IPFD Dog Health Workshop on Genetic Diversity

On May 3, the International Partnership For Dogs (IPFD) hosted their second virtual workshop. Focusing on genetic diversity (primarily from a genetic tests/tools view), 60 participants – including representatives from IPFD and their partner kennel clubs, genetic test providers, breeders, and other key stakeholders – came together online to identify genetic diversity tools and resources, and to discuss priorities and actions for the benefit of all dogs. Half the attendees had been at the 2021 online workshop which discussed Genetic Test Reporting.

The distinguished panel included Prof. John Woolliams (The Roslin Institute, UK), Samantha Hauser (Embark, USA), Katy Evans (Guide Dogs, USA), Saija Tenhunen (Viking Genetics, FI), Pieter Oliehoek (Dogs Global, NL), and Sally Ricketts (University of Cambridge, UK), who shared their time and expertise with us. These speakers had provided short (YouTube) video presentations ahead of the workshop which were the pre-work for participants. These are available to IPFD website members via the Speciality Forums. The workshop was introduced by Katariina Mäki (Acting CEO, IPFD), a quantitative geneticist who previously worked at the Finnish KC.

International and collaborative genetic diversity management is important because different countries and KCs have different policies and tools available, so there is lots of learning that can be shared. Additionally, international populations of dogs/breeds could be sources of diverse genetic material and, increasingly, there are global breeding strategies being developed. 

The problem of Popular Sires

John Woolliams said that everyone talks about Coefficients of Inbreeding (COI) but KCs and breed clubs should be having conversations about what’s happening in a breed and what else can be looked at, especially rates of inbreeding. KCs should be providing simple summary statistics on genetic diversity to breed clubs. Then, of course, the clubs need to understand how to use that information. The Popular Sire effect is potentially damaging for genetic diversity so, perversely, breed clubs publishing lists of the Top 10 winning show dogs might actually be encouraging less knowledgeable breeders to use these dogs at stud and add to the problem. Another attendee commented that one of the main concerns is that the whole pedigree dog culture is traditionally focused on the single successful specimen (or kennel). How can we shift the focus to the population of the breed as a whole? The issue with Popular Sires is that breeds are sidelining other potential sires who could be contributing to the gene pool.

Most UK breeders will be familiar with the Kennel Club’s online tool for Coefficients of Inbreeding. This is based on pedigree analysis and uses all the available pedigree information behind any particular dog. Joanna Ilska, the UK KC Geneticist, said we are discussing the number of generations to use in COI calculations but will still publish full pedigree values. If KCs worked together we could fill in missing import pedigree information. The UK has seen a reduced rate of inbreeding, reported in a paper published in 2015 (Lewis et al). This is mostly due to increased imports arising from the 2012 quarantine legislation change. Joanna said that an analysis of COI after removing imported dogs from the calculations also showed a reduction in inbreeding, and this occurred after introducing the Mate Select Tool. This may suggest breeder awareness has resulted in a change of behaviour. 

What can breed clubs do?

John Woolliams said that the absolute COI value doesn’t matter and that COI will always increase in a closed gene pool (closed stud book). What matters is the rate of increase of COI. He also talked about some of the actions that breed clubs could (should?) take, for example, looking at pedigrees and average relationships (kinship) between dogs to understand how many different dogs contribute to each year’s puppies. In some countries there is a “neutering culture” where non-show puppies are sold with endorsements or contracts preventing them from being used for breeding. This too, leads to a loss of choice and genetic diversity. One of the participants commented “We, especially breeders, need to campaign that any healthy dog is a potential parent dog. By buying a purebred dog, you have become responsible for the heritage that breed constitutes.

Jerold Bell emphasised that there are differences between pedigree COI and genomic COI. With the former, every puppy from a given mating would be calculated as having the same COI. The latter enables you to identify differences between individual puppies in a litter, because each puppy will inherit slightly different combinations of genes from their parents. Embark is one of the providers of genomic COI testing and it can sometimes be a shock for breeders to discover that their puppies’ genomic COI is significantly higher than a pedigree COI value. For example, Brenda Bonnett commented that for a sample of GSDs, genomic COI was around 40%, compared with 30% for pedigree COI. Other recent research papers have shown the same thing. Genomic testing is still relatively expensive for breeders to do, though.

