in Alaskan Malamutes.]

One alternative is restrospective analysis of the pedigrees of affected animals. As one generally needs a number of related animals occurring over several generations, the problem will likely already have become fairly common. The accuracy of such analyses is directly affected by the number of relatives for which data exists - a strong argument for the open exchange of information between owners, breeders, veterinarians and researchers.

Inbreeding

Inbreeding is the practice of breeding two animals that are related (i.e. have one or more common ancestors). The degree of inbreeding may be assigned a value between 0 and 1, called the inbreeding coefficient, where 0 indicates that the animals have no common ancestors. Inbreeding produces animals that acquire the same allele from both parents as a result of their common ancestry. Thus, it increases number of genes that are homozygous. However, it does not discriminate between good alleles and bad, and therefore is just as likely to make genes homozygous for bad alleles as for good ones.

Line breeding is a form of inbreeding practiced by some breeders -- often by ones trying to maintain a recessive color -- where a son (or less commonly a daughter) is bred to a female relative generally less closely related than a first cousin.

Inbreeding occurs in most pure-bred domestic animals as the result of several common practices. One is that some breeders own a small number of animals and breed only within their own group. A second is that many breeders have the idea that outstanding animals can be produced by inbreeding -- by doubling up on the good alleles while somehow avoiding the bad. Even if you were to point out to someone that this is a gamble, they might respond that they are simply helping natural selection.

If we lived in a world where all the genes followed the simple rule that there may only be good alleles, which are dominant, and bad alleles, which are recessive, then inbreeding could be an effective tool for improving a breed providing the latter were rare (see, however, genetic load) .

Unfortunately, geneticists discovered, fairly early in the game, that there are also alleles that could be described as fair or poor. (They are generally ones that retain a portion of their normal function.) Suppose we have a "mutant" allele that has lost only 1/4 of its normal function. In many cases, this would not even have a noticeable effect. If you made an individual homozygous for this allele, you would not even be aware that you had done so. Now consider that the same fate may befall a number of genes during an inbreeding program. Eventually, you will have an individual that is considerably less fit than one carrying the normal alleles for all (or even most of) these genes. There is no magic formula for regaining what you have lost. You must start again.

[Sometimes mutant alleles result in an even more dramatic loss of function, but remain undiscovered under normal conditions. See, for example, the story of vWD in Dobermans.]

About the only animals that are routinely inbred to a high level are laboratory mice and rats. There, the breeders start breeding many lines simultaneously in the expectation that the majority will die out or will suffer significant inbreeding depression, which generally means that they are smaller, produce fewer offspring, are more susceptible to disease, and have a shorter average lifespan. Dogs are no different. If you can start with enough lines, a few may make it through the "genetic bottleneck" with acceptable fitness. However, dog breeders generally don't have the resources to start several dozen or more lines simultaneously.

If that is not sufficient to discourage you, then consider the following. During the past 25 years, geneticists have been going out and measuring genetic diversity in natural populations directly by looking at the DNA or proteins, rather than at the phenotype. The have found that many individuals that cannot easily be distinguished by their phenotypic appearance nevertheless have considerable differences in their genotype. This came as a considerable surprise, as the expectation was that even those alleles that only reduce function marginally should, over time, be selected against in the real world.

This discovery led to the theory of "neutral isoalleles" and the concept that heterozygosity might actually be a good thing -- of itself. Neutral isoalleles produce proteins that are different, but function equally well under normal conditions. In combination, they may function even better. Consider the analogy of a soccer match in which each team is allowed two goalies. One team has identical twins who are good at covering the center, the other fraternal twins, one of whom is better at covering the right and the other the left. All else being equal, which team is going to win?

This is not a universally accepted theory, but today one is hard pressed to find a conservation or zoo biologist, concerned with preserving an endangered species, who would not list maintaining maximum genetic diversity as one of his/her primary goals. They equate inbreeding depression with loss of heterozygosity.

Beyond the conventional close-relative inbreeding there is another type of breeding that has much the same effect -- that is the over-use of a recognized champion. Many, in fact, believe they are doing a "good thing", as they will be increasing the frequency of occurrence of the genes that made him/her a champion. What they may not realize is that they are increasing the frequency of all genes carried by this animal, whether they be good, bad or innocuous -- and that champions, like any other animal, carry a number of undesirable recessive alleles that are masked by wild-type alleles. The result is that almost all the breed carry a little bit of Jake Hugelberg, and any undesirable trait carried by Jake will no longer be rare. Finding a safe, unrelated mate becomes an exercise in futility.

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Notes

• The term wild-type literally means the most common type found in the wild. In a Samoyed, it would be white. In a poodle, it would be black. Though we usually equate "wild-type" with "normal", and a white Samoyed is certainly normal for the breed, Samoyeds nevertheless have a genetic deficiency in pigmentation.
• Actually, we should not be saying that the allele functions abnormally. The allele carries the wrong information. The consequence of that information being used results in an abnormal functioning of some process.
• Agouti is a sort of mottled brown color not seen in poodles. Geneticists try to be consistent in their naming of genes and don't use different symbols for different breeds, or even different species, providing the genes are known to have the same action.
• Inbreeding calculations do not account for the possibility that an allele will become homozygous by "chance", though this too can be calculated if the frequency at which an allele occurs in the whole population is known. Most basic Genetics texts explain how. (See, for example, Willis, pp. 293-295 - "The Hardy-Weinberg Law")

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References

Little, C.C. "The Inheritance of Coat Color in Dogs", Howell, New York, 1957.

Willis, M.B. "Genetics of the Dog", Whitherby, London, 1989.

© John B. Armstrong, 1997

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