Introduction to genetic terminology 

Wisdom Panel’s™ breeder tests employ bespoke marker DNA microarrays, also called DNA chips. This tool is described as a “laboratory on a chip” because it allows the simultaneous testing of many thousands of DNA locations, and yet is contained on a small slide. When a cheek swab sample is submitted for a dog, the DNA is extracted from within those cells to conduct the testing on the chip.  

The genetic markers tested are spread across the dog’s genome, or the full set of DNA information contained within that dog, along the length of all chromosomes. Chromosomes are long strips of DNA, wound and compressed into packages, that come in pairs, one each from the mother and father. Dogs have 39 chromosome pairs, cats have 19. Each chromosome represents a unique selection of half of the parent’s DNA from their mother and father, so that each dog is unique. 

Many of Wisdom Panel's™ thousands of tested markers are located in genes, units of DNA which are inherited as unique sequences and determine some characteristic of the parent or offspring. Genes are called “the basic unit of heredity.” Wisdom’s tests are usually targeted within genes when we are testing for disorders or traits. When testing for genetic diversity, markers are typically located in non-gene areas of the genome where  genetic variability is less likely to be linked to functional changes. This allows for a more accurate assessment of the natural variation in that dog’s DNA, independent of the breeder’s selection for physical traits and appearance. 

Genomes are very large, with many genes and variation within genes, so it is important to be able to communicate location and specific variety accurately with clear language. A locus (plural, loci), is a specific chromosomal location of a gene that tells you which chromosome and where on that chromosome the gene can be found. An allele is a variant of a specific gene. For breeders, it is common to use a letter designation for alleles of a specific gene, giving the dominant allele a capital letter and the recessive allele or alleles a lowercase letter. For example, although the gene that determines if a dog is brown or chocolate coloured is called TYRP1, breeders call that gene the “Brown locus,” and the unique variations or alleles are given names like B for black, bs, bd, bc, basd, etc. for various chocolate alleles. Superscripts are used for clarity when more than two alleles are known for that locus. 

You can think of these terms like a city with streets full of houses. The locus is the specific chromosomal position of a gene, like the house number. An allele is one variant of a gene, akin to the colour of the house. The chromosome can be thought of as the street.  

Sometimes many alleles are known to occur at the same locus and are more or less likely to be visible based on their mode of inheritance. We’ll discuss that further in the Inheritance section. An allele series is the assortment of alleles or variants for a given gene, usually arranged in order of dominance from most dominant on the left to most recessive on the right. For example, for the Extension locus, responsible in part for red coat colour patterns in dogs, there are 8 known alleles at the time of this writing, and the series is currently understood to be: 

EM > E > eA, eH, eG > e1, e2, e3 

Lastly, in dog genetics, it is common to talk about the difference between what a dog shows in their appearance and what they carry in their genome. What a dog displays —for example, their coat colour or the presence or absence of disease— is called phenotype. It is what can be observed. What they carry in their DNA, whether it shows physically or not, is called their genotype. It is important to distinguish between the two, because a dog's phenotype does not tell you their full genetic potential, nor what they could pass on to their offspring. The genes and alleles are always there but their effects may not be visible because of other genes or environmental factors.   

Inheritance 

DNA carries all the genetic instructions necessary for the physical life of an individual from birth, growth, and reproduction to healthy aging, so it is not surprising that the ways  genes and variants are expressed can follow a complex range of mechanisms. The way  genetic variation is expressed when passed from parent to offspring is called genetic inheritance. At any given locus, the alleles inherited from each parent are either the same or different. Scientists refer to these states as homozygous and heterozygous, respectively. 

Simple Mendelian Variants

Simple Mendelian inheritance is the most predictable, and therefore the most intuitive. Because they are easiest to research and discover based on studies of pedigrees and pattern of expression within family trees, simple Mendelian disorders are the most common characterised disorders in dogs. Both parents carry two alleles, and only one will be randomly selected to pass down to each offspring, like the toss of a coin. Recessive alleles are generally denoted with a lowercase letter, dominant alleles with an uppercase letter, e.g., “B” and “b,” as used to indicate brown colouring.  

