Friday, 30 September 2011

UK vets: tough talk on pedigree dogs

Current top winning show Bulldog: Champion Pringham's Eclair Glace

Above:  Leavitt Bulldog - outcrossed for a healthier phenotype  © Lonsdale Bulldogs


Bulldogs were on the agenda at the British Veterinary Association's annual Congress in London last week - as reported in this week's Dog World.

Controversially, vet Emma Goodman Milne - a long-time critic of pedigree dog breeding and author of The Truth About Cats and Dogs - called for Bullodgs and the other 14 breeds on the KC's health "watchlist" to be de-registered arguing that... “...there should be honesty about abnormalities, deformities and disease. These are being bred in." And she urged vets:  "We should be honest to owners and clients who breed. We always tiptoe around clients because we worry about losing business, but if we lose business we should say that that is the right thing to do.”

Emma also called for dog shows to be banned, arguing that the cost to the dogs is too great. “Showing is human entertainment at the expense of animals," she said. And she also believes that we should be promoting crossbreeds as an alternative to purebred dogs; that we should all be less obsessed with looks and learn to appreciate that health first, then temperament, are much more important.

I understand Emma's reasons for her strong stance on this but while appreciating the many benefits that crossbreed dogs can bring (and not least to the dog - dodgy designer-dog breeding aside),  we are not in the same place. I don't think we should give up on purebred dogs. I don't want to imagine a world without them and have always believed that we can have our cake and eat it too.

I have also not quite given up on dog shows being - potentially - a force for the good.  I have always been able to see the benefit of meeting up with others to share information, of seeing other people's dogs in action and to learn from those with more experience.  Combine this with finding a way to reward rude good health, fitness, and ability and I believe the dog show could be reinvented. There is, though, a long way to go.

Also speaking in the Contentious Issues debate on dog-breeding at the BVA Congress was Professor Sheila Crispin, Chair of the Dog Advisory Council that was set up as a result of the various enquiries into dog-breeding that followed Pedigree Dogs Exposed.  We are interviewing Professor Crispin next week for PDE2, so what she had to say was useful background research.

Professor Crispin sounded strong in some respects. She revealed she had been against the Kennel Club registration of Border Collies and believes the show version of the breed is diminished as  result. (There are many who would agree with her, dubbing the prettied-up showdog a "Barbie Collie".) She was also blunt about show Labradors: "“The working Labrador is lovely, smaller with fine bone and a head with a lot of brain in it. The show Labradors, males certainly, have huge, wide heads, and seem to have no brain at all. It really worries me because some breeds are not helped by showing at all.”  She also backs the compulsory microchipping of all dogs as a means of improving traceability - clearly a sensible suggestion (despite the Big Brother fears of some).

But I was a little worried to hear Sheila argue that more scientific evidence was needed before taking more action in certain breeds.  While this is true in terms of quantifying exactly what impact, say,  having a very long and heavy ear leather has on a Basset Hound - surely we already know that such ears impede air flow and increase the likelihood of ear infections?

I also think she was unncessarily negative regarding crossbreeding given the hybrid benefit they can bring. After PDE, said Sheila:  "...everyone jumped on the bandwagon and started breeding crossbreeds, designer dogs as they are called, and charging £1,500 to £2,000 per puppy. It became big business. I think HM Revenue and Customs might be interested in these people’s activities, as they don’t go through the usual tax processes.”

I am sure that Pedigree Dogs Exposed has fueled the "designer" dog trade to some extent, but it was flourishing before PDE and it is just as brisk, if not brisker, in the USA where PDE has not had much impact.  It is true that Kennel Club registrations dropped after the programme - which even the KC attributed mostly to the economy - but they have now largely recovered. You only have to visit epupz to see that ads for purebred dogs (most of them KC-registered) outnumber ones for crossbreeds. And as for not declaring income from puppy sales, I believe this is true of a great many small breeders whether crossbred or purebred - whereas larger licensed breeders (many of them breeding crossbreeds) are required to keep good records and have little choice but to declare their income.

Sheila concluded by suggesting that the answer to the KC bulldog was an outcross to a less conformationally-extreme breed. But of course this has already been done by those ahead of the game, eg: the Leavitt Bulldog (above). So how about the KC de-registering the Bulldog and embracing this healthier phenotype instead?

Yeah, I thought not...


Friday, 23 September 2011

No more protests - official SM scheme starts Jan 2012

I've just reviewed a complaint made to the BBC after Pedigree Dogs Exposed aired in 2008 from a well-known Cavalier breeder - a complaint that over the next two years slowly climbed through the various levels of complaint possible at the BBC. At every level, it was found that there was no case to answer. The complainant, however, decided to take it higher and higher until, eventually, his complaint was heard by the fully-independent BBC Trust. The Trust ruled that the programme had not breached impartiality or accuracy in the way we had reported the brain condition, syringomyelia.

The complainant felt - in common with a lot of Cavalier breeders at the time - that the film had sensationalised syringomyelia and that we had overstated the number of dogs that were affected. He also insisted that there was no proof that SM was genetic (ie inherited) and that the research on which Dr Clare Rusbridge  based her "up to 30 per cent" estimate of the number of affected Cavaliers was "seriously flawed" and "badly biased".

He was also very irate about Dr Rusbridge describing the mismatch between brain and skull size in the Cavalier as being like trying to fit a "size 10 foot inside a size 6 shoe."  He thought this "sensationalist", too.

Well, we now know that Pedigree Dogs Exposed underestimated how serious syringomyelia is in Cavaliers. Recent findings suggest that up to 70 per cent of the breed may show signs of the condition on MRI - and almost every Cavalier has the related chiari-like malformation (CM) which can be painful in its own right.

