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Breeding out inherited diseases


The Dandie Dinmont Terrier Club held a study day on the 2nd February at the Sitwell Arms, Renishaw, Derbyshire, writes Frances Chapman-King. A recent Health Survey conducted among Dandie owners by the Animal Health Trust has shown that one in 20 Dandies are likely to develop Glaucoma. This means that they go blind over a short period of time.

Dr Jeff Sampson, (KC Canine Geneticist) gave an excellent presentation on genetics and the Canine Genome Project and Dr James Wood (Head of Epidemiology AHT) similarly gave us an excellent presentation on the findings of our Health Survey and the way forward in Dandie Dinmonts.

Ever wondered how a single, fertilised egg becomes a perfectly formed individual of its species?

Each fertilised egg contains a set of plans used to control growth and division of cells and is also able to decide which cells become kidney cells, retinal cells etc. These plans are stored in the genes and are made of a complex molecule call DNA. Each fertilised egg contains two complete sets of genes, one from the dam and one from the sire.

It takes some 40,000 different genes to make a dog and these are spread amongst 38 chromosomes and two sex chromosomes. Sometimes the plan within the gene becomes altered by a process known as mutation.

The consequences of a mutation are variable. Some mutations have no consequences; others can affect the gene to cause disease. The main point is that once a mutation has occurred within a gene it is fixed and cannot be reversed. The mutated gene is then passed on and if the consequence of the mutation is a disease state we now have an inherited disease.

Mutation can be caused by certain chemicals or radiation or by a ‘copying’ mistake occurring during cell division. Mutations are either dominant or recessive, involving single genes or can be polygenic (mutation of more than one gene) i.e. hip dysplasia.

A gene is a unit of inheritance and a determinant of a given characteristic. Both male and female contribute to the characteristics of the offspring.

There are 370 diseases in the dog in which inheritance is known to play a part (Patterson’2000), as compared to over 5000 in humans. Of these 370 the vast majority, where the mode of inheritance is known, result from recessive mutations in single genes.

Diseases caused by recessive mutations are the most difficult to address by breeders, as dogs that are clinically normal; may be carriers with one mutant gene. These clinically normal, but carrier dogs and bitches will pass their mutant gene versions on to approximately 50% of their offspring.

In Polygenetic diseases, the story is more complex to unravel as the disease can be seen to skip generations and appear erratic in occurrence.

Another very important factor is that the gene mutation causing the same disease in more than one breed can and has been proven to be caused by different genes in different breeds. i.e. Von Willebrand disease in Dutch Kooikerodgs, West Highland White Terriers and Dobermanns. (Slappendet et al 1998)

Glaucoma in Dandie Dinmonts is unique in its clinical presentation than in other breeds and is likely to be polygenic.

Identifying just one gene in the 40,000 genes that causes an inherited disease is a real ‘genetic needle in a haystack’ problem.

However, some disease in the dog is clinically very similar to inherited disease recognised in man. This enables scientists on rare occasions to take a spectacular short cut and exploit the advances in human medicine to the dog’s advantage. (e.g. CLAD in Irish Setters.) This is called the candidate gene approach.

Unfortunately this candidate gene approach does not exist for the majority of the inherited disease conditions in the dog. Candidate genes can be a very expensive Blind Alley.

Unique

Therefore we need another approach. We know there are 40,000 genes spread amongst 38 chromosomes and two sex chromosomes. Any particular mutant gene will be uniquely position somewhere along one of the chromosomes. Hence the Canine Genome Project - the aim to create a genetic map of the dog.

A useful analogy is to consider a car journey from A to B. If all you have is a fuzzy map of the country, No Road Signs, No Motorways, No Street Names etc. Extremely difficult or impossible to do.

With a genetic map, for our car journey from A to B we get a clear picture, with a road map, motorways and even street names that we can use to pinpoint our exact location.

The work that has generated the present genetic map of the dog has involved placing DNA markers along the length of each and every chromosome, and can also recognise just one of the two chromosome copies (from sire or dam).

