Glaucoma-causing ADAMTS17 Mutations

Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma

BioMed Central Ltd, Canine Genetics & Epidemioloy, May 17, 2019
By Emily C. Jeanes, James A. C. Oliver, Sally L. Ricketts, David J. Gould & Cathryn S. Mellersh

Background
In humans, ADAMTS17 mutations are known to cause Weill-Marchesani-like syndrome, which is characterised by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Breed-specific homozygous mutations in ADAMTS17 are associated with primary open angle glaucoma (POAG) in several dog breeds, including the Petit Basset Griffon Vendeen (PBGV) and Shar Pei (SP). We hypothesised that these mutations are associated with short stature in these breeds. Learn more

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Cancer Link Resources

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RVC research finds potential in ground-breaking new dietary treatment for canine epilepsy, Royal Veterinary College University of London, May 14, 2020. Funded by the American Kennel Club Canine Health Foundation. Learn more

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Diet-associated dilated cardiomyopathy in dogs: what do we know?
Lisa M. Freeman DVM, PhD;  Joshua A. Stern DVM, PhD;  Ryan Fries DVM;  Darcy B. Adin DVM;  John E. Rush DVM, MS
December 1, 2018 Journal of the American Veterinary Medical Association Learn More

Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type
By Darcy Adin DVM, Teresa C. DeFrancesco DVM, Bruce Keene DVM, Sandra Tou DVM, Kathryn Meurs DVM, PhD, Clarke Atkins DVM, Brent Aona DVM, Kari Kurtz DVM, Lara Barron DVM, Korinn Saker DVM, PhD
December 2018 Journal of Veterinary Cardiology  Learn more

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Cardiovascular Link Resources

Diet-associated dilated cardiomyopathy in dogs: what do we know?
By Lisa M. Freeman DVM, PhD;  Joshua A. Stern DVM, PhD;  Ryan Fries DVM;  Darcy B. Adin DVM;  John E. Rush DVM, MS
December 1, 2018, Journal of the American Veterinary Medical Association

(Dilated cardiomyopathy (DCM) is a disease of the heart muscle that is characterized by an enlarged heart that does not function properly.)
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Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type
By Darcy Adin DVM, Teresa C. DeFrancesco DVM, Bruce Keene DVM, Sandra Tou DVM, Kathryn Meurs DVM, PhD, Clarke Atkins DVM, Brent Aona DVM, Kari Kurtz DVM, Lara Barron DVM, Korinn Saker DVM, PhD
December 2018 Journal of Veterinary Cardiology Learn more

 

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Should We Breed With Carriers?

By Cathryn Mellersh, Animal Health Trust, November 2011

carrier‘ is the term given to an individual (of any species) that carries a single copy of a recessive mutation that is associated with a specific inherited condition, usually an inherited disorder. An individual will only suffer from a recessive disorder if in inherits two copies of the causal mutation, one from each parent. If it inherits a single copy of the mutation it will remain healthy but will pass the mutation on to about half of its offspring.

Breeding with Carriers
Once a specific disease mutation has been identified a DNA test can be developed that enables the identification of non-symptomatic carriers. Knowing which dogs carry the mutation and which don’t (the so-called ‘clear’ dogs) enables breeders to make sensible choices about the dogs they mate together. All dogs can be safely bred with provided at least one of the mating pair is clear of the mutation (see Table below). Breeding dogs that will never develop the condition should obviously be the priority for all conscientious breeders and the desire to eliminate a disease-associated mutation from a breed should therefore be the long-term goal. But the instinct to choose only clear dogs to breed from, as soon as a DNA test becomes available, may not always be a sensible choice and the rest of this document discusses why.

If carriers are prevented from breeding the opportunity to pass the rest of their genetic material to the next generation is also lost and the genetic diversity of the remaining population is thus reduced. It is worth remembering that there is a clear and well-established link between the genetic diversity of a population and its overall health, and that breeding closely related individuals tends to lead to the accumulation of deleterious recessive mutations in the population. This is due to the fact that an individual is more likely to inherit two identical copies of a mutation if its parents share common ancestors than if they are unrelated, and the more com man ancestors the parents share the greater that chance is.

