Genetic Diseases: Not so simple after all? January 2017 “Best of Health” article

Best of HealthA recent paper, “The continuum of causality in human genetic disorders” by Nicholas Katsanis caught my eye because it describes some emerging thinking that has relevance in the world of canine genetics.

Katsanis writes about recent advances in our understanding of the overlap between so-called simple and complex diseases. These two extremes are characterised as either diseases caused by mutations in a single gene (“simple”) or those caused by mutations in many genes (“complex”).

In the case of the simple diseases, genetic technology has enabled organisations such as the AHT, Laboklin and VetGen (to name but a few) to commercialise DNA tests for autosomal dominant and recessive mutations. Most readers will be aware of these DNA tests for Progressive Retinal Atrophies, Primary Lens Luxation, Hereditary Cataract and other eye conditions. Tests also exist for conditions such as Urate Stones and neurological conditions such as Cerebellar Ataxia and Lafora’s Disease.

The University of Sydney’s database (Online Mendelian Inheritance in Animals) currently lists 691 traits or disorders known in dogs, of which 289 are Mendelian (Dominant or Recessive) and 215 of them have an identified mutation. That doesn’t mean there are DNA tests for all of these, though!

Complex diseases in dogs include Hip and Elbow Dysplasia, Epilepsy, BOAS and Intervertebral Disc Disease. These are often described as also being associated with multiple environmental factors.

The first challenge Katsanis discusses is “one gene, one phenotype” where we now have examples of single genes actually driving multiple disorders. The best-known is a mutation (CFTR) which is primarily associated with Cystic Fibrosis but is also known to cause male infertility and lung disease. The interaction of CFTR with other genes or environmental factors also now needs to be studied.

Not all “affected” dogs go blind

The second challenge relates to “penetrance”, a term that has basically been created to explain why classically defined dominant or recessive traits do or do not actually manifest as particular phenotypes. Penetrance is defined as the percentage of individuals with a given genotype that exhibit the phenotype associated with that genotype. So, you might find that not all dogs who have two copies (“affected”) of a particular mutation associated with PRA actually go blind. We have an example of this in Dachshunds where people have been asking why so few Miniature Smooths have been reported to have gone blind despite being DNA tested as “affected” for Cord1 PRA.

I am grateful to Dr Cathryn Mellersh for her explanation of this situation and the emerging evidence. The original research that established this association was undertaken with a very inbred colony of Miniature Longhaired Dachshunds that all descended from a small number of animals. In the original colony of dogs, there was absolute correlation between a mutation in the gene RPGRIP1 and the CORD1 phenotype.

Following the original publication, it became apparent that there was considerable variation in the age of onset of disease in dogs that carried two copies of the mutation, indicating (an) additional modifying gene(s) might be involved in determining the age of onset. Additional studies provided firm evidence of a second, modifying gene that influences the effects of the RPGRIP1 mutation.

The overwhelming conclusion from these studies was that the previously reported RPGRIP1 mutation, upon which the widely used DNA test is based, causes cone photoreceptors to malfunction and, together with an additional mutation in a modifying gene, causes early onset cone-rod dystrophy.

Identification of the additional mutation has been the subject of intense research over the last few years and last year reached a successful conclusion with the identification of a mutation in a second gene, called MAP9. This acts as an age of onset modifier of the RPGRIP1 mutation.

Dogs with two copies of both the RPGRIP1 and MAP9 mutations will have early onset Cord1 PRA. Dogs with two copies of the RPGRIP1 mutation but one or no copies of the MAP9 mutation will have impaired eyesight but may not display clinical signs until middle or old age and some may retain vision throughout their life. The fact that the MAP9 mutation is not as common as the RPGRIP1 mutation explains why so many Dachshunds do not have early onset blindness (PRA).

More unexplained variation

Another Dachshund example is the Lafora mutation in Miniature Wirehaired Dachshunds. The age of onset of the disease and the severity and nature of the symptoms are quite variable in dogs that have been DNA tested and found to have two copies of the mutation. The mutation is a dodecamer repeat in the EPM2B gene and it has been speculated that variation in the number of repeats may be associated with the diverse clinical manifestation of the disease. A few years ago, we had conversations with a European genetics research group who felt the Lafora mutation had some similarities with the behaviour of the mutation associated with Huntington’s Chorea, a neurological disease affecting people. In that disease, which is inherited as an autosomal dominant mutation, they said variation in the triplet repeat affected symptoms and age of onset. The more repeats of the mutation there are, the earlier the age of onset. It would be interesting to investigate this for Lafora.

With nearly 50% of Lafora DNA-tested Mini Wires carrying the mutation, it is easy to understand why UK breeders of the other Dachshund varieties are so concerned not to introduce this to their gene pools.

This brings us to Katsanis’ third challenge point; the traditional view that alleles associated with rare disease are themselves rare in a population. Recent research has found that the adverse effects of an allele can be modulated by neutral alleles in the same gene or elsewhere. Another recent study of canine mast cell tumours demonstrated a stepwise accumulation of numerical DNA copy number aberrations (CNAs) as tumor grade increases. So, the concept of simple Mendelian relationships between genes and diseases is becoming less clear-cut.

At the recent KC Breedwatch Education Day, Dr Eleanor Raffan from Cambridge University spoke on the subject of canine obesity and described her research into the genetics of obesity in Labradors. This work identified the POMC mutation in overweight dogs: dogs with 1 copy of the mutation weighed more than wildtype and those with 2 copies weighed yet more and this explained most of the variation in body weight. The presence of the mutation also correlated with dogs’ food motivation. The POMC mutation interrupts the leptin pathway, which regulates appetite, so dogs with the mutation don’t know when to stop eating!

75% of Labradors are wildtype (2 copies of the normal gene) but this was as low as 20% in Guide Dogs. Temperament and “trainability” are the main drivers for selection of assistance dogs, and “positive reinforcement” with food reward is a mainstay of puppy training. Eleanor therefore hypothesised that dogs carrying the POMC deletion may be more likely to be selected as assistance dogs. There are also, of course, genetic factors associated with temperament.

The POMC mutation also exists in Flatcoated Retrievers, a breed not normally associated with obesity. Interestingly, Golden Retrievers don’t have the POMC mutation. The observations of these two breeds were particularly interesting for the Breedwatch audience who felt FCRs were generally not considered to be overweight in the show ring, in contrast to some GRs, which can be overweight.

No “simple” choices to improve health

The Katsanis paper concludes by saying that, “for clinical diagnosis, the emphasis on rare penetrant alleles must persist in order to understand causality and develop intervention strategies; however, this must be coupled with improved statistical models for assessing the contribution of multiple factors, both genetic and non-genetic, to complex traits”.

This is equally true of canine genetics and diseases; simple DNA tests will continue to be helpful to reduce the risk of breeding clinically affected puppies. However, the more tests that become available, the more difficult it will be to make simple choices about breeding away from particular diseases. When you then consider environmental factors, the potential relationships between genes and the effects of genes on the biochemical processes that cause disease, it is clear that “testing” our way out of canine health problems is doomed to fail.

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