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Science Corner: Genetics 101

February 19, 2020

Embark’s Professional Team strives to provide you with the most useful, most actionable test results. To best leverage these results, it’s useful to understand the basics of genetics and what factors need to be considered when applying test results to a breeding program. 

Genetics can be simple or complex, and both are actual scientific terms and mostly reference patterns of inheritance, or transmission, of a disease-causing mutation or rare allele. The term simple referencing a single gene, while complex refers to a multi-factorial (multiple gene interaction) disease.   

Important to note, mode of inheritance (MOI) is not the same for all mutations, and the penetrance, or the proportional expression a mutation has within the population in which it occurs, can vary between mutations and can even vary between breeds for the same mutation. This leads to the difference between genotype (the genetic code) and phenotype (physical impact or appearance). To learn more about MOI and gene interactions we recommend visiting https://www.genome.gov/genetics-glossary.

Related terms to better understand your dog’s reports. 

Variant. To simplify, the word variant is often used interchangeably with the word mutation. Your report may state that your dog has zero, one, or two copies of the variant for which we test. 

Carrier. This term has traditionally been used to describe a dog that has one copy of the variant but is not expected to show clinical signs from that variant (this is applicable to variants with a recessive MOI as described below). 

At-Risk. This indicates that the dog may manifest the disease (and generally is used when a dog has two copies of the variant, but this depends on the MOI).  

Why does Embark use the term at-risk and not affected

Because genetic testing is an assessment of risk and not a clinical diagnosis, the term at-risk is often preferred to affected when describing a dog based solely on genetic test results. 

Modes of Inheritance:

With these points clarified, we move on to the basic MOIs. This discussion will focus on autosomal variants, and we will save sex-chromosome (X-linked) variants for another time.

The majority of genetic variants for which tests have been developed have a recessive MOI. This means that two copies of the variant are thought to be needed to be at-risk for the clinical disease (or have the known phenotype). Why is this a good thing? It allows you to make selective breeding decisions based on pre-breeding genetic testing to not necessarily remove all dogs with one or two copies of the variant from your breeding program. 

Many other factors should be considered as well, such as other qualities of the dog (temperament, adherence to the breed standard, results of non-genetic health tests), the average breed coefficient of inbreeding (COI), the penetrance of the variant, and the frequency of the variant within the breed. Don’t worry, Embark can help you with much of this information!

Other MOIs are dominant, codominant, and additive. With dominant variants, dogs with one or two copies of the variant can express the known phenotype. Some variants, such as the change in the FLCN gene that causes Renal Cystadenocarcinoma and Nodular Dermatofibrosis (RCND) in the German Shepherd Dog, appear to be homozygous lethal. This means that dogs with two copies of the variant do not survive early gestation, and only dogs with zero or one copy of the variant will be born in that litter. Codominant and additive in general are used to describe variants in which dogs with one copy of the variant have a different phenotype from dogs with zero or two copies of the variant (although there is a slight difference between the two terms which goes beyond the scope of this article).

As mentioned above, complex or polygenic conditions have multiple genes at play. A polygenic condition is one whose phenotype is influenced by more than one gene, while a complex condition has multiple genes at play and has environmental factors that impact how the phenotype is expressed for a dog. Hip dysplasia, many heart conditions, and epilepsy are thought to be polygenic or complex. Why is this important? In order to learn more about the genetics of these conditions, large numbers of dogs have to be studied and phenotyped. This is where you and Embark can work together and accelerate genetic discovery! Every Embarked dog can be opted into research, and the information you provide via our health surveys is analyzed by our scientists.

So how or why does this matter in the real world? 

A good example is Progressive Retinal Atrophy (PRA) –  this is a general term used to describe a health condition in which the retina atrophies (decreases in size) over time. There are 20+ known variants that can cause PRA, and there are suspected genetic forms of PRA with no variant test available. Different forms of PRA may have different ages of onset, different penetrance of the causative variant, and some can affect night vision first while others affect day vision first. 

You know your breed club recommends you test for PRA prior to breeding, and you also know that you can register your test results with the Orthopedic Foundation for Animals (OFA) by submitting Embark’s easy to use OFA Submission Report. So, how do you know which PRA(s) Embark tests for in your breed? Go to https://embarkvet.com/breeders/health and search by breed. Embark wants to make testing as comprehensive as possible, so if your breed club recommends testing for a condition with a genetic test, and you do not see that test on our list, please email breeders@embarkvet.com to discuss if Embark is able to add that test in the future. 

You receive a dog’s Embark test results, and he or she has one copy of the variant for PRA caused by a change in the SAG gene. This variant has a recessive MOI. This means that the tested dog is not expected to develop PRA from this variant. It also means that if you breed this dog (with one copy of the variant) to a dog with zero copies of the variant (also referred to as a clear dog), statistically, you will have a litter with ~50% clear puppies and ~50% of the puppies with one copy of the variant. This is good news as none of the puppies would be expected to be at-risk. 

On the other hand, you receive another dog’s test results, and he or she has one copy of the variant for PRA caused by a change in the RHO gene. This variant has a dominant MOI. This means that the tested dog is at-risk of developing PRA from this variant. It also means that if you breed this dog to a clear dog, statistically, you will have a litter with ~50% clear puppies and ~50% of the puppies with one copy of the variant, however, the puppies with one copy of the variant will also be considered at-risk for developing PRA.

Why is genetic testing not the entire picture, and why does a breed club recommend a physical examination (or multiple examinations) by a board-certified veterinary ophthalmologist in addition to genetic testing? This could be for several reasons: not all forms of PRA have a genetic test available; the PRA variant may have incomplete penetrance, meaning not all dogs with the variant will develop clinical disease; and, while your breed may have a genetic test for one form of PRA, there may be another form with no genetic test available or your breed may have another ocular concern, such as juvenile cataracts, for which the dog should be examined.

Some other health concerns with multiple variants that are individually only applicable to specific breeds include Cystinuria, Hereditary Cataracts, von Willebrand Disease, and Mucopolysaccharidosis (MPS). 

Another example to keep in mind is that while many breeds can be born with a cleft lip and/or cleft palate, there are genetic and non-genetic causes of clefts, and the Cleft Lip and/or Cleft Palate (ADAMTS20) variant is only known to be causative in Nova Scotian Duck Tolling Retrievers. 

In Summary:

Genetic variant testing is one part of a comprehensive breeding program. When deciding how to use genetic testing within your breeding program, it is important to understand MOI, penetrance, prevalence, and phenotype for that variant in your breed. It is also important to understand which variants are known to occur in your breed and cause the health condition of concern, and which health conditions have no current genetic testing available in your breed. Embark aims to take some of the guesswork out of that process by offering a search health condition by breed function on our website, improved user experience navigating your dog’s profile, and by providing you with access to our team members via email at breeders@embarkvet.com

We know this is a lot of information, and we are here to help. 

Embark helps you prioritize and apply the health-related genetic information you receive. In addition to the searchable website linked above Embark also offers free consultations with our Veterinary Geneticists.

Help us towards our mission of ending preventable diseases in dogs

Not every health concern has a genetic test available, Embark can partner with your breed club (https://embarkvet.com/breeders/partnerships) to discuss genetic discovery and work together to improve the health and wellness of all dogs.