Complicating Mendelism
In Genetics 101, simple inheritance involving one pair of genes is discussed. Terms such as dominance and recessiveness, heterozygous, homozygous, phenotype, and genotype are discussed and defined in that article. These terms will be used in this article on how some traits are controlled by more than one pair of genes. This is known as polygenic inheritance.
Both PRA and EIC are single-gene, simple recessive traits in the Chesapeake Bay Retriever. However, there are other conditions, such as hip dysplasia and degenerative myelopathy (DM), which are controlled by more than one pair of genes. At this writing, one of the genes for DM has been found, and one for hip dysplasia. However, just because a dog tests At Risk with a gene tests for a polygenic condition, does not necessarily mean that dog will develop that disease. Because it takes more than one gene to cause disease, research is ongoing to determine what those other genes are, and what the exact mode of inheritance is. In this article, these different, complex modes of inheritance are discussed.
Codominance (also called incomplete dominance) is where there is a dominant and a recessive allele at a locus. In the heterozygous state, there is some expression from the recessive allele as well as the dominant one. In simple, Mendelian inheritance, the dominant allele completely masks the expression of the recessive one. In codominance, it's as if some of the genetic information from the hidden recessive allele "leaks" through and also has some degree of influence on the individual. The effect is as if both alleles were dominant, even though they code for a different expression of the trait in question. It is similar to the red gene in cattle. Red is dominant to white, but when a cow is heterozygous (one red allele, one white), instead of being red, as would happen with a complete dominant, the cow is roan, mottled red and white hairs intermingled. While the cow still appears predominantly red to the eye, the white gene is also expressed, creating this mottled effect. It is believed that some types of cataracts in the Chesapeake Bay Retriever are inherited in this manner.
Penetrance goes hand-in-hand with incomplete dominance. Sometimes, individuals with identical genotypes at a locus will show different phenotypes for that trait. That is because some alleles are not expressed every time they are present, even when they are dominant alleles. Penetrance is often shown as a percentage. For instance, in humans, Polydactyly (multiple fingers and toes) is an incomplete dominant, with about 85% penetrance. That means that of every 100 people with this gene, only about 85 of those will actually have extra fingers or toes. The other 15 would appear normal, even though they have the same dominant gene as the others. This is true for certain types of cataracts in Chessies. Some dogs, even though they have the dominant gene for this type of cataract, will not actually have cataracts when examined by a veterinary ophthalmologist. These dogs, however, can pass the dominant gene on to their offspring, who may or may not end up expressing the trait. This is why, even though it is a dominant, it is possible to breed two CERF clear dogs together and get affected offspring. Unlike with a recessive, however, it only takes one parent to pass on the gene to the offspring. Things which affect penetrance may be other gene loci that "switch on" or "switch off" another gene, hormonal factors, or environmental factors. A combination of things can also affect penetrance of a gene.
Multiple allele sites: Some loci have more than just one dominant and one recessive allele possible. Some have a range of possible alleles present in the population. While only two alleles can occupy any locus in any individual, the population as a whole may have a range of alleles available at that locus. For instance, Dog A may have C1 and C2 alleles on his C locus, while Bitch B has C3 and C4 on her C locus. These two dogs have four different alleles that code for slightly different phenotypes. Depending on which allele from the sire pairs up with which allele from the dam, there are four different phenotypes that can result from this mating, rather than just the 2 we would find with a simple dominant-recessive gene. Many Chesapeake color loci are multiple-allele sites, which explains the wide variation in the breed's color, even in the same litter.
Polygenic traits: A polygenic trait is one that results from the expression of a number of genes controlling various factors. Think of an old-fashioned scale. When the "good" genes on one side outweigh the "bad" genes on the other, that dog will have a normal phenotype. When the "bad" genes outweigh the "good" ones, that dog will have an affected phenotype. Note that even affected dogs still have a certain number of good genes as well. Hip dysplasia is a polygenic trait that is caused by many genes that control things like depth of hip socket, bone density, placement and strength of ligaments, tendons and muscles, size of femoral head, length and thickness of femoral neck, and so forth. If a dog has an overall greater number of bad genes for one or more of these traits, that dog will show up as dysplastic on x-ray. The dog will still have some good genes at some of these loci, but it will have overall, more bad genes than good, so will be dysplastic. This is why a dog with bad hips can still produce radiographiucally normal, even OFA excellent, offspring, and vice versa, two x-ray normal dogs can still produce dysplatic puppies. A dysplastic dog, however, has fewer good genes to contribute, so it is less likely to produce overall improved hips in it offspring than a radiographically normal dog.
Metabolism is the sum of all the chemical and physical processes with which life is created and maintained. Enzymes are catalysts that control metabolism. Every enzyme is a protein that is coded for by one or more alleles. Each step of metabolism is controlled by a different enzyme, so we see that genes have indirect influence over each other. Enzyme A must do its job correctly before Enzyme B can do its job. Therefore, the alleles coding for Enzyme A indirectly affect the alleles for Enzyme B. If the alleles for Enzyme A are defective, Enzyme B cannot do its job, and the products of Enzyme A will accumulate in the body. This type of gene interaction is known as epistasis, where one allele at one locus can affect another allele at a different locus by altering a metabolic pathway. Many types of dwarfism are cause by these types of gene interactions, that block one or another metabiolic pathway that control growth. There are about 200 types of dwarfism in humans, and almost that many in dogs, so you see how complex gene interactions can be, and how they can result in a number of different conditions.