It is also now accepted by all but a curmudgeonly few that Dr Rusbridge's imagery about the mismatch between skull and brain size in the breed was justified - the dog's brain is, indeed, too big for its skull.

And, while there is still much to understand about the CM/SM, it has been absolutely confirmed by geneticists that SM has a high enough heritability to offer the hope that careful selection could reduce the number of affected dogs born.

Yesterday came a joint announcement from the British Veterinary Association and the Kennel Club that a new MRI screening scheme for syringomyelia in Cavaliers (and other affected breeds) will launch in January 2012. Despite residual opposition from some quarters in the breed, the results of every scan submitted throught the scheme will be published.  From spring 2012,  buyers (and of course others) will be able to find out if a puppy's dam and sire have been tested and, if so, what the results were.

This is a great result given that, as I reported a few weeks ago,  the Scheme looked dead and buried.  Well done to the British Veterinary Association for its persistence in insisting that results of scans submitted through the Scheme must be made public (one of the sticking points). The Kennel Club, too, also deserves praise for eventually standing firm against a lobby (of diminishing power) within the breed that did not want full disclosure.  Here's hoping both organisations will be as proactive on the very long-overdue official heart-screening scheme for Cavaliers, reportedly currently on hold.

Importantly, the results of scans submitted through the new SM Scheme will be sent to the Animal Health Trust where they are working on  Estimated Breeding Values (EBVs) for Cavaliers.  EBVs juggle pedigree and health info to produce mate-choice guidance for breeders.

Elsewhere, there are several other initiatives aimed at helping to further elucidate CM/SM.  They include the Foetal Tissue Research Project, the Cavalier Collection Scheme, and Rupert's Fund which funds MRI scans of older Cavaliers (6+). Rupert's Fund has so far met the cost of MRI scans for 50 dogs vital to SM research.  If you have a Cavalier, and haven't already done so, please do check out how your dogs could help future Cavaliers by participating in the research.

It is encouraging, then, that the dark days of widespread denial are (almost) gone, and good news that the KC is no longer accusing campaigners like Carol Fowler of "pet-owner over-reaction" in trying to raise awareness of the problem. Hopefully few breeders today would accuse Carol and others (as they used to) of suffering from "Munchausen's Syndrome by Proxy".  And that is because Carol Fowler, along with an ever-increasinging number of Cavalier owners and breeders,  have refused to be intimidated by those in the breed who have sought to de-rail attempts to do the right thing by their dogs.

Whether the breed really can be saved remains to be seen. It is burdened with many other health problems besides CM/SM, notably mitral valve disease.  But let's not spoil a good day for Cavaliers. And let's try not to worry too much that the person who complained to the BBC that Pedigree Dogs Exposed and the researchers featured in it were wrong about syringomyelia is now Chairman of the Cavalier Health Liaison Committee.

Sunday, 18 September 2011

Toller x pups 6-8 weeks old

They didn't arrive in time to include in my last post, but here are the latest pix of the Toller x Aussie pups bred by Alexander Dauber in Germany, growing up fast and hybrid-vigorously so far.





Now there's a caption opportunity I am going to have to resist

Friday, 16 September 2011

Tollers Take Two...


Yes, I know this is not a Toller...

Three and a bit weeks ago, I blogged about German breeder, Alexander Dauber, who had decided to outcross his Nova Scotia Tolling Retriever to an Australian Shepherd - the first step of a project aimed at introducing a shot of genetic diversity into the Toller.  Boy, from the response, you'd have thought I'd advocated murder ("You did... he's murdering the breed!), not just one man's effort to do what he thinks is right which no one else is remotely obliged to be involved with if they don't want to be.

It has become the blog's third most read post of all time. It attracted 74 comments that I published and another 10 or so that I thought were too awful to make public - although I'll share one of them now; this anonymous one from someone clearly very irate that I hadn't published Toller researcher Dr Danika Bannasch's reponse (which I had asked for and which she provided shortly after I'd published the post).
You promised to put Dr. Bannasch's responses on as soon as you got them. You've had them for weeks. Meantime, your anti-purebred shill "researcher" Maki has had multiple chances to comment, which have all been published. Put Dr. Bannasch's information up as you promised - or were you lying and now need time to "spin" things your way?

The rogue breeder has no proven info on health other than what he claims on his website. The dogs are not on OFA nor are they in Tollerdata, which responsible breeders use to post real results, and not just "my vet says" bs put out by people who can't be bothered to follow any rules.

Many people feel if haplotypes were the reason for him using an Aussie male (when Goldens were approved), then what possible excuse is there for not doing it ahead of time? ...except that he's no more than the usual Doodle breeder, sadly given blessing by someone whose never bred in their life.
Nice. And, of course, there's the small point that health test results for German dogs are not normally listed on the (American) OFA database.

I have, in fact, written to Dr Bannasch to apologise and explain the reason for the delay - which is that I have been waiting for a response from Dr Maria Wilbe, another Toller-owning scientist. I explained that I felt that the two responses would be better incorporated into a new post rather than editing into the original, as most people do not go back to review posts they have already read. I also felt they were too important to just post as a Comment where they might not be found.

Anyway, I received the response from Maria Wilbe two days ago and it transpires that a whole bevy of impressive names have signed up to it too, so I am finally in a position to return to the Tollers as promised.

First, if you haven't already read the original post, please do (you can find it here) before reading on.

To quickly recap for those who need a quick reminder, essentially, the fuss centres on  two issues. The first is whether Toller diversity is compromised sufficiently to warrant an outcross; and the second is over the usefulness of DLA haplotyping testing as a means to reduce the incidence of immune-mediated disease in the breed.

On the first, there is clearly a bit of a science stand-off (as documented in the first post), muddied at times by a sometimes near-hysterical response from some Toller breeders to the very idea of sullying their breed with foreign blood. Some won't even consider seeking out and using the unregistered Tollers that can still be found in Canada, one breeder dismissing them as just "Toller-like mutts".

