Download Making Sense of Canine Genetic Information

Making Sense of Canine Genetic Information: Lessons for
Scientists and Dog Lovers
Norine E. Noonan, Ph.D.
School of Sciences and Mathematics
College of Charleston
Charleston, SC 29424
Contact: 843-953-5991
[email protected]
Press contact: Mike Robertson
843-953-5667
[email protected]
Why should dog breeders care about the dog genome sequencing
project? Why should scientists and veterinarians and other animal care
professionals care? Why should folks who just love dogs care? Well,
let me begin by telling a story . . . perhaps you’ve heard it already. . .
When Davy, a blow-dried, fluffed-up Pekingese, waddled past more than
2,000 rivals into the center ring to be crowned the Best in Show at a
prestigious dog show, some of the owners of the Alosers@ were not
amused. Rumors wafted through the crowd like a bad smell that all was
not as it looked for the Perfect Peke. Gossip had it that Davy=s face was
surgically Aimproved@ in order to take his place in the pantheon of
champions. If this were true, the American Kennel Club was quick to
say, Davy would lose not only his titles, but would never set foot (or is it
feet?) in the competitive breed ring again. An investigation was
launched, and, after a time, his outraged owners were cleared. Davy, it
seems, had only had a little throat surgery to improve his breathing, but
this did nothing to change his outward appearance.
We know that the development of dog breeds is an ancient process,
beginning perhaps 6,000 years ago or more B and it continues today. As
we=ve also heard today, the domestic dog likely originated in East Asia
(somewhat of a surprise since the conventional wisdom had the dog
originating in the Middle East). Further, the domestication process
changed the way in which these canids communicate with humans that
may be unique among domestic animals and even higher order primates.
There are about 150 recognized dog breeds in the world and perhaps
another 250 (or even more) that are not recognized by any registering
organization. Collectively, these breeds represent an ongoing
evolutionary Alaboratory@ that essentially is under the direct control of
humans. The range of phenotypes is truly amazing. The weight
difference of the average Chihuahua and St. Bernard is about 100-fold.
The behaviors of the Basset Hound and the Border Collie lie at opposite
ends of the spectrum. The coats of the Norwegian Elkhound and the
Whippet couldn=t be more different. Yet any dog can be mated to any
other dog and, barring some physiological problem, viable and fertile
offspring will result. Domestic dogs are also inter-fertile with wolves,
coyotes and jackals. To date, what humans have done in domestic dogs
is to harness the power of the laws of genetics, short generational times,
and relatively large populations to create perhaps the largest number of
different phenotypes of any living species B many in response to the
needs of humans for assistance with specific tasks.
The Adark side@ of all of the attention to breeding dogs over the
centuries from those early domesticated canids has been the appearance
and perpetuation of genetic defects and diseases. Just as in people, there
are many genetic defects and diseases that have been reported in the dog.
Table 1 shows a sampling of dog breeds and their genetic problems.
This is not a comprehensive list, by far. It simply illustrates that there
are a lot of problems out there. It=s been estimated that one in every 400
dogs has a genetic disorder. In some breeds, the incidence of one or
more of these disorders is much higher. For example, in the German
Shepherd dog, there are about 140 genetic disorders that range from
conformation Afaults@ to frank disease. The incidence of
hypothyroidism in this breed is about 0.6/100 dogs; cryptorchidism (the
failure of both testicles to descend) about 1.2/100 dogs; and overshot
jaw about 0.1/100 dogs. For Newfoundland dogs the situation is worse.
It is estimated that about 66 percent of the individuals in this breed have
defects of one sort or another (Noonan, personal communication).
Further, in Doberman Pinschers, 77 percent of the individuals in the
breed have the gene for von Willebrand’s disease (an bleeding disorder
similar to hemophilia that is inherited as an autosomal recessive trait).
And lest you think that a AHeinz 57" mixed-breed dog from the local
shelter is genetically healthier, there have been more than 200 genetic
problems reported in mongrels, more than occur in any purebred breed
(Noonan, personal communication). Of the nearly 400 genetic diseases
and defects currently described in the dog, the mode of inheritance is
known for only about half.