Who owns the problem?

For individual breeders making decisions about their next litter, the most important generation is the potential sire and dam you have in front of you. You can’t do much about Great-great Grandparents! Calculating the COI of that potential litter when you know you’re not using the whole gene pool may be interesting but is not going to solve the problem of genetic diversity. The actual percentage of dogs bred from is small in most breeds. In Finland, they have found that only 2% of male dogs are used for breeding. Breeders should consider having more 1-time litters and avoid repeat matings. The idea of using double matings (2 stud dogs on 1 bitch) could be a way to generate a more diverse litter of puppies (who would need DNA parentage profiling).

Kennel Clubs can (and should) provide the tools and education to help manage genetic diversity within breeds, including offering the option to open stud books for appropriate cross-breeding projects. Breed clubs are best placed to look at what is happening across their breed (nationally and internationally) and should be using this information to provide advice and guidance to breeders. 

Pieter Oliehoek made a really important point early in the workshop: the focus should not be on inbreeding but on genetic diversity. Breed clubs and breeders need to understand this important difference.

Brenda Bonnett reminded the attendees that any discussions and decisions on inbreeding or genetic diversity must be considered in the overall context of dog health. Extreme phenotypes bring with them health problems. There is no point “sorting out” genetic diversity if the dogs still can’t breathe, see, move or behave normally as dogs!

You don’t know what you don’t know!

It’s well-known that when you ask people to rate their driving skills, the majority say they are better than the average driver. Clearly, that’s impossible because, by definition, more than 50% of people can’t be “above average”. Apparently, it’s the same when it comes to dog breeders understanding of (even basic) genetics. A recent poll by Carol Beuchat on her Institute of Canine Biology Facebook Group asked people to rate their own understanding of genetic management and that of other people in their breed. On a scale of 1 to 5, most people rated themselves at 3 or more, while rating their breed peers below average (lots of 1s).

This might be another example of the Dunning-Kruger Effect which I have mentioned before. The Dunning-Kruger effect is a cognitive bias where people believe that they are smarter and more capable than they really are. Essentially, some people do not possess the skills needed to recognise their own incompetence. This leads them to overestimate their own capabilities. Charles Darwin wrote in his book The Descent of Man, “Ignorance more frequently begets confidence than does knowledge.

At the other end of the spectrum, Dunning and Kruger found that highly competent people held more realistic views of their own knowledge and capabilities. Additionally, these experts actually tended to underestimate their own abilities relative to how others did.

Carol went on to explain in her blog why this lack of knowledge about genetic management is such a problem for pedigree dogs. She says: Inbreeding in dogs is FAR higher than in any other mammal, wild or domestic. Inbreeding of wild animal populations is usually in the very low single digits. Breeders of livestock begin to panic as inbreeding approaches 10% because the negative effects are so significant. In fact, they worry about every percentage point of increase.

In a closed gene pool, inbreeding can only increase over generations and the gene pool can only get smaller. With that comes the inevitable consequences of inbreeding depression such as reduced longevity, smaller litter sizes and the appearance of more inherited diseases associated with deleterious mutations.

Breeding strategy

Tom Lewis, formerly the KC’s geneticist, published a paper in 2015 showing data on changes in inbreeding coefficients across numerous KC registered breeds. The data show that breeders are choosing inbreeding as their preferred strategy and, although the data show some evidence of reductions in breed average COI, this is mostly due to the effect of imported dogs with few generations of pedigree data. The data also show COI to be lower than reality because the KC’s pedigree information used in the study only goes back as far as 1980 and therefore excludes breed founders.

In her blog, Carol says there are 2 problems that need to be fixed: firstly, “the significant inbreeding problem that severely imperils essentially every breed”. Then, “we need to breed sustainably” which requires an understanding of the tools used for the management of other animal populations. Clearly, there is much we could learn from the worlds of farm animal production and zoological conservation.

Beyond the Tipping Point?