Simple recessive disorders will only manifest if both parents donate the matching recessive variant to their offspring, and dogs with only one copy of the variant will not show signs of the disease. Dogs with one copy of a recessive disorder are commonly called “carriers” and dogs who inherit two copies of a simple Mendelian disorder are called “affected” (if there is certainty they will develop disease) or “at risk.” The classic appearance of simple recessive inheritance is that when two carrier parents are bred, approximately 25% of the offspring will show the recessive variant. On a Punnett square, which is the most common way of illustrating simple Mendelian traits or disorders, the recessive variant is often shown in the lower right corner. 

Simple dominant disorders or traits can manifest if any copies of the variant are inherited by the individual. That means only one disorder variant, among the four possible variants or alleles between the two parents, is necessary for disease onset. Because breeders understand that many disorders are heritable, and would not breed an unhealthy dog, typically dominant variants either manifest later in life, after the typical age of breeding, or do not consistently cause visible signs of disease in all individuals, which will be discussed further, below. 

Semi-dominant, incompletely dominant, and co-dominant Variants

Semi-dominant, co-dominant, and incompletely dominant variants are similar, and are usually predictable in their effects. Incompletely dominant and semi-dominant are equivalent terms to describe variants that produce an additive effect, such that dogs with no copies, one copy, or two copies of a variant can be noted as having degrees of expression, or an intermediate appearance. A good example of this is “breed-defining chondrodysplasia,” in which dogs with no copies will have normal leg length (assuming no other gene variants are present which affect leg length), dogs with one copy will have moderately shortened legs, and those with two copies will have very short legs. Co-dominant variants exert an equally strong effect, such that both alleles are fully expressed if present, rather than an intermediate effect. An example of co-dominance is blood type in humans and dogs.   

Complex Inheritance

For complex forms of inheritance, a breeder may encounter several unfamiliar terms, including incomplete penetrance, polygenic, multifactorial, hormone-dependent, or just “complex.” These terms are all designed to describe how often, how much, or what types of other factors may be involved in expression of the genes in question. 

Incomplete penetrance is a description for inheritance in which the major variant associated with the disorder or trait is known, but other genetic or environmental factors exist that influence whether the dog will go on to display signs of the disease or trait. Additional gene contributions to risk are often suspected. Incomplete penetrance is often qualified as “low penetrance,” “moderate penetrance,” and “high penetrance” to indicate how likely signs of the disorder will be when the risk variant is present. Incomplete penetrance is common with dominant disorders, and is especially frustrating for the breeder, as it seems these types of disorders spring up at random in a most unwelcome way from apparently healthy dogs and can lead to a great deal of strife and superstition. However, as the additional factors involved are not yet known, careful study of the pedigree, trial breedings, and excellent records for future breedings are sometimes all that can be done. Special care must be taken with disorders of incomplete penetrance in rare breeds, as the fear of an incompletely penetrant disorder can cause breeders to neglect maintaining the genetic diversity of the breed gene pool. Low-to-medium penetrance disorders are often also described as complex or multifactorial, depending on how many additional genes or external factors are suspected. 

Polygenic inheritance can be understood from the name, “poly” meaning many, and “genic” referring to genes. Polygenic disorders and traits are influenced by many genes and variants and are therefore best understood as the averaging of more and less influential genes to create the observed disorder or trait. In particular, many features of a dog’s conformation, such as the shape of the head, are polygenic. 

Multifactorial variants are ones known to have both genetic and external or environmental influences to express the associated disease or trait and can also be described as complex. Predisposition to cancer is known to be multifactorial, as diet, exercise, genetic factors, sex, etc. are all known to play a role. 