Breeders and fanciers have made some effort to control some of the most
obvious genetic problems, but it is well to remember that in the dog as in
people, phenotype does not equal genotype (especially for Acarriers@ of
a genetic trait). Breeders have sought desirable phenotypes that
approach the official breed “standard” via a process known as
inbreeding or Aline breeding@ (line breeding is a bit less incestuous, but
a form of inbreeding, nonetheless). In this regard the dog is no different
from corn, potatoes, rice or dairy cattle. Inbreeding is essentially
cloning the old-fashioned way. It=s a time-honored way to rapidly
generate a higher percentage of offspring that have Agood@ traits (in this
case, offspring who are “typey” (i.e., approaching the standard) in their
looks, movement and temperament). But inbreeding or line breeding is
also more likely to result in homozygosity; further, these techniques
can=t tell the difference between a gene for a thick, beautiful coat in the
rough-coated Collie (good) and a gene for ACollie eye,@ an ocular defect
(bad). Genes sort and recombine without regard (mostly) for the
phenotypic result (the exception, of course, being lethal gene
combinations that result in miscarriages or resorbed fetuses). It is also a
basic principle of population genetics that gene frequency, whether
normal or defective, does not change between parent and offspring – this
is true regardless of the level of hetero- or homozygosity of the parents
or whether the mating is linebreeding, inbreeding or outcrossing. Thus,
it is the selection of the parent breeding stock that changes gene
frequency, not the type of mating.
However, as the level of homozygosity increases throughout the
genome, the resulting combinations of genes can result in the unmasking
of latent genetic defects. For example, two humans will have about
seven in 10 chances of a difference at any single gene locus. Among
mongrels this drops to a little less than six in 10, in purebred dogs it=s
about two in 10 and in some breeds it=s less than one in 10 (Budiansky,
2000). It’s also the case that “outcrossing,” the opposite of inbreeding,
may actually exacerbate the loss of genetic diversity, although breeders
sometimes use this technique in the mistaken hope that it will increase
heterozygosity and hence reduce the appearance of genetic defects.
Of course, the whole purebred thing is complicated by the fact that a
large percentage of genetic traits in the dog, especially behavioral traits,
are probably polygenic so that the nice, neat Hardy-Weinberg Law
won=t work. As far as we know, there is no single gene for Ano peeing
in the house@ or Afailure to chew shoes.@ These behaviors are probably
not genetically based. In addition, there are few, if any, rewards for
breeders who advance the health of the breed as a whole by eliminating
(not literally, just genetically) or restricting the genes from carrier or
affected dogs. In fact, the Amatador effect@ is quite prevalent in many
breeds today. The Amatador effect@ is the reduction in genetic diversity
that comes from the use of a small number of popular sires or
Amatadors.@ These dogs are usually major show winners and highly
sought after by breeders to sire litter after litter of puppies. This is
inbreeding on a grand scale and the fact that some of those Amatadors@
may have latent (or even patent) genetic defects makes no difference to
the proud owner of such a dog. However, over time, the reduction in
genetic diversity that comes from the matador effect is likely to show at
least the major genetic defects that can be traced back to that dog B but
by then, he and his offspring could be driving the genetic train of that
particular breed. For example, when idiopathic aggression
(unpredictable and abnormal aggressive behavior) began appearing in
Bernese Mountain Dogs (not in the U.S.), breeders were able to trace
this problem back to two Amatadors@ imported into that country. Hard
decisions and careful screening of pedigrees have succeeded in nearly
eliminating the problem (Van der Velden, et. al. 1976). However,
unpredictable aggressive behavior in a 100+- pound dog resulted in the
euthanasia of many individuals. What a costly and emotionally
wrenching price to pay for a puppy from a Achampion.@
Right now, the greatest selective pressures in the dog world are C
advertising and gossip. Advertising in publications such as Canine
Chronicle, widely read by breeders and judges, identifies dogs with the
potential to be Amatadors.@ I can name several among Basset Hounds. I
see them at our National Specialty show each year. Gossip, of course, is
the great leveler and is the basis of most of the current information on
the incidence of canine genetic disorders. I should note here that some
national and regional breed clubs have been very proactive in trying to
eliminate genetic diseases in their breed. For example, the Irish Setter
Club of America funded research to develop a genetic test for
progressive retinal atrophy (a degenerative eye disease) and now
requires that all breeding animals be tested. This has dramatically
reduced the incidence of that disease in this breed. The participation of
breeders in the screening and grading program of the Orthopedic
Foundation for Animals and Penn Hip has reduced the incidence of
potentially-crippling (and certainly painful) hip dysplasia in many larger
breeds. Tests for Von Willebrand=s Disease are available and are being
used to identify carriers in many breeds including the Basset Hound.
National breed clubs help fund such research through the American
Kennel Club Canine Health Foundation (donor advised funds and the
Parent Club Partnership Program).
But the current state of affairs may be about to change.