Regarding DLA haplotype testing, this is a DNA test which looks at a key section of the immune system. In 2009, Swedish scientist Maria Wilbe and her co-authors found an association between one particular DLA haplotype* and immune-mediated rheumatic disease (IMRD). This is one of two troublesome immune-mediated conditions found in Tollers (and which together are often called Toller Disease). The team found an elevated risk of developing the condition in dogs with one copy of this haplotype - and a higher risk in dogs that had two copies of it. (Abstract here.)

(*haplotype = a group of genes inherited as one)

So, given that a test is now available that allows you to ensure that there would be no doubling up of the IMRD-risk haplotype in any puppies bred,  surely it would make sense for breeders to avail themselves of the test? Well, no - not according to the scientists who have signed the statement below. In fact, they absolutely insist that breeders should not make breeding decisions on the basis of any such test until all the genetic risk factors (and it is true that there are others) are known.

This statement and Dr Bannasch's are in full below (as well as Dr Bannasch's answers to three supplemental questions I asked).

As you'll see, Dr Bannasch views outcrossing as an absolute a last resort and argues that Tollers are only as inbred as any other pure breed. (Not a huge comfort, surely?) I was also disappointed that she feels it impossible to collect reliable information re the incidence of immune-mediated disorders in the breed given that it is perfectly feasible to recruit a birth cohort of Tollers and follow them through their lives. (This has been done in other breeds.) And I was surprised that Dr Bannasch cited laboratory mice as an example of a healthy inbred population when, in fact, over 90 per cent of these inbred lines die out in the process of creating them, many do indeed suffer from specific genetic problems and all have to be kept in a protected environment - unable to withstand the environmental, bacterial and viral onslaught they would be exposed to in the real world.  Not something we'd want for our dogs.

As for the joint statement issued by the various researchers involved in DLA testing, I do understand the scientists' caution, but I believe that if some early adopters want to expore DLA testing then they should be free to do so, as long as they are fully aware that it is only one small part of the story and things might not work out as planned. I would hope too, that, what they discover along the way is passed on to the scientists to help their research - and the breed.

Why wouldn't you want to avoid doubling up on a haplotype if its been found that two copies of it increases the risk of IMRD, even if other genetic risk factors are involved? After all, cutting down on butter is only one way of reducing cholesterol, but it is better than doing nothing at all. 

I can also see some sense in, generally, using DLA testing to try to ensure as diverse an immune system as possible in a breed as we know that is, in general, a good thing (notwithstanding that some individual haplotypes might be associated with a specific disease).  In fact , this is the whole basis of the commerial DLA haplotype testing offered by Professor Hannes Lohi at Genoscoper whose name appears on the statement below advising against DLA testing as a means of reducing the risk of immune-mediated disease in Tollers.

DLA testing also affords an opportunity to increase the number of dogs carrying very rare haplotypes. Although 11 in total have been found so far in the breed, only five have been found with any great frequency and the rest are vanishingly rare. This table is in Finnish but you'll get the idea..and see how common the IMRD risk haplotype is. (NB again, it is only a risk factor and one of several. There are Tollers who have one and two copies of this haplotype who have never gone on to develop IMRD and, equally, those that don't have any copies of it who have.)


Click to enlarge

So there we go. As clear as mud, I expect. But it's a complex subject.

DR BANNASCH'S RESPONSE

I would be the first person to support purposeful cross breeding and in the event that we discover through our research that it is the ONLY way to correct an inherited problem in the breed I will be the first one leading the effort.

The most important point that you and others are missing is that the Maki report does not compare the NSDTR to other purebred breeds. This could be done for all breeds and may uncover that certain breeds are in more critical shape than others.  The NSDTR breeders are fortunate that since the breed was more recently admitted to registration status we have computer access to complete pedigrees since that time.  That is what gives the apparently very high inbreeding coefficients.  If this same analysis could be done in other breeds the numbers would likely be similar. It is not correct to compare the numbers to wild animal populations and make conclusions about the dire straits that this breed is in.  You assume that tollers are much worse off than other breeds and I believe based on our unpublished data (see below) they are about average among purebreds.

My laboratory has been working on identifying the genes that causes tollers to develop Addison's disease.  As part of this work we have genotype data from the NSDTR as well as other breeds and can compare the genotype based inbreeding coefficient.  These numbers are based on data for about 30,000 markers in 10 unrelated animals.

Dachshund- 0.1242, Lab 0.1635, Beagle 0.2043, NSDTR 0.2064, German Shepherd 0.3150 and greyhound 0.3238

We also performed Y haplotype analysis of 33 tollers and obtained diversity values of 0.76 +/- 0.04 based on identifying 5 different haplotypes in the NSDTR.  You can see numbers from other breeds in the following paper for comparison:

Y chromosome haplotype analysis in purebred dogs
(pdf) Danika L. Bannasch,1 Michael J. Bannasch,2* Jeanne R. Ryun,1* Thomas R. Famula,3 Niels C. Pedersen

Review
Inbreeding and genetic diversity in dogs: Results from DNA analysis  (Claire M. Wade)
You also state that 11 DLA haplotypes is "low" for a breed but actually although most of the scientific manuscripts on the subject do not have the haplotypes published in this way, 11 is above average for a purebred dog breed. Please see partial reference list below.

This paper found 11 haplotypes in the GSD:
MHC class II risk haplotype associated with Canine chronic superficial keratitis in German Shepherd dogs. Päivi Jokinena, Elina M. Rusanenc,  Lorna J. Kennedy and Hannes Lohi.

