However I will keep stressing the more the merrier.    We need to run the WGS on multiples of 12 samples, so 24, 36, 48 etc.  As we hopefully will have 15/16 cases + 13 controls we are already over 24 samples, so it makes sense to aim for at least 36 samples by the time the new SNP chip arrives. 

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Canine Genetics Progress Report : February 2010

Canine Genetics Progress Report

Breed: Gordon Setter

Condition: Progressive Retinal Atrophy

Date: February, 2009

Recent / Current Funding:

The AHT staff that are currently investigating PRA in the Gordon Setter are generously supported by the Kennel Club, as part of the Kennel Club Genetics Centre at the Animal Health Trust, but resources such as consumables and laboratory materials are currently being funded by donations from breed clubs and individuals.

The AHT has received donations totalling almost £11,000 towards the cost of the PRA research from Gordon Setter Clubs, Associations and Societies, as well from a number of individuals. In addition, the Lupa consortium (www.eurolupa.org), of which the AHT is a member, has agreed to fund the cost of an initial Whole Genome Scan (WGS) with 42 samples, at a cost of approximately £6300, which is very good news because it means the total £11,000 can be preserved for subsequent stages of the research.

 Sample Collection and Current Progress

The AHT currently holds samples from 86 Gordon Setters. Eighteen samples are from dogs that are affected, or are probably affected, with generalised progressive retinal atrophy (gPRA). Nineteen samples are from dogs with clear eyes that were over the age of 10 at their last eye examination, and 10 of those dogs were over the age of 11. Because PRA has such a late age of onset in the Gordon Setter it is very important we collect samples from dogs with clear eyes (controls) that are as old as possible, so we can sure they are truly free of the disease.

It is very important that the AHT is told about any relevant health changes that occur to any of the dogs we hold samples from. For example, if any of the dogs develop gPRA after their DNA sample has been submitted to the AHT it is very important the AHT is informed. Dogs that are incorrectly categorised as ‘unaffected’ when they are in fact affected (or vice versa) can seriously confound genetic studies.

Brief Summary of Project

In brief, this project aims to compare the DNA from Gordon Setters affected with PRA with DNA from unaffected dogs and identify a region of the genome that is consistently similar between the affected dogs and different in the unaffected dogs. This is known as a Whole Genome Association Analysis (GWAS). Once a region associated with PRA has been identified we will carry out additional experiments to investigate the region in greater depth and to possibly reduce and refine the region. This stage of the project is known as ‘fine-mapping’. When we have refined the region as much as possible we will sequence candidate genes within the region to find the actual mutation responsible for each condition and develop a DNA test that we will offer to breeders.

Current Activities

We were informed of LUPA’s decision to cover the cost of the GWAS on 10 th February, 2010, and now we will proceed to:

• double check all the information we have for each dog
• select which 42 dogs (a mixture of cases and controls) will be included in the initial GWAS.
• extract, purify and quality control DNA from each selected sample
• submit the DNA from the 42 cases and controls to the LUPA genotyping centre

We plan to submit the DNA within the next four weeks (by mid March), and hope to receive the WGS data back within 6 weeks (end of April). The analysis will take several weeks, but by the end of May we hope to know whether the GWAS has identified a region of the genome that is associated with PRA in the Gordon Setter.

To request a DNA swab sampling kit please email Bryan McLaughlin (Bryan.mclaughlin@aht.org.uk)

For more information about the project please email canine.genetics@aht.org.uk

The Animal Health Trust would like to thank all Gordon Setter owners and breeders who have submitted samples and information from their dogs, and/or who have made financial contributions to the project. The DNA technology available with which to identify mutations is now exceptionally sophisticated but nevertheless is of little use without DNA from appropriate dogs or without sufficient funding. The

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PRA AHT Research Update : June 2010

"The DNA samples have been sent off to the genotyping centre in France and we are waiting to hear when we can expect the data. I am very hopeful that the genotyping data will reveal the position of the mutation and that we will be in a good position to offer a test soon."
Dr Cathryn Mellersh, Animal Health Trust

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PRA AHT Research Update : August 2010

Canine Genetics Progress Report

Breed: Gordon Setter

Condition: Progressive Retinal Atrophy

Date: August, 2010

Recent / Current Funding:

The AHT staff that are currently investigating PRA in the Gordon Setter are generously supported by the Kennel Club, as part of the Kennel Club Genetics Centre at the Animal Health Trust, but resources such as consumables and laboratory materials are currently being funded by donations from breed clubs and individuals.