In some breeds, not only do they face the genetic challenges described above but they also have phenotypic issues associated with exaggerated conformation. You may recall my article last year about the seminar I ran for the Whippet Breed Council. I described the poll we ran for the attendees and their number one concern about the breed for a viable future was conformation and exaggeration. Their number two issue was genetic diversity including inbreeding and popular sires, i.e. everything I have described in the first part of this article.

To me, it was quite surprising that conformation and exaggeration was seen as such a hot topic in Whippets. I’m no expert on the breed, but they don’t strike me as one of the breeds that ought to be overly concerned about that issue. Closer to home, I’m much more concerned about exaggeration in my own breed, Dachshunds. Our Breed Standard was amended last year to make it even more explicit that excessive length of body and a lack of ground clearance were highly undesirable traits. Our health committee produced a paper illustrating a range of types from unacceptably long, heavy and low, through to excessively tall and leggy.

The concept of Tipping Points is, I believe, really useful when considering exaggerated conformation. It is evident from what we see getting awarded in the showring that different judges vary in their view of what is acceptable. The Kennel Club’s Breed Watch programme should be a way to help judges (and exhibitors) recognise the point where exaggeration tips over into visible points of concern, including those with obvious health implications.

Typical dogs

We are also now seeing such discussions about tipping points in published research papers. For example, a paper was published in December 2021 titled: French Bulldogs differ to other dogs in the UK in propensity for many common disorders: a VetCompass study. In it, is this sentence: “In support of a view that French Bulldogs have diverged substantially from the mainstream of dogs in the UK and, are in many respects, no longer even a typical dog, is reflected in their higher differences in disorder propensity.”

I’ve had several interesting conversations about exaggeration recently with vets. Some of those centred around the five welfare needs of dogs which I wrote about in February. We also talked about the dangers of vets (and others) using terms like “normal for a xxx” (insert a breed’s name). The worry here is that we are starting from the perspective of what has become normalised in a particular breed, rather than remembering these should be dogs first. This leads to the question of whether there is a tipping point beyond which a particular breed can no longer be considered to be viable as a dog. When you see pictures of the grossly exaggerated “toadline bulldogs”, it’s pretty clear that a line has been crossed.

For an interesting discussion on exaggeration, listen to Dr Sean McCormack’s wildlife podcast featuring Rowena Packer and Alison Skipper:

play.acast.com/s/seanswildlife/the-flat-faced-dog-dilemma

One person suggested to me that judges’ education should ignore canine conformation and movement and learning should start with looking at horses. That way, judges would learn about virtues and faults without the hindrance of considering what might be “normal for a breed”. I can’t help thinking there is an urgent need for a robust discussion about tipping points and for breeders and judges to go back to basics in defining where we should draw the line on what is acceptable.

Every day is a learning day

One of the potential barriers to improving the health of pedigree dogs is breeders’ lack of understanding of genetics. Most breeders are, by now, familiar with DNA tests for genetic mutations for health conditions such as PRA, CLAD, DM and many more (often also with 2 or 3 letter abbreviations!). The principles of recessive mutations with 3 genotypes; Clear, Carrier and Affected and what these mean in terms of clinically healthy or unhealthy dogs is generally known by breeders. This may be less clearly understood by buyers who may still think that Carriers are likely to be a problem and get ill. 

As we move into discussing which combinations of those 3 genotypes can safely be bred together, there are still a range of opinions on whether DNA Affected dogs should be bred from. As long as an affected dog is mated to a clear dog, any puppies will not be affected but will be carriers. In many breeds, where there are small gene pools, it is reasonable to breed with affected dogs (mating only to clears). While it might be argued that not using affected dogs is a quicker way to remove deleterious mutations, it also has the effect of removing all that dog’s genes from the population. Removing dogs from breeding on the basis of one genetic mutation alone is often not in the best interests of the breed.

When it comes to coats and colours, far fewer breeders seem to be educated or to make the effort to understand the genetics. All too often, discussion of colours seems to be based on historical urban myths or worse, on fashion and personal prejudices. It’s such an emotive topic, as we have seen with numerous discussions over many months about Colour Not Recognised (CNR) and Non Breed Standard (NBS) colours.

