快猫短视频

AS PUPPIES, the dogs seemed no different from their litter mates. The
disease developed insidiously. By the age of two their night sight had
deteriorated, and by middle age they were completely blind. The cruel irony
was that these dogs were Labrador retrievers bred to become guide dogs for the
blind.

The animals had inherited a disease called progressive retinal atrophy
(PRA) which afflicted many of the animals trained by the Guide Dogs for the
Blind Association during the 1970s and 1980s. Screening young dogs for early
signs of the disease has prevented new cases developing in the past five
years. But the condition could return if new dogs are brought in for breeding
purposes. This potential threat, along with past experience, persuaded the
charity to fund a research project at the Animal Health Trust (AHT),
Newmarket. The aim of the project, which was set up in 1991, was to help to
eradicate PRA and many of the 300 genetic diseases which affect pedigree dogs.
A similar project was being funded in the US by the American Kennel Club.

Working with colleagues at the University of Leicester and several research
institutes such as University of California at Berkeley and the University of
Michigan in the US, the British scientists are mapping the DNA of the dog.
When the map is complete, it will enable scientists to develop diagnostic
tests for conditions like PRA which are caused by a mutation in a single gene,
and may eventually lead to treatments for hereditary diseases in dogs, and
could help researchers investigating the genetic basis of diseases in
humans.

The project is also expected to shed new light on the genetic basis of
behavioural traits in retrievers, such as guarding and retrieving. It should
also improve our understanding of the genetic basis of body shape in an animal
which is second to none in its astonishing variety. Given the same range in
humans you might find adults little bigger than three-month-old babies and
giants weighing more than half a tonne.

Any genetic disease is caused by random mutations in the DNA which persist
and are passed on to succeeding generations. Such conditions seem to be more
common in dogs than in other species because many breeders mate animals which
are closely related and therefore genetically similar. 鈥淭here are just crazy
levels of inbreeding in many breeds of dogs,鈥� according to Jasper Rine, of the
University of California, Berkeley, one of the leaders of the dog genome
project.

The bulk of canine disorders are caused by recessive genes which means that
a faulty gene must be inherited from both parents for the dog to develop the
disease. Inbreeding increases a dog鈥檚 chance of inheriting two copies of the
faulty gene. Genetic diseases which are dominant have been largely stamped out
鈥� here the disease will develop even if the faulty gene is inherited from only
one parent, so the affected animals can be identified and stopped from
breeding.

A breeder may suspect that a disease has a genetic basis when several dogs
in a kennel are affected. Vets may notice higher than expected numbers of dogs
in a breed with the same defect. Any organ in the body can be affected, but
defects involving the bones and joints, eyes and nervous system have been
easiest to identify because they produce the most obvious clinical signs. In
recent years, as veterinary diagnosis has become more sophisticated thanks to
new medical procedures, it has been possible to identify other genetic
conditions, affecting the heart, blood and hormone system. Poodles, collies
and Pomeranians, for example, are found to be affected by patent ductus
arteriosus, a genetic heart condition in which a blood vessel found only in
the fetuses of normal animals is retained after they are born, putting a huge
strain on the heart.

Finding the facts

However, it can be difficult to determine how widespread a condition may be
in a particular breed of dog. In Britain, no one keeps proper records of
disease incidence, and in any case, professional breeders may be reluctant to
advertise problems in their animals. Puppies which die soon after birth are
rarely examined, so diseases may go undiagnosed 鈥� according to recent
laboratory studies, stillbirths and early mortality often ranges from 15 to 30
per cent, or even higher in some breeds, compared with less than 5 per cent in
mongrels. In the US, the American Kennel Club is in the early stages of
helping to set up a database on genetic disorders at the University of
Pennsylvania, which should one day be available to vets and dog breeders
around the world. At present, the only useful source of information is vets鈥�
records which may exaggerate the extent of a disease because vets usually only
see sick animals.

Such records suggest that the problem is widespread. 快猫短视频s are adding
to the list of known genetic disorders in dogs all the time, with about ten
new ones identified every year. Most of the 500 different dog breeds in the
world are affected by at least one genetic disease. Pedigree dogs of about 170
breeds are registered by the UK Kennel Club, and only 28 have no known
defects. Vets鈥� reports suggest that certain breeds suffer more genetic
problems than others; the briard, for example, a herding dog which originated
in France. Peter Bedford, an ophthalmologist at the Royal Veterinary College,
London says that 30 per cent of these dogs over 18 months old are affected by
PRA. The dog genome project using the same methods as the human genome project
(see 鈥淕enome on the production line鈥�, 24 April 1993). Genes which lie close
together on the chromosome are usually inherited together, so by studying how
often groups of different genes are passed on to the next generation together,
researchers can piece together a rough picture of the position of various
genes on the chromosomes. The locations can be pinned down more precisely if
any other landmarks, such as 鈥渕icrosatellites鈥�, can be located. Scattered
throughout the genome, these are short repetitive sequences of DNA which have
no known function in the cell 鈥� they don鈥檛 carry 鈥渋nstructions鈥� for producing
particular proteins, but at the same time have no harmful side effects. Again,
those lying close to a specific gene are likely to be inherited with it.

More than 400 such microsatellites have now been identified in dogs. They
can easily be detected using the polymerase chain reaction (PCR), a powerful
technique for copying short lengths of DNA. The sequences can be cloned and
tagged with a fluorescent marker, then mixed with dividing cells in which the
DNA has separated out into recognisable chromosomes. The cloned probes then
link up with the equivalent section of DNA and the fluorescent tag shows up
its position on the chromosome, a process known as fluorescence in situ
hybridisation. In this way, scientists can build a progressively more detailed
picture of the dog genome.