The AHT has received donations totalling almost £11,000 towards the cost of the PRA research from Gordon Setter Clubs, Associations and Societies, as well from a number of individuals. In addition, the Lupa consortium (www.eurolupa.org), of which the AHT is a member, has agreed to fund the cost of an initial Whole Genome Scan (WGS) with 42 samples, at a cost of approximately £6300, which is very good news because it means the total £11,000 can be preserved for subsequent stages of the research.

 Sample Collection and Current Progress

The AHT currently holds samples from 122 Gordon Setters. Twenty four samples are from dogs that are affected, or are probably affected, with generalised progressive retinal atrophy (gPRA). Nineteen samples are from dogs with clear eyes that were over the age of 10 at their last eye examination, and 10 of those dogs were over the age of 11. Because PRA has such a late age of onset in the Gordon Setter it is very important we collect samples from dogs with clear eyes (controls) that are as old as possible, so we can sure they are truly free of the disease.

It is very important that the AHT is told about any relevant health changes that occur to any of the dogs we hold samples from. For example, if any of the dogs develop gPRA after their DNA sample has been submitted to the AHT it is very important the AHT is informed. Dogs that are incorrectly categorised as ‘unaffected’ when they are in fact affected (or vice versa) can seriously confound genetic studies.

Brief Summary of Project

In brief, this project aims to compare the DNA from Gordon Setters affected with PRA with DNA from unaffected dogs and identify a region of the genome that is consistently similar between the affected dogs and different in the unaffected dogs. This is known as a Whole Genome Association Analysis (GWAS). Once a region associated with PRA has been identified we will carry out additional experiments to investigate the region in greater depth and to possibly reduce and refine the region. This stage of the project is known as ‘fine-mapping’. When we have refined the region as much as possible we will sequence candidate genes within the region to find the actual mutation responsible for each condition and develop a DNA test that we will offer to breeders.

Recent Progress

DNA from forty two Gordon Setters was submitted for genotyping to Centre National de Génotypage (CNG) the genotyping centre used by the LUPA consortium. The genotyping data, which consisted of 172,000 separate genotypes for each of the 42 dogs, was returned to us during July and has now been analysed. We are extremely please to be able to report that we have identified a single region of the canine genome that is significantly associated with PRA in this breed – in other words, we have identified the region of the genome that contains the mutation that is causing PRA in this breed. This stretch of DNA has not been previously associated with PRA in any other breed, which means the Gordon setters have a new mutation that has not been identified before. DNA is a very complex molecule and a very simple analogy is to think of DNA as beads on a string. The canine genome (the complete genetic composition of an animal) consists of 2.4 x 10 9 (two and a half thousand million) nucleotides (beads) of DNA. If each nucleotide was 1mm long the canine genome would stretch from Land’s End to John O’Groats and back again. We have now narrowed the search for the Gordon Setter PRA mutation to about 2km of road on the route from Land’s End to John O’Groats and back. This means we still have to hunt through 2 million nucleotides of DNA, but as this is less than a tenth of 1 per cent of all the DNA the dog has this should be considered a major breakthrough.

The Next Steps

We will now examine in depth the 2 million nucleotides of DNA where we know the mutation resides. If we are lucky we will find a provocative ‘candidate gene’ that has been shown to cause a similar disease in another species, or that has a function that we might expect to cause PRA if disrupted. If that is the case we will home in on that gene and examine it in depth. If no such genes are present we will have to examine all 2 million nucleotides, one by one, to find the precise mutation that is causing PRA. Depending on what we find as we begin this phase of the work will determine how long it will be until we identify the mutation, but a major milestone has been reached.

To request a DNA swab sampling kit please email Bryan McLaughlin (Bryan.mclaughlin@aht.org.uk)

For more information about the project please email canine.genetics@aht.org.uk

The Animal Health Trust would like to thank all Gordon Setter owners and breeders who have submitted samples and information from their dogs, and/or who have made financial contributions to the project. The DNA technology available with which to identify mutations is now exceptionally sophisticated but nevertheless is of little use without DNA from appropriate dogs or without sufficient funding.

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BVA Eye Scheme Update : February 2011

Gordon Setters were put on Schedule B (under investigation) of the scheme in January 2010. The BVA will be publishing a report on their findings sometime in April.

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PRA AHT Research Update : February 2011

 

Identification of Mutation for Progressive Retinal Atrophy in the Gordon Setter

A mutation responsible for the development of Progressive Retinal Atrophy (PRA) in the Gordon Setter has been identified by geneticists working in the Kennel Club Genetics Centre at the Animal Health Trust.

PRA is a well-recognised inherited condition that many breeds of dog are predisposed to. The condition is characterised by bilateral degeneration of the retina which causes progressive vision loss that culminates in total blindness. There is no treatment for PRA.

