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3.2 Modes of Inheritance

Lowell Ackerman, DVM, DACVD, MBA, MPA, CVA, MRCVS

Global Consultant, Author, and Lecturer, MA, USA

BASICS

3.2.1 Summary

To understand genetics, we try to make it as simple as possible. We like to believe that traits have to be dominant or recessive and appear either on the sex chromosomes or the autosomes. We enjoy nice, clean statistics such as “approximately 25% of offspring will be affected.” In reality, the deeper one delves into genetics and statistics, the more one realizes that, for most conditions, hard statistics do not apply unless a direct test for the genotype exists, and the condition is fully penetrant and expressed. Although people want black or white, without being able to actually determine genotype, genetics is more like shades of gray.

3.2.2 Terms Defined

Allele: A variant or alternative form of a gene, found at the same location on a chromosome, and which can result in different observable traits.

Dominant: Heritable characteristics, traits or diseases that are expressed when inherited even from one parent.

Genetics: The study of genes and how traits or conditions are passed from one generation to the next

Genome: The complete set of genes for an animal.

Genomics: The study of the entire genome, and its combined influence on complex diseases and the impact of environmental factors such as diet, exercise, medications, and toxins on genes.

Genotype: An individual's genetic constitution.

Heterozygote: An individual with two different alleles for a given gene.

Homozygote: An individual with two identical alleles for a given gene.

Locus: A fixed position on a chromosome for a gene or marker.

Phene: A trait or characteristic that is genetically determined.

Phenotype: Observable characteristics or traits that result from the interaction of genotype with the environment.

Recessive: Heritable characteristics, traits or diseases that are expressed only when inherited from both parents.

MAIN CONCEPTS

When an animal inherits the same version of an allele from both parents (e.g., TT or tt), we say it is homozygous for that trait. When the alleles in a gene pair differ, we say the animal is heterozygous for that trait (e.g., Tt). For an X‐linked trait, affected males are hemizygous for the trait because they have only one X chromosome, which they get from their mother (they got the Y chromosome from their father). Whatever the combination, the pairing of actual genes is what constitutes the genotype.

On the basis of this pairing of genes, we have rules to determine the impact of genetic combinations on progeny. These rules are most applicable when a single gene pair determines how the trait will be expressed, which is known as monogenic inheritance. Progressive retinal atrophy (PRA) in Irish setters is an example of this. Other traits, such as hip dysplasia, are caused by the product of multiple gene effects, which is known as polygenic inheritance, sometimes also referred to as quantitative or multifactorial inheritance.

In a monogenic trait involving one pair of genes for locus A, four genotypic outcomes are possible (AA, Aa, aA, aa), but only three phenotypic expressions (AA, Aa, aa), because of how the alleles from mother and father combine in offspring. When two gene pairs are involved, 16 genotypic combinations are possible and, assuming all genotypes are expressed equally, nine possible phenotypes. For every n gene pairs involved in a trait, there are 4ⁿ possible genotypic outcomes and 3ⁿ possible phenotypic expressions.

When you realize that most traits are controlled by many gene pairs, you start to appreciate just how complicated predicting genetic outcome can be. In addition, modifiers, incomplete penetrance, epigenetics, and variable expressivity may have a significant effect on phenotypic outcome (see 3.3 The Genetics of Disease).

Because accurately predicting genotypes with polygenic traits is difficult and because the environment can have a profound influence, genetic involvement in a trait is typically expressed as heritability (h ²), which is a mathematical representation of the variance in breeding values divided by phenotypic variance. A trait's heritability can vary from 0 (no heritable component) to 1 (complete inheritance).

Dogs have 78 chromosomes (39 pairs) and cats have 38 chromosomes (19 pairs), two of which are sex chromosomes. Females are XX and males are XY. The rest of the chromosomes, which have nothing to do with sex determination, are called autosomes. Some traits, such as hemophilia, are transmitted on the X chromosome, but to date few if any disease traits seem to be transmitted on the Y chromosome of dogs and cats. Accordingly, a trait can be sex linked (actually almost always X linked, because few Y‐linked traits have been documented) if it resides on the X chromosomes, or autosomal if it resides on one of the other chromosomes. Sex‐linked traits and sex‐limited traits have to be differentiated. An example of a sex‐limited trait is cryptorchidism, the presence of undescended testicles, in that it can be seen only in males. This fact does not imply that a female cannot carry the gene for cryptorchidism or that it is sex linked and carried on the Y chromosome, which we know is not the case.