This paper found 6 haplotypes in Pugs:
Necrotizing meningoencephalitis of Pug Dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. K. A. Greer et al.
This paper found 9 haplotypes in Weimaraners:
Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations. N. Safraa, N.C. Pedersena, Z. Wolfa, E.G. Johnsona, H.W. Liua, A.M. Hughes, A. Young and D.L. Bannasch

This paper found 6 haploytpes in over 500 Dobermans:
Association of hypothyroid disease in Doberman Pinscher dogs with a rare major histocompatibility complex DLA class II haplotype. (pdf) L. J. Kennedy1, H. J. Huson, J. Leonard, J. M. Angles, L. E. Fox, J. W. Wojciechowski, C. Yuncker & G. M. Happ

JH supplemental questions:

JH: what is your estimate of the incidence of immune-mediated disorders in the breed? 
DB: Unfortunately this number is extremely difficult to get or even estimate.  When polls are taken more people with diseased dogs are likely to respond.  The ideal sampling would be to follow a cohort of dogs and report their incidence of disease.  Obviously this is impossible.

JH: an Ne of 18  is extremely low  - Calboli et al found only one breed lower of the 10 they looked at. 
Why do you now consider this a problem? (Ne is "effective populaton size" - a measure of genetic diversity).
DB:Again if you look closely they followed out nine generations not to the beginning of the closed stud book.  It is like comparing oranges to steak.

JH: how is saying that other breeds are worse an argument for not taking action in the Toller?

DB: I don't know if you are familiar with inbred mice.  There are 100s of laboratory strains that are completely inbred- ie homozygous at every locus.  They breed prolifically and are healthy.  They are not living in the wild but neither are domestic dogs.  Purebred dogs are definitely inbred and have small effective population sizes.  The majority of them are healthy, look and act like each other (within a breed) which is what people want. It may be that there are some breeds that are in danger- I have not seen any scientific evidence for that.  The "action" that I have read about in the Toller was not based on a scientifically documented need.  In addition the "action" that I read included testing parents of the outcross to ensure that they did not have or carry all the diseases that NSDTR have been documented to get.  The problem with that is we do not have tests for those diseases...  Outcrossing without a clear scientific plan does not make sense to me.

STATEMENT FROM MARIA WILBE ET AL

To whom it may concern

A statement concerning the genetic basis for the immune-mediated rheumatic disease and steroid-responsive meningitis arteritis disease complex in Nova Scotia duck tolling retriever dogs
It has come to our attention that our recent publications concerning the genetic risk factors for the immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis arteritis (SRMA) disease complex in Nova Scotia duck tolling retriever dogs or “Tollers”, has left some uncertainty concerning the genetic basis for the disease complex. We would therefore like to explain our views and to clarify this subject and its implications for breeding. The disease is complex and has many genetic risk factors and therefore we cannot provide recommendations for breeders exclusively on the basis of genetic testing for dog leukocyte antigen (DLA) class II genotype.

1. The inheritance of the IMRD and SRMA disease complex All our data and all data we are aware of concerning the inheritance of IMRD and SRMA disease complex indicate complex inheritance. This means that there are several genetic factors involved that will influence the disease phenotype. Furthermore, environmental factors will also influence disease status. This means that any given Toller dog has inherited a particular combination of genetic risk factors and that the development of and severity of disease will depend on which combination of the genetic risk factors it has inherited, but also the overall genetic background and the environmental factors that the dog will experience during its lifetime. Importantly, like in other complex diseases, as a consequence of unique environmental exposure the disease aetiology for the disease complex will differ in different Tollers even though they have inherited the same set of genetic risk factors.

It should be noted that our genome-wide association (GWA) study presented in our Nature Genetics paper from 2010 (Wilbe et al. Nature Genetics 42:250-254) was based primarily on a case- control population of Tollers from Sweden and Finland and validated using Tollers from the US. In these Tollers, significant association was obtained for all five regions. Importantly, some were stronger than others and only two was shared between IMRD and SRMA. The frequency of the actual genetic risk factors may differ in different Toller populations present in different countries. However, they are likely to be similar given the population structure in Tollers and how the breed was created. All of the current Tollers, world-wide, are derived from a small group of dogs that survived two devastating outbreaks in the early 20th century of canine distemper virus epidemics. This resulted in what geneticists call “genetic bottle-necks” and a strong founder effect for the genetic risk factors causing IMRD and SRMA.

The results from the GWA study identified five regions containing many strong candidate genes involved in T-cell activation (Wilbe et al. Nature Genetics 42:250-254). In our Immunogenetics paper from 2009 (Wilbe et al. Immunogenetics 61:557-564) we showed that dog leukocyte antigen (DLA) is another genetic risk factor for development of IMRD. The studies provided conclusive evidence that there are multiple genetic risk factors underlying the IMRD and SRMA disease complex. Importantly, we showed that some of these risk factors were specific for IMRD and that some were common between IMRD and SRMA. The actual mutations causing the disease have not yet been conclusively determined. Intensive research efforts in our laboratory are in progress to identify and validate such mutations. When the mutations have been identified and correlated genetically to disease development genetic tests for all the mutations can be developed.