Emerging science

What I find really fascinating is the rate at which the science underpinning the genetics of coats and colours is developing. Some of the research is being enabled by Citizen Science where dog owners’ contributions help research teams by providing DNA samples and photographs. One such study published last year resulted in an improved understanding of one of the earliest coat colour mutations, designated as ancient red (eA). This genotype is associated with “domino” in Alaskan Malamute and other Spitz breeds, “grizzle” in Chihuahuas and “pied” in Beagles.

Another new paper (2021) explains variations in the PMEL gene which causes dapple (merle) in Dachshunds. A previous study of this gene in Australian Shepherds had correlated the length of an insertion into the PMEL gene with 4 broad phenotype clusters of merle, described as “cryptic”, “atypical”, “classic” and “harlequin”. This new paper reports on a similar study in Dachshunds and identified numerous cases of “hidden” merle in light red dogs. The paper suggests that the frequent identification of cryptic, hidden and mosaic variants of the merle pattern makes DNA testing critical to avoid producing puppies with serious health problems. Double-merles are known to be at risk of deafness, blindness and microphthalmia (small eyes) and are banned from registration by the KC.

Time for cocoa?

Another lesson I learned recently was the existence of a gene associated with the brown (liver/chocolate) colour. Variants of the B locus are the most common cause of the brown coat colour, with 5 known mutations of the TYRP1 gene that explain the majority of dogs with brown coats and noses. One exception has been the brown or chocolate French Bulldog which, when tested, is found to be BB (i.e. not chocolate as normally expressed). Recent research (2020) has identified a mutation on the HPS3 gene associated with brown in FBs and which has been called “cocoa”, for which a DNA test is now available. 2 recessive copies of this mutation (co/co) are required for the dog to be brown/chocolate.

5, not 4, basic coat colour patterns

The most recent paper I have been reading was published by Dannika Bannasch and her colleagues at the University of Bern. Professor Bannasch and one of her collaborators, Prof. Tosso Leeb, have both been winners of the prestigious International Canine Health Awards. The study clarified how coat colours and patterns are genetically controlled but also discovered that the light coat colour in many modern dog breeds is due to a mutation that originated in an extinct species more than 2 million years ago. 

Dogs can make 2 types of pigment; black (eumelanin) and yellow (pheomelanin). Production of these 2 pigments in the right place on a dog’s body results in very different coat colours and patterns. The agouti signalling protein (ASIP) is the main switch for the production of yellow. Without ASIP, black pigment is formed. 

In addition, there are 2 “promoters” which result in ASIP production on (a) the belly and (b) banded hairs. The study identified 2 versions of the ventral promoter and 3 versions of the hair cycle promoter, resulting in 5 possible combinations which cause different coat colour patterns in dogs. Previously, it had been thought that there were only 4 basic patterns.

Image source: https://www.nature.com/articles/s41559-021-01524-x.pdf

Within each of these 5 pattern types, there may be further variation due to other factors such as the position of the boundary between red and black areas, the shade of red (from dark to nearly white) and the presence of a black facial mask or white spotting caused by genes other than ASIP. 

Prof. Bannasch said: ‘While we think about all this variation in coat colour among dogs, some of it happened long before ‘dogs’ were dogs. The genetics turn out to be a lot more interesting because they tell us something about canid evolution.’

Learning from history

While a lot of the science and understanding of the genetics may be new, many breeds have a wealth of historical information on coats, colours and patterns. Much of that is held in Kennel Club registries or breed archives. These should be essential resources to inform any discussion about colours that can or cannot exist legitimately in any breed. I am aware of a study in one breed, looking at dogs from the early part of the last century, which clearly shows that colours that are not currently fashionable were around over 100 years ago. 

The fact that some of these colours are associated with recessive mutations should make it unsurprising that those colours can still crop up and be bred today. There are plenty of examples of breeds where breeders have specifically selected for a particular colour or pattern and that’s not something new. We should be very careful not to forget our breeds’ histories and their genetic origins, and not fall into the trap of altering Breed Standards simply on the basis of what is or isn’t fashionable today. That, of course, applies to conformation as well as to colours!