Sex-linked Variants

Sex-linked variants are those in which the location of the variant is either on the X or the Y chromosome. This distinction is significant because unlike all other chromosome pairs, the X and the Y chromosomes are not equivalent and they house special genes not present on the other.  

Male dogs only have one X chromosome, so recessive disorders on the X chromosome can be seen in males if only one copy of the risk variant is present, as they do not have another normal allele present on a second X chromosome as the females do. Because of this, sex-linked disorders are usually X-linked in dogs, and are seen more often in male dogs than in female. The most well-known example of this is hemophilia in humans, a bleeding disorder that afflicted European royalty in the past. It was seen in the males, but not the females, as they too carried the variant on one of their X chromosomes, but did not show signs of the disease in the presence of a normal allele on their second X chromosome. Dogs show a similar pattern, as hemophilia is X-linked.  

In females, some genes undergo what is called X-linked gene inactivation. In this case, the gene on one of the X chromosomes is effectively turned off or ignored, and only one copy of the gene is used, which can lead to traits like tortoiseshell colouring in cats. Notably, some disorders are expressed in the presence of certain sex-based hormones, but these are not called sex-linked, they are called hormone-dependent, androgen-dependent (for males), or estrogen-dependent (for females). 

Glossary 

Affected: also called “at-risk,” in the context of genetic type, or genotype, refers to an individual that has inherited one copy of a dominant trait or disorder variant, or two copies of a recessive trait or disorder variant. 

Allele: a variant of a specific gene. For breeders, it is common to use a letter designation for alleles of a specific gene, giving the dominant allele a capital letter and the recessive allele or alleles a lowercase letter, e.g. E, e. 

Allelic frequency: how often a variant or allele is found within a population (e.g., a breed). Since each individual carries two alleles (one from each parent) for most genes, everyone contributes two copies to the total for the population. For example, if 1 out of 10 dogs carries a single copy of a given allele, then the frequency is 1/20, or 5% allelic frequency. 

Allele series: the assortment of alleles or variants for a given gene, usually arranged in order of dominance from most dominant on the left to most recessive on the right. 

Autosome: a non-sex chromosome. In dogs, there are 38 autosome pairs. In cats, there are 18. 

Carrier: in the context of genetic type, or genotype, refers to an individual that has inherited one copy of a recessive trait or disorder variant. 

Chromosomes: long strips of DNA, wound and compressed into packages, that come in pairs, one each from mother and father. Each half of a chromosome pair represents a unique selection of half of the parent’s DNA from their mother and father, so that each individual is unique.  

Co-dominant: variants that exert an equally strong effect, such that both alleles are fully expressed if present, rather than a blended or intermediate effect. An example of co-dominance is blood type in humans and dogs.  

Complex inheritance: also called non-Mendelian inheritance, expression of complex traits and disorders depend on more than one locus, or have variants that do not behave in a simple dominant or recessive manner. Examples include incomplete penetrance, polygenic inheritance, multifactorial inheritance, and hormone-dependent expression. 

Direct marker test: tests in which the presence or absence of the variant in question is directly assayed. This is considered the gold standard for simple disorders and traits, as it provides the highest level of accuracy. 

DNA microarray: also called a DNA chip, microarrays are often described as a “laboratory on a chip” because they allow the simultaneous testing of many thousands of DNA locations, and yet are contained on a small slide. 

Epistasis: when one gene prevents or masks the expression of another gene. 

Eumelanin: one of two primary pigments seen in dogs, responsible for the dark pigments of black and brown, also called chocolate and liver, or if dilute, Isabella, lilac, lavender, blue or grey.  

Gene:  the “the basic unit of heredity,” genes are units of DNA which are inherited as unique sequences and determine some characteristic of the parent or offspring.  

Genome: the full set of DNA information contained within an individual. 

Genotype: the variants or alleles an individual carries in their DNA, whether or not they can be physically observed. 

