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 109 (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.