Testing times

This map of the dog鈥檚 basic building blocks may then point the way to a
simple test for a genetic disorder. First, a microsatellite close to the
faulty gene in diseased animals is identified. Using a drop of blood from the
animal being tested, DNA is cloned, then chopped up and separated into chunks
of different lengths by an electric current. Radioactive DNA probes are mixed
with the separated bands of DNA to identify the bands on a photographic plate,
revealing the animal鈥檚 unique DNA profile. If the microsatellite sequence is
present, the dog is either affected by the disease or a carrier of the faulty
gene.

The Guide Dogs for the Blind Association is particularly keen to identify
disease in apparently healthy animals who can nevertheless pass on the disease
to the next generation. The tests could also be used to pinpoint animals with
those diseases which only become obvious late in life, usually after the
affected animals have had puppies of their own which may carry the affected
genes. By having all its young dogs tested for early signs of PRA, and
laboriously checking back through breeding records to identify the carriers,
the association has recently been able to eradicate the disease. However, the
charity is continuing to support the genome project 鈥� it invested a further
拢1 million in the project this year 鈥� because it fears the disease may
return as new dogs are bought in for its breeding programme, says its welfare
officer Mandy Jones.

Development of genetic tests for specific diseases is already under way.
Vets at the AHT and the University of Edinburgh have developed one PRA test
for a form of the disease that affects Irish setters. At the University of
Pennsylvania, Urs Giger has produced a test for phosphofructokinase
deficiency, a disease in springer spaniels. Affected dogs suffer damage to
their muscles and red blood cells, especially after strenuous exercise. Both
diseases were good candidates for genetic testing because similar diseases are
found in mice, and the affected genes were already known.

Other conditions which are unique to dogs will be more difficult to test
for, according to Matthew Binns, a microbiologist at the AHT. But he is
confident that testing programmes will be developed for at least some of these
diseases in the near future. Other early targets are likely to include PRA in
different breeds, haemophilia in German shepherd dogs and copper toxicosis, an
enzyme deficiency in Bedlington terriers.

Man鈥檚 best friend

Future developments may well have direct benefits for humans. Most of the
funding for a research programme at the University of Pennsylvania veterinary
school comes from agencies which normally support work in human medicine.
Indeed, Donald Patterson, head of the school鈥檚 department of medical genetics,
has high hopes for the research throwing some new light on the genetic basis
of various human diseases.

Patterson鈥檚 team is looklng for similarities in the DNA of dogs and humans
to try to find treatments for diseases affecting both, such as prostate
cancer. Dogs are particularly useful in tracklng down rogue genes because a
pedigree dog can easily have 200 living members in its family with very
similar DNA. Most human families are too small for comparisons between
individuals to be statistically significant. For some of the shared diseases,
the dog studies may point the way to the faulty human gene.

Patterson鈥檚 colleague Peter Felsberg is researching severe combined X-
linked immunodeficiency syndrome. This is a rare recessive defect which is
carried on the X chromosome. This means that women are carriers and only male
babies develop the disease which causes a total breakdown in the normal immune
response. In September Felsberg鈥檚 team announced that a gene causing the
disease in their colony of beagle/basset crosses is exactly the same as the
human disease gene. They can now develop a test to screen both humans and
other dog breeds which carry the defect.

And more importantly, the team is now working on a gene therapy technique
to repair the damage caused by the defective gene. Normal copies of the gene
would be inserted into a virus. The virus is then used to infect blood cells
held in suspension. This treated blood can then transfused back into the
animal. The method could then be tried out on dogs before being tested in
humans.

Diseases like PRA are caused by a defect in a single gene. But dogs also
suffer from polygenic conditions, involving several genes. Eradicating these
diseases is likely to take much longer because it depends on identifying a
number of genes, so in these cases selective breeding methods are likely to
remain the main method of disease prevention. For some, environmental factors
are important, and the genetic blueprint only gives a rough guide to how the
disease will develop. Although the condition is partly inherited, other
factors such as diet and exercise may determine whether the disease appears
and how severe it becomes. It鈥檚 unlikely that DNA tests will be suitable for
controlling such complex conditions.

One example of this is hip dysplasia, a condition common in several large
breeds, such as German shepherd dogs, in which the hip joint is abnormally
shallow. The joint dislocates, causing arthritis, pain and lameness. The best
indicator of future problems is to take an X-ray of the dog鈥檚 pelvis and look
for abnormalities in the shape of the ball and socket joint at the top of the
leg. After introducing this type of testing in 1967, the German Shepherd Breed
Club in Germany reduced the incidence of the disease by 20 per cent over 10
years. All dogs with poor scores on the grading system used were prevented
from breeding.

Better breeding

For over 20 years, the UK Kennel Club and British Veterinary Association
have also run a testing scheme for hip dysplasia. The results have been
disappointing because the scheme is voluntary and many breeders don鈥檛 have
their dogs tested. Bedford says that the Kennel Club must insist that testing
is carried out before a dog is entered on the Kennel Club pedigree register.
But the club maintains that it has no powers to force breeders to have their
dogs tested, arguing that breeders are individuals who must take
responsibility for their own actions. And some breeders may be unwilling to
acknowledge that a problem exists.

But, to eradicate disease breeders must be prepared to use the diagnostic
tests produced via the dog genome project. Although changes in the Kennel
Club鈥檚 rules may not be the solution, there is another powerful incentive to
use the technology. In 1986, a pet owner won compensation from the breeder of
a dog which developed hip dysplasia. The dog had not been tested for the
condition and the court ruled that the breeder had not taken reasonable steps
to avoid the problem. Such cases may become commonplace as knowledge of
genetic diseases and how to prevent them improves. So pet owners may have
recourse to the law 鈥� if not to the Kennel Club 鈥� if they feel they have been
sold a pup.