Remember, prejudice is a great time-saver; it enables you to form opinions without having to gather the facts.

Blue is the colour; CNR is the name…

Blue is the colour; CNR is the name…

Recently, we had the misfortune to discover that Johanna Konta (Tennis player) has bought a Blue Dachshund and was proudly sharing pictures on her Instagram page. The picture received over 4000 “Likes” and generated lots of discussion among Dachshund Facebook Group members.

Blue is a colour that occurs legitimately in the genetics of Dachshunds but is a “Colour Not Recognised” (CNR) as far as Kennel Club registration is concerned. Our survey data suggests that between a third and half of Blue Dachshunds can suffer a skin condition – Colour Dilution Alopecia (CDA – and there is no DNA test for this condition). Hence, we have been working hard on social media to educate potential owners not to buy dilute coloured Dachshunds (we also have Isabella – sometimes referred to as “Lilac”). We also encourage owners of these dogs not to breed from them.Blue

In the past year there has been a significant increase in the number of dilute coloured Dachshunds being sold in the UK. The majority are being bred by French Bulldog and English Bulldog extreme-colour breeders; many using dogs imported from the USA or Eastern Europe, presumably as they see an opportunity to make significant money from “rare-coloured” Dachshunds.

I suppose we can be thankful that, unlike in some other breeds, blue hasn’t been introduced recently by cross-breeding from another breed.

The KC created a CNR Working Group to look at this issue because it has caused much concern among other breeds. I understand they are due to report soon. We raised the CDA and CNR issue with the KC when we met to discuss our Breed Health and Conservation Plan.

No simple solutions

The CNR issue is a classic example of what’s known as a “Wicked Problem”. Lots of people have lots of different views on, and interests in, the problem; it’s not the same problem in every breed; there is no single, simple solution and any actions have the potential to result in unintended consequences. This is the realm of Systems Thinking where lots of factors are interconnected. Logical, cause and effect (reductionist) thinking is unlikely to help us understand how the “CNR system” works nor how to intervene to improve things.

The first step in identifying how to change the system is to understand the forces at play. Wicked problems benefit from being examined in a more holistic way and one of the tools to do that is a Causal Loop Diagram (CLD). It’s a pictorial way to link variables (e.g. Demand for “rare” colours, Registration income) and to tell the story of what’s happening in the system. The example CLD tells the story of what might be happening in Dachshunds (it may be different in other breeds). CNR System Causal Loop Diagram PDF

cnr sd model

In the model, if 2 variables are linked with a “plus” arrow, it means they increase together (e.g. the more demand there is, the more dogs are bred). A “minus” arrow means that, as one variable increases, the other decreases (e.g. the better educated buyers are, the lower the demand for rare colours). This Causal Loop Diagram also shows us that there are 4 distinct perspectives on the CNR problem in Dachshunds:

  • Demand
  • Supply
  • KC Registration Policy
  • The health and welfare of Dachshunds

These perspectives help us to see that, if we want to change what happens as a result of the system, multiple actions will be needed.  

How to change the system

Once you can see the systemic forces at play, you can then consider the conditions that either enable or hinder change. That way, you can reduce the chances of cherry-picking “simple but wrong” solutions. We need to look for “leverage points” but it’s important to understand that some of these will have minimal impact or might actually make things worse.

There are plenty of models describing how to change systems and, generally, they highlight 3 levels at which interventions can be made. Of course, being a system, the interventions and the levels are interdependent.