Sex-linked inheritance: This is sometimes referred to as X-Linked inheritance, because the alleles in question occur on the X chromosome. In the dog, there are 36 pairs of chromosomes; 35 of these pairs are called autosomes, they control most of the genetic inheritance of the dog. One pair is called the sex chromosomes and determine the sex of the individual; two X chromosomes for a female, one X and one Y for a male. These chromosomes are called "X" and "Y" because of their shape. The X chromosome has two long "arms" and looks like a letter X, while the Y chromosome has two shorter "arms", and resembles the letter Y. These chromosomes control more than just the sex of the individual, however. They control many other traits as well. Because the Y chromosome has one pair of arms that are shorter than the X chromosome's arms, many traits can show up in the male from the presence of an allele (dominant or recessive) in that region on the X chromosome that is not paired up by the Y chromosome. As there is no chance for the Y chromosome to "cover up" any allele on that region of the X chromosome, even a recessive gene will be expressed. Hemophelia A is a bleeding disorder that is more common in males, because the locus for this disease is on the long arm of the X chromosome, where the Y chromosome cannot hide it. Even though the gene for hemophelia A is recessive, only one copy of the gene is needed in the male in order for the individual to be affected. Fewer females are affected, because one gene would have to be passed on from the mother, and one from the father. Since the male carrying this gene would be affected, his chances of reproducing are very small. Therefore, few females are ever affected. However, carrier females occur in the population, so affected males continue to be born.
This is a photo of a pair of XY chromosomes. The Y chromosome is on the left, while the X is on the right. Note how much smaller the Y chromosome is. This explains why some of the alleles on an X chromosome can be expressed, even when they are recessives.
Sex-limited traits: A sex-limited trait is one that is inherited by both males and females, but because of the presence of metabolic products or endocrine influences (hormones) made by other gene pairs, the gene is only expressed in one sex or the other. Sex-limited traits can be located on any pair of chromosomes, and behave oppositely between males and females. Pattern baldness in humans is caused by the same gene in males and females, but because of the internal hormonal environment, it acts as a dominant in males, and a recessive in females.
In some genetic disorders, many gene interactions as well as sex influences take place. For instance, entropion is an inrolling of the eyelids that is caused by a number of genes affecting shape of skull, bone density, shape and depth of eye sockets, and amount and thickness of the skin around the eyes. Male dogs, due to testosterone and other hormones, tend to have bigger heads and thicker skin than females. Thus, it is not unusual to find more males with entropion in a breed than females. Both sexes can get the diisease, but the interaction of the genes for head conformation and for hormonal expression is a complex one that influences which dogs will have clinical symptoms of entropion.
Influence of environment: Environment can play several roles in influencing the expression of some genes. In hip dysplasia, for instance, environment can influence how dysplastic a dog becomes. A dog cannot become dysplastic unless it has a majority of "bad" hip genes. However, when a dog does have a majority of bad genes, and it is kept overweight or allowed to grow too fast, or is exercised too much or too little, that dog will end up with a worse case of hip dysplasia than it otherwise would have had.
Environment can also play a role in triggering events. For instance, a dog that has the genes for epilepsy may begin seizing after an event, such as exposure to stress. Any dog may seizure under certain circumstances, but the normal dog will not continue to have seizures periodically, while the epileptic dog will. Sometimes, we will hear people say that a specific event, such as a thunder storm, caused their dog's epilepsy. The thunder storm triggered the initial siezure, but the genes for epilepsy are already there. Once the seizure activity threshold has been reached, the dog will continue to have seizures periodically throughout its life, even long after any triggering event has passed.
We can see that many hereditary characteristics of our Chesapeake Bay Retrievers have complex genetic roots. Because the genetic diseases of our breed are often complex, dedicated breeders continue to use the tools available to them in an effort to improve the quality of the breed, while reducing as much as possible, the health problems. For many, that means routine use of OFA and CERF examinations for the most common problems in our breed, hip dysplasia, elbow dysplasia and cataracts. Breeders who routinely screen for these conditions may have their dogs listed as CHIC-screened breeding stock. There are additional DNA-based tests for several, less-common diseases of the Chessie, including DM, EIC, PRA, and MPS-VI. Researchers are currently working on developing DNA-based tests for other disorders that our, and other breeds are prone to. As more tests are developed, the opportunities for breeders to test their stock will increase.
Breeders and puppy buyers need to be aware that our breed is a relatively healthy one. However, the dog genome consists of approximately 30,000+ gene pairs. It is not possible for a breeder to get all 30,000+ of those genes exactly right! A dog may be clear for disease A, B and C, but not D. It is no longer a simple case of eliminating from breeding every dog that does not pass every test. As more tests are developed, we will see that every dog will fail at least one test. The key when selecting breeding pairs is to not double-up on the same problems. The dog clear for A, B & C but affected with D, should not be bred to a bitch that is a carrier for D. However, a bitch that is clear for D but a carrier for A (for instance) can be bred to this dog. Neither one needs to be removed from the gene pool. It is important that one should breed for an overall good dog, not get so focused on one disease or test result that it becomes what drives the breeding program. This is the challenging of breeding dogs; to produce quality animals with as few defects as possible.
©2002 Lisa Van Loo, Revised ©2008 |