2. The role of dog leukocyte antigens (DLA) class II in Immune-mediated rheumatic disease The results presented in our Immunogenetics paper from 2009 (Wilbe et al. Immunogenetics 61:557- 564) identified one DLA class II type as a genetic risk factor for the immune-mediated rheumatic disease (IMRD) but not for steroid-responsive meningitis arteritis (SRMA). If a dog has inherited the risk DLA class II type from both parents it likely has an increased risk of developing IMRD. Importantly, the DLA class II type is not the only genetic risk factor, which means that some dogs without this risk factor can still develop IMRD and the opposite is also true. Some individuals with the DLA class II risk type do not develop disease. Our data clearly showed that homozygosity for the risk DLA type is increased among IMRD-affected Tollers. The results from this study were based on a case-control population, which means that we used all our cases and compared to the same number of healthy dogs. Therefore, neither the frequencies of diseased dogs nor the frequencies of haplotypes do reflect the total frequency in the Toller population. A total of five DLA class II haplotypes was identified and this is similar to most other dog breeds. Furthermore, Hughes et al. (Tissue Antigens 75(6):684-90, 2010) identified two additional haplotypes which gives the Tollers a total of seven known DLA haplotypes. Typically, one or a few DLA types are increased in frequency in any given dog breed. However, we cannot accomplish reduced incidence of IMRD only based on a breeding practice based on DLA genotyping. Inadvertent increase in the frequency of any of the other five known genetic risk factors may be a consequence. We anticipate that when we have DNA tests for all genetic risk factors and knowledge of how they interact we may be able to give potential breeding recommendations how to reduce incidence of the disease.

3. DNA tests and Recommendations for breeding Commercially available DNA tests for DLA have been offered to Toller breeders since 2010. This DNA test can be used to identify carriers of the DLA risk type in heterozygous or homozygous form. Any DNA laboratory skilled in the art of DNA testing can perform this test and there is no patent protecting its use. Importantly, we have not yet established diagnostic DNA tests for the other five genetic risk factors. The establishment of such tests will require some further research. However, at present testing for DLA only is of limited use. We cannot provide recommendations for breeders exclusively on the basis of genetic testing for dog leukocyte antigen (DLA) class II genotype. We strongly discourage breeders to perform their dog breeding only on the basis of DLA genotyping. This may lead to increased risk of inheriting unwanted combination of other major genetic risk factors for the disease complex. Attempts to reduce the incidence of the IMRD and SRMA disease complex can and should only be based on genotype data on all the genetic risk factors, thereby avoiding the most disadvantageous combinations of genetic risk factors. Therefore, there is no current way for breeders to perform DNA testing to reduce or eliminate this disease.

Göran Andersson1, Dannika Bannasch2, Helene Hansson-Hamlin3, Kerstin Lindblad-Toh4,5, Hannes Lohi6, Claire Wade7 and Maria Wilbe1 1Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Biomedical centre, Box 597, SE-751 24 Uppsala, Sweden.
2Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA 3Department of Clinical Sciences, SLU, Box 7054, SE-750 07 Uppsala, Sweden 4Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, SE-751 24 Uppsala, Sweden.
5Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. 6Department of Veterinary Biosciences, University of Helsinki, Box 63, 00014 Helsinki, Finland. 7Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia
September 12, 2011
Edit September 20: added links to Dr Bannasch's references

Wednesday, 7 September 2011

A ridge too far?

Illustration: Kevin Brockbank

The Rhodesian Ridgeback is an undeniably handsome beast: fit, functional and unexaggerated.  They have real presence and to meet one is to get some sense of why they were so valued in their native Africa - not just as a tough multi-purpose dog that could hunt, herd and protect, but one brave enough to track lion. Of course the cats they encounter these days are rarely bigger than next door’s moggie – and am sure they keep a very respectful distance.
As most people will know, the breed is marked by the ridge of hair that grows in an opposite direction along the dog’s spine, usually topped by a couple of swirls of hair, at the withers-end of the spine, called “crowns”.
The ridge originates from the breeds’ native African ancestors, some of whom had ridges, bred with European dogs to create the breed.  Some of these crosses had ridges, too, and the ridge became the hallmark of the dogs’ tough forbears. The belief also grew that the dogs with a ridge were better hunters – eventually leading to the ridge becoming the defining feature of the breed.
In fact, the genes that have been identified as being involved in the development of the ridge are known to govern tissue development, not temperament, so the presence of the ridge is unlikely to link to any functional advantage. But the story endures and the ridge is hugely cherished by Ridgeback breeders.
And there would be no harm in that except for two things – as we highlighted in Pedigree Dogs Exposed three years ago.
The first is that some ridgebacks are born without a ridge and, traditionally, these pups were often put to sleep (although this happens more rarely now). The second is that the ridge on the Rhodesian Ridgeback  (and the lesser-known Thai Ridgeback) has long been associated with a health problem – a condition called dermoid sinus (DS)  - and pups born with one or more DS are also sometimes put to sleep.
Dermoid sinus is a defect that is caused by the incomplete separation of the covering of the neural tube (from which the spine develops) and the skin during the development of the embryo.  It usually manifests in a pinprick-sized hole in the skin along the dog’s spine that leads to a narrow tube (a sinus).  The sinus can be of varying lengths – sometimes very shallow, occasionally deep enough to connect to the spinal cord – and they are troublesome because they can become infected. This infection can be life-threatening (particularly if the sinus is a deep one).
The most reliable data, from Swedish litter records, suggest that about five per cent of Ridgebacks are born without a ridge and about 10 per cent with dermoid sinus.  The most recent breed survey in the US found the reverse (ridgeless – 10 per cent; DS – five per cent)  and this survey also found that being born ridgeless was the leading cause of death in the breed (7.25 per cent) – with dermoid sinus the second (2.5 per cent).
But the US figures are 10 years old now (from 2001) and Ridgeback breeders insist that very few dogs are euthanised for either reason today. “I do not know a single person who puts down dermoids or ridgeless dogs any more,” says US breeder Ann Chamberlain.  “Back in the days, we put down the dermoid pups because otherwise their quality of life was compromised.  Now that the operation to remove the dermoid is so commonplace, and surgical techniques have improved so much, there is not one reason in the world to put the dog down. “
In the UK, rules brought in since Pedigree Dogs Exposed expressly forbid the culling of dogs for cosmetic reasons (in any UK breed), and some DS pups are now successfully operated on  – but unfortunately this is not true elsewhere. The Rhodesian Ridgeback Club of Ireland still requires that DS pups are “culled at birth”; so do the Swedish and Australian breed clubs. In fact, the RR Club of Victoria still advocates culling ridgeless (although does offer neutering as an alternative). 
Breeding for the ridge, then, still results in some puppies being killed.
Four years ago, Swedish scientists announced that they had worked out the genetics of both the ridge and dermoid sinus. Their findings, published in one of the most prestigious science journals in the world (Nature Genetics), caused a firestorm in Rhodesian Ridgebacks.
The scientists reported that:

• the ridge is a dominant trait – in other words, that a Ridgeback only had to carry one copy of the ridge mutation to have a ridge.
• the ridge mutation predisposes the dogs to dermoid sinus.
• the highest risk of dermoid sinus is in dogs that carry two copies of the ridge mutation.
• ridgeless dogs do not carry the ridge mutation and are therefore not at risk of dermoid sinus.
Lastly,  the Swedish researchers stated that that the incidence of dermoid sinus could be drastically reduced, maybe even eliminated, if breeders were willing to breed from Ridgebacks born without a ridge. To many Ridgeback breeders, this was tantamount to sacrilege as they’ve spent decades trying to get rid of ridgeless dogs.
The findings, then, raised a big ethical question: was adherence to the breed standard at simply too great a cost to the dogs – and should breeders dump the ridge as the hallmark of the breed?
Highlighting this in Pedigree Dogs Exposed caused a huge fuss and led to Rhodesian Ridgeback breeders receiving abuse from the public – abuse that they felt was very unfair.
Some of the abuse was unfair. We made a mistake in the UK version of Pedigree Dogs Exposed in referring to the ridge as “a mild form of spina bifida”.  In fact, it is dermoid sinus that some sources within the breed describe as being similar to a mild form of spina bifida, not the ridge. So although we were right in our central tenet – that breeding for the ridge costs some dogs their lives  – our mistake made the problem appear greater than it is.  For this, I would like to apologise to Rhodesian Ridgeback breeders.  
However, the fact remains that breeders have not acted on science that many people outside of the breed believe is sound enough to warrant a reconsideration of the ridge as such a defining feature of the breed.
 “There has never been any attempt to hide our known adverse condition of dermoid sinus in the Rhodesian Ridgeback , quite the reverse. We understand the problem and information is widely disseminated to the best of our ability," insisted  UK breeder Ann Woodrow in a recent article in a dog magazine. Ann featured in Pedigree Dogs Exposed, controversially putting the case for euthanizing dogs born without a ridge (essentially the fear that they would fall into the hands of "the fighting people"). “
Information in respect of how to detect and deal with dermoid sinus is, indeed, widely available - but information on using ridgeless to breed away from the condition is not. The Swedish research findings have never been published on the Rhodesian Ridgeback Club of Great Britain’swebsite - even though the Club part-funded the research - and Club guidelines still insist that ridgeless dogs should never be bred from.
I asked the Club if this was under review; also why they had not published the Swedish findings on their website and whether they were funding any current research.  Back came this brief statement:

“As the scientific research into dermoid sinus in the Rhodesian Ridgeback is still ongoing, there are no further details presently available.”
It essentially boils down to this: Ridgeback breeders believe that that the science – if not flawed - should be considered interim and that until further evidence is forthcoming, they should not change the way they breed their dogs.
 “Any one study's results, especially with such a small sample size, needs to be replicated to verify the original results,” says US Ridgeback breeder Jan Koler-Matznick. “As you know, many study results are amended or discounted with further investigations. So, this one study provided a basis to do a larger study on the inheritance of the DS, not definitive facts.”
It is of course true that all science is always subject to review. So is Jan right? “Nature Genetics only publishes research that meets the very highest standards of expert geneticist,” says editor Myles Axton. "The paper published in Nature Genetics in 2007 identifies a gene duplication in Rhodesian Ridgeback dogs that is responsible both for the ridge trait and for the predisposition to dermoid sinus… [It} provides enough evidence to give sound advice to the dog breeder on how both to produce the ridge trait and how to avoid the dermoid sinus defect.”
Even if it s true, though, Jan argues that the relatively low incidence of dermoid sinus is a mitigating factor. “Only around five per of dogs are born with dermoid sinus and most can be fixed with no resulting health consequence. That is a lot better than say 30% of some breeds having hip or elbow dysplasia and living on drugs or in pain most of their lives. Given the choices available, I don't see how Ridgebcks do not come out good for health issues in comparison to most breeds.”
The breeders have support from one of the authors of the Swedish research, Nikki Salmon Hillbertz. Nikki, who has Ridgebacks herself, is using a £13,250 grant from the Kennel Club to further research the link between the ridge and dermoid sinus. Questions that still need answering include: why doesn’t every Ridgeback with a double-dose of the ridge mutation develop dermoid sinus? And how come some dogs with only one copy of the mutation (although considered low-risk) have been born with a DS (as indeed, the Swedish research found)

The answer might simply be one of “expression” or “penetrance” – genes often have a “volume” button that varies their influence. Or it might be that there are other genes involved. The latter possibility, particularly, offers hope that a new genetic marker could be found to identify which dogs are most at risk of producing DS. Also useful would be a DNA test that can identify dogs that carry two copies of the ridge mutation in order to avoid breeding dogs with the highest risk of DS.
Another reason for caution, say breeders, is that since the research was published, there have been reports of Ridgebacks without a ridge being born with a dermoid sinus.  On the face of it, this is unexpected.  The Swedish scientists looked at 600 litters registered in Sweden and Germany between 1989 and 2003 and, of the 5,376 puppies recorded, not a single ridgeless dog was found with a dermoid sinus.
But there is an explanation: dermoid sinus does occur occasionally in other, non-ridged breeds. Cases have been reported in American and English Cockers, Boxers, Chows, Golden Retrievers, Shih Tzus, Siberian Huskies and Yorkshire Terriers.  In fact, DS sometimes occurs in humans, too. 
It is perfectly possible, then, for the occasional ridgeless ridgeback to have a dermoid sinus as an unlucky one-off ie. it is not thought to be inherited in any other breed than the Rhodesian and Thai Ridgeback.