3.2.3 Recessive and Dominant Traits

When two copies of a disease‐causing gene (one from each parent) are required to cause a specific problem, the trait is said to be recessive. Thus, PRA in Irish setters is recessive because, to manifest the disease, an animal must inherit a defective gene from each parent (i.e., both parents). If the parents of an Irish setter with PRA appear phenotypically normal, they must both be carriers (heterozygous for a recessive character) of the trait because each contributes a disease‐causing gene to their offspring. Because the trait is recessive, both carrier parents appear normal.

When only one copy of a gene is necessary for a trait to be expressed, that trait is said to dominant. In our PRA example, the gene for normal retinal development is dominant, which is why carriers look outwardly normal even though they carry an abnormal allele and a normal one.

In the simplest terms, if one gene pair controls a trait, conventional use is to capitalize the dominant form and use lower case for the recessive form. For example, imagine that the coat color in a fictitious breed, the American car‐chasing terrier (ACCT), is controlled by a single gene pair. The dominant presentation is black (B), and the recessive presentation is brown (b). Because black is dominant over brown in this example, individuals with a heterozygous genotype (Bb) will appear black. Those with a homozygous genotype will be either black (BB) or brown (bb).

If we did not have a genetic test to identify coat‐color genotype, we would have to determine it the old‐fashioned way, by progeny testing. If you were to breed a black dog (we know that at least one allele is B) to a brown dog (bb) and any of the puppies were brown (bb), the black dog would have to be a heterozygote (Bb). If all the pups were black (BB or Bb), the black parent is most likely a homozygote (BB). Similarly, if we were to breed two black dogs and any of the pups were brown, we would know that both parents had to be heterozygotes for the black color gene (Bb).

If only things were this simple! Although we could indeed give many examples of traits that are inherited in a simple fashion, many more are not nearly as easy to determine or the phenotype is the expression of more than one gene pair. Consider a genotype example for Labrador retrievers, in which nine different coat‐color genotypes are possible (from 16 possible gene combinations). Some genes can affect more than one function, such as the genes affecting coat color that can also be associated with deafness, ocular anomalies, or both. When one gene affects two or more traits in the same individual, it is termed pleiotropy.

In addition to all the new information available on coat‐color genetics, distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R‐spondin‐2, fibroblast growth factor‐5, and keratin‐71, respectively), together account for most coat phenotypes in purebred dogs [1].

3.2.4 Cytoplasmic Inheritance

Most DNA is found in the nucleus, but mitochondria in the cytoplasm contain their own DNA, derived entirely from the mother's ovum. Sperm contain few mitochondria, and none survive fertilization. Therefore, defects in mitochondrial DNA can be passed only from the mother but are transferred to both male and female offspring.

EXAMPLES

Seamus McTigue is a 6‐month‐old neutered male Scottish terrier that has presented with difficulty in chewing and swallowing, and has early evidence of swelling of the mandible. A genetic panel performed at 12 weeks of age indicated that Seamus was homozygous recessive for the craniomandibular osteopathy genetic variant (SLC37A2). Mrs McTigue has confirmed that neither of Seamus' parents had been affected by the condition, which is entirely consistent with a disorder presumed to have autosomal recessive inheritance. Ordinarily Mrs McTigue would have been more alarmed, but since the veterinary team had apprised her of the likelihood of the issue, and had an action plan in place for dealing with it, she felt that Seamus was in good hands and she felt prepared to deal with the situation as needed.

TAKE‐AWAYS

Monogenic traits (those controlled by a single gene pair) are often described as being dominant or recessive, but the actual pattern of inheritance observed may not be clear cut.

Most traits have polygenic inheritance, in which disease manifestations are controlled by a variety of genes, often with environmental influence.

Heritability is the term used to describe how much of a condition is due to genetic influences.

Many more conditions are caused by variants on the autosomes than on the sex chromosomes.

Mitochondria contain their own distinct genes, and genetic diseases caused by mitochondrial DNA variants are transmitted from mothers to both male and female offspring.

MISCELLANEOUS

Reference

1 1 Cadieu, E., Neff, M., Quignon, P. et al. (2009). Coat variation in the domestic dog is governed by variants in three genes. Science 326: 150–153.