The biggest leverage and impact usually results from challenging the system by understanding its goals, the mindsets that created it and the current narratives. For CNR Dachshunds, these could include:

  • Only register Breed Standard colours of dogs with a known pedigree vs. Register any dog that looks like a Dachshund, whatever its colour/pattern
  • Keep the breed “pure” vs. Recognise that cross-breeding has always happened
  • KC registration is “exclusive” vs. KC registration is “inclusive”
  • “Greeders” vs “Breeders”

The next most effective areas to look for leverage points are the relationships and the power dynamics in the system. These could include:

  • Groups working in isolation vs. Engaging with campaigners (e.g. RSPCA, DBRG, CRUFFA, CARIAD)
  • One-size fits all solutions vs. Open source, marginal gains solutions
  • Individual communication & education campaigns vs. Joined-up campaigns
  • The KC sets the registration rules vs. Collaborative rule-setting
  • The show community shapes the rules vs. Breeders, owners & others shape the rules

People who don’t think about the system tend to start by looking for actions which, typically, have the lowest leverage and impact. Often, these relate to the policies, practices and resources that exist in the system, such as:

  • Registration rules & “acceptable” colour lists
  • Registration pricing policies
  • Data sharing on numbers of CNR dogs and how many have health issues (vs. non-CNR)
  • Legislation on imports & enforcement of this
  • Licencing regulations
  • ABS rules & guidance
  • Breed Club Codes of Ethics
  • Availability of alternative registries
  • Colour/pattern clauses in Breed Standards
  • Breed Club resources for communication & education

Some, or many, will need to be changed, but only after addressing the higher-leverage issues. Starting with these is like looking through the wrong end of a telescope!

Light at the end of the tunnel?

One of the other useful features of the Causal Loop Diagram is that we can identify 2 types of feedback loop. Reinforcing loops occur when an initial action is reinvested to create more of the same type of change. For example, the more a celebrity’s Instagram picture of a blue Dachshund is liked and shared, the more people see it and the more demand it creates for blue Dachshunds. Growth can’t continue forever so, wherever there is a reinforcing loop, there is typically a balancing loop to stabilise the system. However, this might not be as strong as the reinforcing loop or it might take time to kick-in. In our case, a balancing loop is owners finding their blue Dachshunds have health issues, which more people become aware of and which then reduces demand. Another balancing loop might be that unsuitable owners discover that Dachshunds were bred to work and aren’t suitable to live life as “fur-babies” or fashion accessories, and when they share their problems on social media other people become less likely to want one.

Behind every growth in demand is at least one reinforcing loop but there are also, invariably, balancing loops which come into play to resist further increases in demand. In the case of dog health and welfare, the question is whether those balancing loops kick-in soon enough to avoid a crisis for the dogs and their owners.

In a way, we’re lucky that the demand for, and supply of, blue and other “rare”coloured Dachshunds is still quite low compared with the CNR (and other colour) challenges facing the French Bulldogs, Bulldogs, Pugs and Staffordshire Bull Terriers (to name just 4 breeds). We have time to look at our particular CNR system and identify workable solutions. What works for us may well not work in other breeds and vice versa. However, we can and should all learn from each other.

For every complex problem there is an answer that is clear, simple, and wrong”.
L. Mencken

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Complex diseases; can we really “find the genes”?

Many breeds have been pinning their hopes on finding the genetic mutations responsible for diseases and health issues with the expectation that breeders will be able to test their way out of problems.

In some breeds, we have been “fortunate” to be able to identify so-called simple mutations from which DNA tests have been developed. In theory, these enable breeders to make informed decisions before breeding from a dog and bitch so that no “affected” puppies are born. It is, of course, important that we know how these single genetic mutatioons directly correlate with the clinical manifestation of the disease. There is also the potential unintended consequence of a reduction in overall genetic diversity in these breeds which may result from removing Affected (and sometimes, Carriers) from the breeding population.

I’ve written before about a couple of examples where “simple” recessive mutations may, in fact, subsequently turn out not to be so simple. One example is Cord1 PRA in Miniature Dachshunds where we now know there is a second mutation (MAP9) which influences the age of onset of blindness. This second mutation helps explain why some Cord1 Affected dogs don’t suffer retinal degeneration until old age (if at all). The other example is the POMC mutation which was associated with obesity in Labradors. The mutation is also found in Flatcoated Retrievers, but this breed is not noted for having an issue with obesity.

In the case of so-called complex diseases (e.g. Hip Dysplasia, Epilepsy, BOAS) there has been an assumption that multiple genes are involved in these conditions as well as environmental factors.

