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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.
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