But the stalemate endures - with most Ridgeback breeders arguing that the science is not definitive enough to change current breeding practice – and others disagreeing.
I asked geneticist and Boxer breeder Bruce Cattenach for his view. He says he is persuaded by the science. "In my view, despite the historical connection to ridging, which is presented as characterising the breed,  RR breeders would be best advised to breed away from the ridge in future.   I think tying the RR to the ridge diminishes this impressive breed.”

But at the last Rhodesian Ridgeback World Conference in 2008, just before Pedigree Dogs Exposed but after the key Nature Genetics paper was published, breeders voted overwhelmingly to keep the ridge as the “escutcheon” of the breed.
Shortly after, the senior authors of the Nature Genetics paper issued a statement* [see below] confirming their findings and again making the point they believed that dermoid sinus could be “virtually eliminated” if breeders were to accept and breed from ridgeless Ridgebacks. Like the original research findings, this has never been published on the UK Club’s website – nor on any other international Club websites that I could find, despite having been distributed to all Rhodesian Ridgeback Clubs worldwide – a strong indication, I believe, of how most breeders feel about the science
But I did find one breeder prepared to challenge the status quo - Ann Chamberlain, an American biologist and teacher who has been breeding Ridgebacks since 1965. Ann recently mated her ridgeless bitch to a dog thought to carry two copies of the ridge mutation. As the science predicts, she got a litter of nine puppies, all with a ridge and none with dermoid sinus (although this was not the reason for the mating).
“I bred my bitch because she is the most conformationally-correct dog I have ever owned and, otherwise, I would have lost the line,” says Ann, who will be donating their DNA to the further research effort. “I hope breeders will realise that under certain circumstances it may be beneficial to use a ridgeless dog or one with an imperfect ridge”.
Ann is not convinced by the science (she says she has only ever produced one dermoid sinus in 20 litters anyway) but she does feel that the breed should accept their ridgeless dogs and less than perfectly-ridged dogs – and says there are a handful of other breeders who feel this way, too.
“Ridgeless pups and those with other than perfect ridges should no longer be summarily discarded from the gene pool,” says Ann, who is currently conducting a world survey on Ridgebacks..  “We are discarding, potentially, the healthiest and most conformationally correct dogs for what is truly a ridiculous reason.  If the ridge had anything to do with function I would not advocate using anything but perfect ridges.  However, this is not the case and therefore, at times, I truly believe a breeder may actually need to use a ridgeless or a dog with a ridge anomaly.”
Closed stud books are not healthy for pure-bred dogs, especially a breed with very few founders.  Throwing out a third of your gene pool for the ridge is just plain stupid, no matter how you look at it. Since Rhodesian Ridgebacks had so few founders, it is genetically impossible to "outcross", as so many seem to think they can.  They simply do not understand that importing a dog from Australia to mate with an American dog is still shuffling the same genes, and who knows what has been lost along the way.” 
The Ridgeback row will, I fear, continue for many years – and I do understand why it is difficult for Ridgeback breeders to lose their attachment to the ridge.  But there is hope in breeders like Ann Chamberlain  - and in the fact that ridgeless dogs are now in greater demand as a pet (undoubtedly helped by the fact that breeders sell them for less, meaning you get an awful lot of dog for your money).
“You have no idea how many people ask for a ridgeless pup,” says Ann. “Now that the breed is so popular it is easy to place ridgeless and often easier than placing a ‘show’ prospect.“

This is good to hear and it does make it a little less of an issue than it used to be.  I also accept that the breed as a whole enjoys better overall health than many other breeds where a higher incidence of problems causes much less controversy.
But, bottom line, the breed standard still costs some Ridgebacks their lives. That  - in my view – is a problem.  But what do you think?
If you are a Ridgeback breeder, Ann Chamberlain would greatly appreciate help with a current breed survey. The survey form is online here . Or contact Ann Chamberlain:  email: mazoerr@gmail.com. Please feel free to crosspost this information.


THE STATEMENT FROM THE SWEDISH SCIENTISTS
To whom it may concern

A statement concerning the genetic basis for the hair ridge and the congenital malformation dermoid sinus in Rhodesian Ridgeback dogs

It has come to our attention that the recent World Congress of the Rhodesian Ridgeback Association has left some uncertainty concerning the genetic basis for the hair ridge and the dermoid sinus in Rhodesian Ridgeback dogs. We would therefore like to clarify this subject and its implications for breeding.

1. The inheritance of the Ridge
All our data and all data we are aware of indicate that the Ridge is inherited as a fully dominant trait. The dominant allele causing the Ridge is denoted R whereas the recessive wild type-allele is denoted r. This means that a ridged dog may either be homozygous (R/R) or heterozygous (R/r) for the Ridge allele whereas all ridgeless dogs should be homozygous r/r for the normal allele. The result presented in our Nature Genetics paper from 2007 (Hillbertz et al. Nature Genetics 39:1318-1320) provided conclusive evidence that the mutation causing the ridge in Rhodesian Ridgeback as well as in Thai Ridgeback dogs is a 133 kb duplication on dog chromosome 18. [A duplication means that each Ridge chromosome has two copies of this 133 kb fragment whereas a normal chromosome has only a single copy. It is this doubling or duplication of the chromosome region that constitutes the Ridge mutation.] So far all tested dogs with the characteristic dorsal hair ridge have been heterozygous or homozygous for this mutation whereas all ridgeless dogs we have tested lacked the duplication. The duplication contains four complete genes (FGF3, FGF4, FGF19 and ORAOV1) and we assume that it is the higher than normal expression of one or more of these genes, attributable to their greater number, that leads to the development of the hair ridge.