Owners report that their affected dogs develop night blindness in the first instance, which is indicative of a rod-cone degeneration, so we have termed this mutation rcd4 (for rod-cone degeneration 4) to distinguish it from other, previously described, forms of rod-cone degeneration.

The mutation is recessive and 19 out of the 21 Gordon Setters in our study that had clinical signs of PRA were homozygous (carried two copies) for this mutation, indicating it is the major cause of PRA in the breed. Two dogs in our study had PRA but did not carry the rcd4 mutation, indicating there might be another, genetically distinct, rarer form of PRA segregating in this breed.

The Animal Health Trust has developed a DNA test for the rcd4 mutation that will be available from Monday 14 th March, 2011. DNA test kits will be available to order online, via our website (www.aht.org.uk) from March 14 th. The price of the test will be £48 per sample, which includes VAT.

The research that led to identification of the rcd4 mutation was funded by many different organisations, including the Kennel Club Charitable Trust, the British Gordon Setter Club, the Gordon Setter Field Trial Society, the Gordon Setter Association, the Gordon Setter Club of Scotland and the LUPA project (www.eurolupa.org.uk) as well as several individuals who have also contributed significantly. The AHT would like to thank sincerely all the organisations and individuals who donated funds to help support the research as well as all the owners who contributed DNA and information from their dogs.

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Gordon Setter Breed Council PRA Seminar - 17th April 2011

The first opportunity to find out more about the current situation re PRA and the new DNA test will be at a Seminar following the GSA AGM. This will be a Gordon Setter Breed Council Seminar hosted by the GSA. Speaker : Dr Jeff Sampson BSc DPhil - Kennel Club Canine Genetics Coordinator. Time 12.30 for lunch, start at 1.00 pm. Venue : Stoneleigh Village Hall. Cost : £7.00 per person to include light lunch. Tickets and further information from Kathryne Wrigley, Tel: +44 (0) 1530 814885, Email: Kathryne Wrigley.

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Progressive Retinal Atrophy in the Gordon Setter - 8th March 2011 

Progressive Retinal Atrophy in the Gordon Setter

Progressive Retinal Atrophy (PRA ) is a well-recognised inherited condition that many breeds of dog are predisposed to. The condition is characterised by bilateral degeneration of the retina which causes progressive vision loss that culminates in total blindness. There is no treatment for PRA, of which several genetically distinct forms are recognised, each caused by a different mutation in a specific gene. The various forms of PRA are typically breed-specific, with clinically affected dogs of the same breed usually sharing an identical mutation. Clinically affected dogs of different breeds, however, usually have different mutations, although PRA-mutations can be shared by several breeds.

Mutation Identified

Geneticists at the AHT have identified a recessive mutation that is associated with the development of PRA in the Gordon Setter . The DNA test we are offering (from March 14 th 2011) examines the DNA from each dog being tested for the presence or absence of this precise mutation and is thus a ‘mutation-based test’ and not a ‘linkage-based test’.

Other Forms of PRA

The research we have carried out to identify the PRA mutation has revealed that there are at least two forms of PRA segregating in the Gordon Setter. The DNA test we are offering is for the mutation that causes one of these forms, which we are calling rcd4 ; the mutation that causes the additional form has yet to be identified.

Our research indicates rcd4 is the most common form of PRA among Gordon Setters and the development of this test therefore enables breeders to slowly decrease the frequency of an important form of PRA in their lines. However, because we know that at least one other form of PRA exists within the breed, we cannot guarantee that any dog will not develop PRA, even if they are clear of the rcd4 mutation.

Breeders using the test will be sent results identifying their dog as belonging to one of three categories:

CLEAR : these dogs have two normal copies of DNA. Clear dogs will not develop PRA as a result of the rcd4 mutation, although we cannot exclude the possibility they might develop PRA due to other mutations they might carry that are not detected by this test.

CARRIER : these dogs have one copy of the mutation and one normal copy of DNA. These dogs will not develop PRA themselves as a result of the rcd4 but they will pass the mutation on to approximately 50% of their offspring. We cannot exclude the possibility that carriers might develop PRA due to other mutations they might carry that are not detected by this test.

GENETICALLY AFFECTED : these dogs have two copies of the rcd4 mutation and will almost certainly develop PRA during their lifetime. The average age of diagnosis for dogs with rcd4 is 10 yo, although there is considerable variation within the breed.

Advice

Our research has demonstrated that the frequency of the rcd4 mutation in Gordon Setters is high and as many as 50% of dogs might be carriers. The mutation is recessive which means that all dogs can be bred from safely but carriers and genetically affected dogs should only be bred to DNA tested, clear dogs. About half the puppies from any litter that has a carrier parent will themselves be carriers and any dogs from such litters that will be used for breeding should themselves be DNA tested prior to breeding so appropriate mates can be selected.