It is also worth remembering that the disease mutation for which there is a DNA test is not the only mutation a carrier has. Every human, on average, carries about 50 recessive mutations and there is no reason to believe the average dog won’t carry a similar number. So the only real difference between a clear and a carrier is the single mutation that can be tested for. Both dogs will both carry around 49 other mutations that the breeder doesn’t know about and can’t test for. If carriers are not bred from and clear dogs are used extensively then there is a real risk that other mutations will increase in frequency in the breed and new inherited disease(s) could emerge.

There is no reason why the eventual elimination of a disease mutation from a breed shouldn’t be the goal, once a DNA test for that mutation becomes available. But, providing all breeding dogs are tested for the mutation prior to mating, the breeders can take their time and ensure that desirable traits are not eliminated along with the disease mutation and that the genetic diversity of the breed is not reduced.

Mutation Frequency
The speed with which the mutation can be eliminated depends on several factors, including the frequency of the mutation, the population structure and the rate of inbreeding for that breed. The more frequent the mutation is the more slowly it should be eliminated. Calculating the true frequency of a mutation is not trivial, and requires a random subset of a breed be screened. Dogs that are tested once a commercial DNA test becomes available are not always representative of the breed as a whole, and similar1y cohorts of dogs that have been sampled by a research institute during development of the DNA test are also rarely characteristic of the breed.

The frequency of a mutation is typically expressed as the fraction of chromosomes in a population that carry the mutation. For example, if the frequency of a mutation is described as 0.1, this means that 10% of the chromosomes in that breed carry the mutation and the remaining 90% carry the normal copy of DNA. If 10% of the chromosomes carry the mutation then just under 20% of dogs are expected to be carriers and about 1 % of dogs will be affected.

Breeding Advice
Carriers should always be included in the first one to two generations that follow the launch of a DNA test for a recessive mutation, regardless of the frequency of the mutation, to give breeders the opportunity to capture desirable traits, such as breed type and temperament, before they start to select for dogs that are clear of the mutation. Specific breeding policy for future generations should be breed-dependent and ideally formulated after consideration of factors such as the population structure and rate of inbreeding. But in general terms, carriers should only be removed from the breeding population if the frequency of the mutation is below 0.01 (1 %), as this will mean only around 2% of dogs will be prevented from breeding. Avoiding carriers of a mutation that is more frequent will result in a greater number of dogs being prevented from breeding and could lead to a detrimental loss of diversity for the breed.

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Genetic Testing and Genetic Counseling in Pet and Breeding Animals

by Jerold S. Bell, DVM, Tufts University School of Veterinary Medicine  Jerold.Bell@tufts.edu

Genetic testing and genetic counseling are not just for breeding animals. They include; testing for the bleeding disorder von Willebrand’s disease before performing surgery on susceptible breeds, altering diets for pets that are prone to developing bladder stones or crystals, and switching from rapid growth puppy food to lower calorie foods in young, large breed dogs, so that joint tissues can develop at a more uniform rate.

The hallmark of genetic disease is the ability to predict disease before its onset. This allows the possibility of medical or surgical intervention in order to prevent later suffering. Knowledge of breed-related genetic disease and the tests that are available permit early diagnosis and treatment.

Breeders and veterinarians have been utilizing genetic tests since the beginning of domestic animal breeding. Most genetic tests measure the phenotype of an animal, or what you can see. These include radiographs, blood values, eye examinations, skin biopsies, urinalysis for crystals or metabolites, observations on structure or behavior, and ausculting for heart murmurs. Most tests of the phenotype only identify affected individuals, and not carriers. These may, or may not directly relate to the genotype, or the genes regulating the defect.

A test of the genotype is one that assesses the DNA of the animal. These tests can be run at any age, regardless of the age of onset of the disorder. Utilizing polymerase chain reaction (PCR) technology, affected, carrier, and normal individuals can be identified. As the majority of genetic disorders are recessive or have a major recessive component, the identification of carriers is important for effective management.