Heterozygous: when the two alleles for a locus are different from each parent 

Homozygous: when the two alleles for a locus are the same from each parent 

Hormone-dependent: some disorders are expressed in the presence of certain sex-based hormones. These are not called sex-linked, but hormone-dependent, androgen-dependent (for males), or estrogen-dependent (for females). 

Incomplete penetrance: inheritance in which the major variant associated with the disorder or trait is known, but other genetic or environmental factors exist that influence whether the individual will go on to display signs of the disease or trait. 

Linked-marker test: also called an indirect marker test, are those in which a marker very close to the marker in question is tested. When very close together on the chromosome, the markers are said to be “linked” and are usually inherited together, giving a reasonable indication of whether the disorder or trait variant was inherited. 

Locus (plural, loci): a specific chromosomal location of a gene that tells you which chromosome and where on that chromosome the gene can be found. 

Multifactorial disorder/trait: disorders or traits known to have both genetic and external or environmental influences to express the associated disease or trait. It differs from polygenic inheritance in that environmental factors are also known to influence expression. 

Phaeomelanin: one of two primary pigments seen in dogs, responsible for red, cream, and yellow pigments. Variation in amount of red pigment deposited is referred to as intensity. 

Phenotype: what an individual expresses or displays that can be observed —for example, their coat colour or the presence or absence of disease. 

Polygenic inheritance: disorders and traits that are influenced by many genes and variants and are therefore best understood as the averaging of more and less influential genes to create the observed disorder or trait. A form of complex inheritance. 

Predictive risk-based tests: tests based on machine learning or AI using an algorithm and a training dataset. The data used can vary, but should include a large number of individuals with genetic testing and paired medical, behavioural, or other records for accuracy. An algorithm is developed by using all those pieces of data to determine which appears to predict or contribute to risk of the disorder, trait, or behavior in question. Examples of data which may be used in the algorithm to predict risk include breed, breed type, sex, age, geography, care history, and dozens to thousands of genetic markers. The result is a predictive risk score for that individual. Predictive risk-based tests are usually used for complex disorders or behaviors that are known to be multifactorial in nature. 

Punnett Square: a table used by breeders and geneticists to show all possible genotypes of offspring given the genotypes of the parents. The parents’ alleles are listed as columns and rows respectively, with each possible offspring genotype combination listed in the resulting cells of the table. A Punnett square allows calculation of probability of a given genotype in the offspring being produced.  

Semi-dominant: also called incomplete dominant, describes variants that produce an additive effect when combined with other variants, such that individuals with no copies, one copy, or two copies of a variant can be noted as having degrees of effect, or an intermediate appearance. 

Sex chromosome: also called allosomes, sex chromosomes are designated X and Y in mammals. Unlike autosomes, sex chromosomes do not house the same genes as other chromosome pairs. Normally males have one Y chromosome and one X chromosome, and females have two X chromosomes. 

Sex-linked inheritance: disorders or traits that are located on either the X or the Y chromosome. Unlike all other chromosome pairs, the X and the Y chromosomes are not equivalent and they house special genes not present on the other. Disorder variants located in sex chromosomes are more likely to be seen in males than females. 

Simple Mendelian: also called simple inheritance, simple Mendelian traits or disorders are determined by a single locus, with only dominant or recessive alleles. 

Simple dominant: disorders or traits that manifest if any copies of the variant are inherited by the individual at that locus. That means only one copy of the disorder or trait variant, among the four possible variants or alleles between the two parents, is necessary. 

Simple recessive: traits or disorders that will only manifest if both parents donate two recessive variants to the individual at that locus. Individuals with only one copy of a recessive variant will not show signs of the trait or disease. Those with one copy of a recessive disorder are commonly called “carriers” and those who inherit two copies of a simple recessive disorder are called “affected” or “at risk.” 

X-linked gene inactivation: when the gene on one of the X chromosomes is effectively turned off or ignored, and only one copy of the gene is used. Can lead to traits like tortoiseshell colouring in cats.