It is advisable for all breeding dogs to have their eyes clinically examined by a veterinary ophthalmologist prior to breeding and throughout their lives so that any cases of PRA caused by additional mutations can be detected and that newly emerging conditions can be identified.

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DNA TEST FOR PROGRESSIVE RETINAL ATROPHY (rcd4) IN GORDON SETTERS - 8th March 2011

DNA TEST FOR PROGRESSIVE RETINAL ATROPHY (rcd4) IN GORDON SETTERS

The Animal Health Trust is pleased to announce the launch of our DNA Test for progressive retinal atrophy in Gordon Setters. Further details of the test, which has been developed from research at the Animal Health Trust, are given in the Information Sheet attached.

You will be able to order the test from the 14th March 2011 by going to our WebShop (http://www.ahtdnatesting.co.uk/) or via the Animal Health Trust Website http://www.aht.org.uk/genetics_tests.html).

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DNA TESTING UPDATE - 14th March 2011

Now that the Animal Health Trust has made a DNA test available for PRA in Gordons, the Breed Council has asked the Kennel Club / AHT to set up a Health scheme to cover this. More information will follow on this.

A letter has gone from The Breed Council to ask the AHT to make permanent ID , a mandatory requirement for the test. This will have to be verified by a veterinary professional.

Once in place samples not fitting this criteria will be rejected.

Anyone sending in dna samples immediately should therefore get this ID done by their own vet before they send it in. There is a place on the form you get with the dna kit for your vet to sign.

To keep costs down the BC is looking into the feasibility of holding testing days at the earliest opportunity

Elaine Roberts
GS Breed Council Chairman

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Gordon Setter Breed Council PRA Release Form - 29th March 2011

Gordon Setter Breed Council : Seminar April 2011

Late Onset PRA rcd-4 Speaker: Dr Jeff Sampson

In the wake of the recently available dna test from the Animal Health Trust Dr Sampson made the following main points:

1. It is evident that there is a wide age range for onset of PRA in Gordon Setters – on average it is confirmed at around 10 years of age but there have been cases as young as 6. There are several Gordons who are genetically Affected but with perfect eyesight and clinically Clear certificates at 11 and 12 years of age and who will never develop the problem in their lifetimes.

This is encouraging and it gives us some time to deal with the problem as it means we do not a have something which is causing dogs to suffer terribly from a young age.

Two dogs in the research showed a different form of PRA and if more dogs appear with this type more research will be needed and owners must be vigilant.

2. We must be careful not to “throw out the baby with the bathwater”, in other words not to concentrate so much on eradicating PRA that we deplete the genetic pool and then encounter other problems. It will take some time to get an accurate picture of how many Clears / Carriers / Affected dogs we have. We may need to use Carriers to Clears for a short while to avoid this.

The AHT will provide analysis on carrier frequency.

3. Breeders should make use of dna testing of litters to ensure progress is made. They should also use Kennel Club endorsements to determine which puppies are to be bred from. The breeder must own the dog at the time the endorsement is put on and stipulate in writing the full meaning of it and why it might be lifted; this must be signed by all parties. Endorsements can only be lifted by the Breeder.

4. The Gordon Setter Breed Council confirmed that with the agreement of all the Breed Clubs, they had requested that the Kennel Club set up a Health Scheme to cover PRA. Once this is operational the KC will publish dna results in Breed Records Supplement, KC website (Health Finder and Mate Select). Registration Certificates will be marked with these results.

If both parents are genetically CLEAR a new Registration Certificate can be issued denoting that the progeny is HEREDITARY CLEAR without the need for further dna testing.

The Registrations scheme is likely to advise: DNA test before mating:

CLEAR – no restrictions

Carrier – restrictions (very unlikely any dog would be discarded because it was a Carrier) ; should not be mated to an untested dog ;should not mate to another Carrier;

Should not be mated to an AFFECTED.

When a CARRIER is mated to a NORMAL litter screening advised to identify CARRIERS.

Advice was to pick a puppy because it is a quality specimen in the first instance not because of its genetic status.

5. Clinical Eye Testing is recommended for all breeding stock. Dr Sampson suggested he would clinically test when young, in middle age and in old age.

6. The Gordon Setter Breed Council confirmed that until the KC Scheme gets going they will keep and publish on the website lists of CLEAR/CARRIER/AFFECTED dogs. Documentary evidence must be submitted and ID checked by a vet.

Dr Sampson indicated that he was not so concerned about ID and it is not an AHT requirement. Any mistakes would very quickly be discovered.

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