As additional DNA tests are developed for disorders, the role of genetic counseling becomes more important. Without these tests, the number of individuals that can be identified as carriers is low, even though many may be suspect due to having affected relatives. Breeds have closed gene pools; in other words, the diversity of genes in a given breed is fixed. The number of individuals removed from consideration for breeding based on concerns regarding a specific genetic disease is usually low. While this has slowed the management of genetic disease, it has also prevented genetic drift and diversity problems for pure breeds.

History has shown that breeders can be successful in reducing breed-wide genetic disease through testing and making informed breeding choices. However, there are also examples of breeds that have actually experienced more problems as a result of unwarranted culling and restriction of their gene pools. These problems include: reducing the incidence of one disease and increasing the incidence of another by repeated use of males known to be clear of the gene that causes the first condition, creating bottlenecks and  diminishing  diversity by eliminating all carriers of a gene from the

breeding pool, instead of breeding and replacing them, and concentrating on the presence or absence of a single gene and not the quality of the whole animal.

DNA tests have to be developed specifically for each breed (or group of related breeds that share an ancestral mutation). There are two different types of tests of the genotype; direct gene tests and linkage-based tests. Direct gene tests check for a specific mutation in a defective gene.  The animal either carries the defective gene, or does not.

Linkage-based DNA tests can be developed even if the defective gene causing a disorder has not been identified. Genome research has identified thousands of genetic markers, or “marker-DNA” that are spread across the chromosomes of the species. A linked-marker is a piece of DNA that lies close to the defective gene on a chromosome.

Breeders can use linkage-based genetic tests the same way direct genetic tests are used. The only difference is that you are not directly testing for the defective gene, only an associated marker; so false-positive and false-negative test results can occur.

A genetic crossover between paired chromosomes mixes the genes that an individual receives from its sire and dam. This occurs on a regular basis during the formation of eggs and sperm. As a defective gene and the linked marker are different areas of DNA that lie close together on a chromosome, it is possible that a genetic crossover can occur between them. This would separate the marker from the defective gene and create false positive (testing for the marker without the defective gene), or false negative (testing as normal, but having the defective gene) results. Depending on the relative distance between the marker and the defective gene on the chromosome, researchers can predict the frequency of false results for a linkage-based test; for example: 1 in 100.

If an individual’s linkage-based test for the defective gene is producing false-positive or false-negative results, all of its descendants that inherit this portion of the chromosome will also have false test results. This has been documented with families of Bedlington Terriers tested for the autosomal recessive copper toxicosis gene.

It is obvious that direct gene tests are better than linkage-based tests. However, a test with 90% or 95% confidence is better than no test at all. As genomic research progresses, researchers can identify the defective genes responsible for disorders, and can develop direct gene tests to replace linkage-based tests. The defective gene for copper toxicosis in the Bedlington Terrier has now been identified, and a direct gene test is now possible.

Based on the mode of inheritance of a disorder, and the availability of genotypic or phenotypic genetic tests, breeding management recommendations can be used to prevent or reduce the frequency of carrier or affected offspring. See the article “Breeding Strategies for the Management of Genetic Disorders” in the proceedings for specific recommendations.
Once a genetic test is developed, it allows breeders to positively determine if an individual is a carrier of a defective gene. The typical response of a breeder on finding that their animal is a carrier is to remove it from a breeding program. If a majority of breeders do this, it puts the breed’s gene pool through a genetic bottleneck that can significantly limit the diversity of the breed. The goal of genetic testing is to allow the superior genes of a breeding individual to be propagated, even if the animal is a carrier. One defective gene that can be identified through a genetic test, out of tens of thousands of genes is not a reason to stop breeding. If an owner would breed an individual if it tested normal for a genetic disease, then a carrier result should not change that decision.