The search for simple and complex genetic explanations for canine diseases has been accelerated by the development of Genome Wide Association Studies (GWAS). These are large-scale investigations of genetic disease that aim to identify genetic variants scattered throughout the whole canine genome. The canine genome is a sequence of 2.4 billion letters of DNA (G, A, C and T), so the scale of these studies is truly enormous and requires massive computing power. In human genetic research, the number and scale of GWAS have been growing year by year. In 2016, of more than 400 published studies, around 50 involved studying the genomes of samples of more than 100,000 people. A similar situation has occurred in dogs. Last year, a team from Cornell University published a canine GWAS paper based on a sample of more than 4200 dogs from 150 breeds as well as mixed breeds. They tracked down two loci linked to Elbow Dysplasia and one for Hip Dysplasia. They also identified loci associated with epilepsy and lymphoma.

There has, however, been some debate about the extent to which GWAS in humans has actually led to useful clinical applications. For example, they may not fully explain the genetic familial risk of common diseases and there is a small size effect for many of the identified associations. They have also proved to be of limited value in predicting disease risk. All these shortcomings, of course, would mitigate against GWAS being of much practical use to dog breeders.

A new omnigenic model

A paper published in the journal Cell in June this year adds further challenge to the idea that there are relatively simple, causal, links between genetic variation and disease. In their paper, geneticists Boyle, Li and Pritchard from Stanford University suggest that many genetic variants identified by GWAS have no specific biological relevance to diseases. Their view is that common illnesses could, in fact, be linked to hundreds of thousands of DNA variants. Their conclusion is that, for complex traits, association signals from a GWAS tend to be spread across the whole genome, including near many genes without any obvious connection to the disease. They also state that most heritability can be explained by effects on genes outside core pathways. They called this an “omnigenic model” whereby most genes matter for most things!

There’s been this notion that for every gene that’s involved in a trait, there’d be a story connecting that gene to the trait,” says Pritchard. But he thinks that’s only partly true because genes don’t work in isolation. They influence each other in networks so, if there is a variant in one gene, it could well change a whole gene network. All this suggests that the search for simple genetic causes of complex diseases will continue to be challenging and breeders are unlikely to have new DNA tests for these conditions anytime soon. Of course, GWAS may well continue to help identify simple recessive mutations and it is important to remember that the paper is critical of the value of GWAS in human studies where the population structures are likely to be rather different to pedigree dogs with their closed gene pools and high levels of inbreeding.

I recently saw a comment by Carol Beuchat (Institute of Canine Biology) that 70% of genetic disorders in dogs are caused by recessive mutations. We also need to know the extent to which these have an impact on canine welfare as many of them could be relatively trivial. Developing yet more DNA tests for some of these would actually make life more difficult for breeders. Given that many of the high welfare-impact diseases are in the remaining 30% of complex conditions, it’s going to be virtually impossible to “breed away” from the “bad genes”.

Hope for the future

The AHT’s “Give a dog a Genome” project is a current example of Whole Genome Sequencing (WGS) which has the potential to avoid some of the shortcomings of non-sequencing GWAS. Here, by sequencing the genomes of different breeds, the AHT hopes to identify the variations that exist within the canine genome. Having built a database of “neutral variants” from healthy dogs, the genomes of dogs affected by particular diseases can be compared. The different variants between healthy and unhealthy dogs potentially lead to the identification of the associated disease mutation.

The AHT can already claim some success for their WGS work; on their website, they showcase the development of the DNA tests for cerebellar ataxia in Hungarian Vizslas and primary open angle glaucoma in the PBGV. The Vizsla genome sequence can now be used as a control sequence in future studies of inherited diseases in other breeds. With more than 70 breeds participating in the Give a dog a Genome project, the AHT expects to see many more useful and practical developments like those in the Vizsla and PBGV.

I’m sure all the breeds who are participating in the GDG project will recognise the scale and complexity of this project. I hope they see it as a longer-term opportunity to address health issues. In the meantime, they need to look for and implement other strategies that address the root causes of disease in pedigree dogs; closed stud books and high levels of inbreeding.

 

[There’s a presentation – pdf- by Boyle, Li and Pritchard here]

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