2. The genetic basis for dermoid sinus (DS)
The mode of inheritance of DS is not as clear as the inheritance of the Ridge but our data clearly showed that the Ridge mutation (i.e. the duplication described above) is the major risk factor for the DS malformation in Rhodesian Ridgeback dogs. Most DS dogs in our study were homozygous R/R (10 of 12) for the Ridge mutation but two were classified as heterozygous R/r. However, DS or DS-like malformations also occur in humans so it is possible that this type of malformation may occur in dogs in the absence of the Ridge mutation. But its frequency in unridged Ridgebacks should be as rare as it is in non-ridged breeds.

3. DNA tests
In our Nature Genetics paper we described a simple DNA test that can be used to identify the presence of the Ridge mutation (the duplication). Any DNA laboratory skilled in the art of DNA testing can perform this test and there is no patent protecting its use. It is therefore easy to distinguish a ridged dog (R/R or R/r) from a ridgeless dog (r/r) by the DNA test but we have not yet established a diagnostic test that on a routine basis can distinguish animals that are heterozygous carriers (R/r) from homozygous ridged (R/R) with 100% certainty. The establishment of this test will require some further research. 

4. Recommendations for breeding
The most straightforward way of reducing the incidence of DS in Rhodesian Ridgeback dogs is to reduce the frequency of homozygotes for the Ridge mutation. This can be accomplished by allowing the use of ridgeless dogs for breeding. While we are aware that dogs with a DS are not usually kept for breeding, matings between homozygous (R/R) ridged dogs (presumably without DS) and ridgeless dogs (r/r) would give progeny all of which would be heterozygous ridged (R/r) and therefore show ridging, and the incidence of DS would be low. In matings between a heterozygous ridged dog (R/r) and a ridgeless dog (r/r), 50% are expected to be heterozygous ridged (R/r) and 50% are expected to be ridgeless (r/r). In these matings no homozygous ridged progeny, which are the major problem as regards the incidence of dermoid sinus, would occur. It should therefore be possible to retain the ridge while keeping the incidence of DS to its absolute minimum. It would be useful to develop a diagnostic test to distinguish carriers (R/r) from homozygotes (R/R) because this would allow breeders to avoid matings such as R/R x R/r that will produce homozygous ridged (R/R) progeny.
            It will of course be decided by the individual breeders and to Ridgeback breeding organizations whether they prefer to keep the Ridge and minimize the incidence of DS using the approach described above or whether they would like to completely eliminate the problem with DS by allowing the Ridge mutation to disappear from the population over time. If one decides to eliminate the Ridge mutation it should not be done too quickly (during a few generations) since that will lead to increased inbreeding in the breed as too many potential breeding animals are eliminated.

Leif Andersson1, Kerstin Lindblad-Toh1,2 and Göran Andersson3

1Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, SE-751 24 Uppsala, Sweden.
2Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
3Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Biomedical centre, Box 597, SE-751 24 Uppsala, Sweden.

This article is adapted from the version that appears in the September 2011 issue of Dogs Today magazine.  Dogs Today is now available internationally for iPad and iPhone for the bargain price of 59p for the app, which includes one edition free.

Thursday, 1 September 2011

Does greater inbreeding always mean poorer health?


I spend a lot of time writing about the perils of inbreeding so it's interesting to find a report - albeit a preliminary one - that found that inbreeding did not lead to poorer health.

"One problem in modern dogs is a high occurrence of physical diseases, defects, and disorders. Many breeds exhibit physical problems that affect individuals already at young ages, and veterinary care and/or various drugs are in some cases needed throughout life," report the authors of the report in the Veterinary Journal of Behaviour . "A potential cause of these problems is inbreeding and loss of genetic variation that is known to reduce the viability of individuals and is associated with increased occurrences of hereditary disorders governed by autosomal recessive alleles. During recent years increasing conservation genetic focus has been devoted to domestic animal populations. This attention includes both scientific efforts and international and national policy work. Domestic populations are traditionally bred through strong selection. Only a few animals are used in breeding, resulting in considerable loss of genetic variation. Conservation breeding aims at reducing the rate of loss of genetic variation, and this includes reducing selective pressures. This research addresses the question of whether “unhealthy” dog breeds exhibit elevated rates of inbreeding and loss of genetic variation as compared to “healthy” breeds."
The researchers used pedigree records from the Swedish Kennel Club database and classified the 14 breeds they looked at as "healthy" or "unhealthy" based on data from four Swedish pet insurance companies.

The “unhealthy” breeds were Bull Mastiff, Dogo Argentino, Bulldog, Mastiff, Neapolitan Mastiff, Irish Wolfhound and Shar Pei,. The “healthy” breeds were Finnish Lapphund, Norrbottenspitz, Norwegian buhund, Norwegian elkhound black, Småland hound and Coton de Tuléar.

The preliminary results did not find any difference between healthy and unhealthy breeds with respect to the average level of inbreeding among living animals. However, there were indications that the rate of loss of genetic variation was slightly higher among unhealthy breeds.

The authors stress that the results are preliminary. The pedigree data only went back to the start of the Swedish KC electronic database (around 1970) so may not be a true indicator of the breeds' level of inbreeding. The researchers also only looked at small-population breeds. But the findings are interesting nevertheless and serve to illustrate that inbreeding may not always result in a less-fit population.

"The plan is to also include breeds with larger population sizes and we hope to publish something more this winter," says co-author Mija Jansson, a population geneticist from the Institute of Zoology at Stockholm University.