Owners of carrier animals who are of breeding quality in other health, temperament, performance and conformation aspects should be bred to normal testing mates. This prevents the production of affected offspring. The breeder should be counseled to test the offspring prior to placement; to determine whether a pet or breeding home is appropriate. The goal is to replace the carrier parent with a quality, normal testing offspring that carries on the lineage of the breeding program.

If the only quality offspring is also a carrier, then breeders can use that offspring to replace the original carrier. The breeder has improved the quality of the breeding stock, even though the defective gene remains in the next generation. The health of the breed does depend on diminishing the carrier frequency and not increasing it. Breeders should therefore limit the number of carrier-testing offspring placed in breeding homes. It is important to carry on lines. A test that should be used to help maintain breed diversity should not result in limiting it.

By breeding and not selecting against carriers, breeders are selecting for a carrier frequency of fifty-percent; higher than most breed averages. Each breeder must assess the frequency of the defective gene in their own breeding stock and determine their own rate of progress. As each breeder reduces the number of carrier breeding stock, the frequency of the defective gene for the breed will decrease.

We know that most individuals carry some unfavorable recessive genes. The more genetic tests that are developed, the greater chance there is of identifying an undesirable gene. Remember, however, that an animal is not a single gene, an eye, a hip, or a heart. Each individual carries tens of thousands of genes, and each is a part of the breed’s gene pool. When considering a mating, breeders must consider all aspects – such as health issues, conformation, temperament and performance – and weigh the pros and cons.

Without tests, the management of genetic disease involves breeding higher-risk animals to lower-risk animals. Occasionally, a breeding male is determined to not carry a defective gene for which there is no carrier test. The tendency is for everyone to breed to this male, as a guarantee against the disorder.  Any major shift in the breeding choices to a limited number of males will restrict genetic diversity, and increase the possibility of propagating additional undetected defective recessive genes in a breeding population. Such genes have become widespread even in populous breeds due to prolific breeding of popular sires.

Breeders are the custodians of their breed’s past and future. “Above all, do no harm” is a primary oath of all medical professionals. Genetic tests are powerful tools, and their use can cause significant positive or negative changes. Breeders should be counseled on how to utilize test results for the best interests of the breed.

This article can be reproduced with the permission of the author. Jerold.Bell@tufts.edu

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Breeding Strategies for the Management of Genetic Disorders

Jerold S Bell DVM, Clinical Associate Professor of Genetics, Tufts Cummings School of Veterinary Medicine

With each new generation of dogs, breeders ask, “How can I continue my line and improve it?” Aside from selecting for conformation, behavior and ability, breeders must consider how they are going to reduce the incidence of whichever genetic disorders are present in their breed. There are no answers that will fit every situation. There are, however, guidelines you can follow to preserve breeding lines and genetic diversity while reducing the risk of producing dogs that carry defective genes, or are affected with genetic defects.

Autosomal Recessive Disorders
In the case of a simple autosomal recessive disorder for which a test for carriers is available, the recommendation is to test your breeding- quality stock, and breed carriers to normal-testing dogs. The aim is to replace the carrier breeding- animal with a normal-testing offspring that equals or exceeds it in quality. You don’t want to diminish breed diversity by eliminating quality dogs from the gene pool because they are carriers. As each breeder tests and replaces carrier dogs with normal-testing dogs, the problem for the breed as a whole diminishes.

For some disorders there are tests known as linkage-based carrier tests, which can generate a small percentage of false positive and negative results. When using these tests to make breeding decisions, it’s advisable to first determine whether the results correlate with the test results and known genotypes of relatives.

When dealing with a simple autosomal recessive disorder for which no carrier test exists, breeders must assess whether each individual dog in their breeding program is at high risk of being a carrier. This requires knowledge of the carrier or affected status of close relatives in the pedigree. An open health registry that is supported by the parent club makes it easier for breeders to objectively assess these   matters. By determining the average carrier-risk for the breeding population, breeders can select matings that have a projected risk which is lower than the breed average.