The most recent genetic map of the dog includes over 1600 different DNA markers, so we have the motorways and some towns on the map, but few street names and addresses yet.

How does the map help to track down the genes responsible for inherited disease?

By comparing the DNA of clinically affected dogs and the clinically clear dogs and then analysing them with the markers that make up the map to see if any of the markers are always present in affected dogs, and known carriers, but not always present in clinically clear dogs. The marker then gives the link to the disease gene.

This requires analysis of some 50 to 100 dogs with at least 10 that are clinically affected.
A new and exciting aspect of the Canine Genome Project, which promises to have a far greater impact on our ability to identify individual genes in the dog has been pioneered by The Animal Health Trust, Newmarket in collaboration with scientists at the nearby world famous Sanger Centre. The Sanger Centre scientists were at the forefront of the worldwide effort to map the Human Chromosomes (23 chromosomes in man).

Together they have managed to separate and purify all 38 canine chromosomes, and 23 human chromosomes into pots. By some amazing scientific techniques these have been turned into chromosome-specific fluorescent paints.

So if you mix canine and human florescent paint it has been found that you can link which canine and human chromosomes correspond and contain exactly the same genes.

Dogs apparently have essentially the same genes in their DNA as humans. This has great significance. Within the next few years we will know where each and every human gene is to be found and we will know what it does.

When we do, we will also know all of the genes of the dog. This will enable us to put in the ‘street names and addresses’ on our canine map.

Once the mutant gene has been identified, a DNA Test can be developed. This will enable us, as breeders, to use DNA testing as part of our selection process in our breeding programmes.

WE MUST LAY DOWN our DNA banks NOW for future reference.

Simply removing carriers and affected dogs may not work in breeds with a small gene pool as you may throw the baby out with the bath water.

The availability of a DNA test allows much more subtle manipulation of breeding programmes to reduce the frequency of a particular mutation whilst retaining some of the positive features present in affected lines.

Thus carrier and even on occasion affected dogs will be used on clear dogs with the resultant offspring screened to ensure only clear or carriers are retained in the breeding programme and so on, until all affected and carriers are eliminated from the breeding programme.

Concerned

Meantime breeders have to use epidemiology, or the study of disease to inform their breeding programme.

In Dandies we are currently looking at primary Glaucoma as the disease to tackle first. Our survey shows that we are right to be concerned, with 12% of dogs in the survey over five years with primary Glaucoma.

Primary Glaucoma in man is of slow onset and is open angle.

Primary Glaucoma in Dandies is closed/narrow angle with precipitous onset with second eye usually following first eye fairly rapidly.

Secondary Glaucoma is a different disease and occurs as a result of some other disease i.e. Uveitis, Lens Luxation.

Different disease = different genes and research into causes of Secondary Glaucoma will not help to identify cause or prevention of Primary Glaucoma.

This is most important as currently dog lovers world wide are getting mixed or confused messages that research into lens luxation with Secondary Glaucoma in other breeds using a candidate gene approach may benefit Dandie Dinmont Terriers. These claims do not bear scrutiny and are the means by which Molecular Biology will be discredited in the eyes of dog lovers for giving false hope.

Already we have seen this happen in other instances (e.g. PRA different in different breeds, different genes, different DNA test) and also when some overseas laboratories insist on maintaining high fees, in this country, for DNA tests perfected abroad.

Breeders and dog lovers need to be sure they know the facts before investing personal or club funds in this way.

For Dandies with Primary Glaucoma the Animal Health Trust are prepared to work with us on a screening programme unique to our own breed and disease to maximise prevention during the period that the DNA technology needs to provide us with a test for this polygenic condition.

The Dandie Dinmont Terrier Club is working with the Animal Health Trust to put this programme in place. Watch our website (address) or contact the Club Secretary Pam Bradley, dog@pamela22.freeserve.co.uk or my self inzievar@freeuk.com.