If breeding a dog that is at high risk of being a carrier, the best advice is to breed to a dog that has a low risk. This will significantly diminish the likelihood that affected dogs will be produced, and can reduce by up to half the risk that there will be carriers among the offspring. Using relative-risk assessment as a tool, breeders should replace higher-risk breeding dogs with lower-risk offspring that are equal to or better than their parents in quality. Relative-risk assessment allows for the continuation of lines that might otherwise be abandoned due to high carrier risk.

Breeding a dog only once and replacing it with an offspring allows breeders to improve their chances of moving away from defective genes and also limits the dissemination of defective genes. When dealing with disorders for which carriers cannot be identified, the number of offspring placed in breeding homes should be kept to a minimum.

Autosomal Dominant Disorders
Autosomal dominant genetic disorders are usually easy to manage. Each affected dog has at least one affected parent, but it can be expected that half of the offspring of an affected dog will be free of the defective gene. With disorders that cause death or discomfort, the recommendation is to not breed affected dogs. To produce the next generation of a line, a normal full sibling of an affected dog can be used, or the parent that is normal can be used.

A problem with some autosomal dominant disorders is incomplete penetrance. In other words, some dogs with the defective gene may not show the disorder. Roughly half their offspring, however, may be affected.  If a genetic test is available, this is not a problem. Otherwise, relative-risk assessment can identify which dogs are at risk of carrying incompletely penetrant dominant genes.

Sex-Linked Disorders
For sex-linked (also known as x-linked) recessive defective genes for which carrier tests exist, breeders should follow the same “breed and replace” recommendations as are outlined above in the discussion of autosomal recessive disorders. If there is no test, the defective gene can be traced through the pedigree. If a male is affected, he would have received the defective gene from his carrier mother. All of his daughters will be carriers, but none of his sons. By using relative- risk assessment to breed him to a female that is at low risk of being a carrier, you can prevent affected offspring, and select a quality son for replacement.

There are rare instances in which a female is affected with a sex-linked disorder. In such cases, she would have received the defective gene from both parents; specifically, an affected father and a mother who is either a carrier or is affected herself. If an affected female is bred, all the sons will be affected, and all the daughters would be carriers, so affected females clearly should not be bred. A normal male that is a littermate to an affected female, however, would be able to carry on the line without propagating the defective gene.

Sex-linked dominant disorders are managed the same way as autosomal dominant disorders are. The difference is that affected males will always produce all affected daughters.

Polygenic disorders
Polygenic disorders are those caused by more than one pair of genes. Most polygenic disorders have no tests for carriers, but they do have phenotypic tests that can identify affected dogs.With polygenic disorders, a number of genes must combine to cross a threshold and produce an affected dog. These are known as liability genes. In identifying a dog’s liability for carrying defective genes for  a  polygenic disorder, the breadth of the pedigree (that is, consideration of all siblings of individuals in the pedigree) is more important than the depth of the pedigree (consideration only of parent-offspring relationships.) A clinically normal dog from a litter that had one or no individuals affected with hip dysplasia (which is a polygenic disorder) is expected to carry a lower amount of liability genes than a dog with a greater number of affected littermates. This is why it is important to screen both pet and breeding dogs from your litters for polygenic disorders. Information on the siblings of the parents of potential breeding dogs provides additional data on which to base your breeding decisions.

Genetic disorders without a known mode of inheritance should be managed in the same way as polygenic disorders. If there are multiple generations of normalcy in the breadth of the pedigree, then you can have some confidence that there are less liability genes being carried. If a dog is diagnosed with a genetic disorder, it can be replaced with a normal sibling or parent and bred to a mate whose risk of having liability genes is low. Replace the higher-risk parent with a lower-risk offspring that equals or exceeds it in other aspects, and repeat the process.

Genetic tests are extremely useful tools to help manage genetic disorders. Even when there is no test, or a known mode of inheritance, much can still be done to reduce the incidence of affected and carrier animals. The use of these guidelines can assist breeders in making objective breeding decisions for genetic-disease management, while continuing their breeding lines.

This article can be reproduced with the permission of the author. Jerold.Bell@tufts.edu

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