The canine genome project is intended to produce a map of all of the
genes on all of the 78 chromosomes in dogs, which can then be used to
create a functional map of the genes causing disease and those
influencing morphology and behavior. Just as the completion of the map
of the human genome has begun to change our way of thinking about the
causes and cures for many diseases, the availability of a full map of the
canine genome, thanks to a particularly inbred Boxer named Tasha, may
open the vistas for unprecedented progress in canine health and will
likely also contribute to human health as well. A framework linkage
map has existed since 1997, but thanks to the work of the folks on this
panel, this map is rapidly being filled in. Once the Boxer map is
finished, the genomes of perhaps 10-20 additional breeds will be
Asampled,@ that is, a sort of quick pass will be made through those
genomes in an attempt to identify breed-specific conditions.
What does this portend for the future? Instead of elaborate recordkeeping for pedigrees, genetic information may allow breeders to keep
track of the Atags@ that identify a Bulldog as a Bulldog and a Basset
Hound as a Basset Hound. Newer breeds are likely to be tougher to
identify because of their still fluctuating genetic base. But these
Aidentity tags@ may be useful in tracking both pedigrees and
individuals. Further, the inbred nature of the dog should make it easier to
identify the genes responsible for specific diseases that are common to
canine and human and from there devise therapeutic modalities that
might work in either species.
For example, cancer is one of the most prevalent diseases in dogs. Many
canine cancers resemble the human counterpart disease more closely
than induced cancers in rodents. As a case in point, osteosarcoma occurs
10 times more frequently in the dog than in humans and, although it
appears similar, it metastasizes sooner in dogs. For osteosarcoma in a
canine limb, amputation is the therapy of choice because of the
aggressive nature of this cancer. However, in children with
osteosarcoma, new combinations of chemotherapies have enabled limb
sparing. Genetic keys to osteosarcoma could improve the odds of limb
sparing and life saving treatments for canine disease.
The availability of canine genetic sequence information combined with
sophisticated chemo- and immunotherapy (not just for cancers, but for
other diseases as well), will define a future filled with opportunities to
decode and describe the genes that lie at the center of debilitating
conditions or perhaps even negative behaviors.
Already there are both mutation-based and linked-polymorphism-based
diagnostic tests to elucidate the genetic status for breeding purposes.
Mutation-based testing recognizes the specific change in DNA that
causes genetic disease. Of course, this kind of testing will detect both
affected dogs and carriers but it requires that the “normal” sequence of
the specific genes be known. Linked-polymorphism-based tests examine
variations in areas of DNA close to a gene causing a disorder. Specific
polymorphisms must be known and must be linked to the specific
disorder for this test to be effective (although it is not necessary to know
either the exact mutation or even the gene involved in the defect). This
type of screening is most accurate for entire families of dogs where both
parents and all siblings can also be tested. Table 2 illustrates a number
of genetic tests already available for specific breeds.
Jolly and collaborators (Jolly, et. al., 1981) have outlined several criteria
for a successful genetic screening program:
 The genetic defect or disorder is frequent enough to be of serious
concern.
 The test for heterozygote “carriers” is accurate and cost-effective.
 Genetic diversity can be maintained in the breed without carrier
and affected dogs being in the breeding population.
 Test and control programs are accepted by breeders and
accompanied by education and public outreach programs.
 Breeders can obtain genetic counseling to assist their efforts
 Parent clubs reinforce the importance of and the need for testing
for the overall health of the breed (perhaps by mandating testing of
broodstock as with the Irish Setter Club.)
The UK Kennel Club in cooperation with the Animal Health Trust in
Newmarket, England, has just undertaken a major survey to get
information on the first point, frequency, among more than 70,000
owners with the cooperation of 180 breed clubs in the United Kingdom.
The survey is intended to give, for the first time, a realistic baseline
picture of canine genetic disease and other health conditions. It is hoped
that it may also uncover previously unrecognized defects with a genetic
component. Results are expected to be available in the Fall of 2004 and
will certainly be useful not only to breeders in the UK, but also in the US
and elsewhere. So, gossip and anecdotal information – take heed!
When you put molecular level genetic information together with
rigorous and thorough frequency information, all of the breeders,
exhibitors, fanciers and people who just love dogs will have both the
ability and the responsibility to eradicate diseases and reduce the
incidence of genetic defects. There will be no excuses and nowhere to
hide. The lesson for scientists is that their work can be of tremendous
benefit in improving breeding programs and eradicating canine and
human disease. Further, this work can be greatly assisted by close
collaboration with owners, breeders and exhibitors. The lesson for dog
lovers is that we don=t actually have to wait B there are things we can do
right now while the ongoing genomic research progresses to reach its
full potential. Together we can make real and substantial progress to
ensure a future filled with healthy, happy dogs.
As far back as 100,000 years ago, a group of Paleolithic hunters
gathered around their fire in the darkness listening to the sounds of wild
animals deep in the forest primeval. From the perimeter, a rustling
sound and then, inching toward the fire=s warmth, a wolf-like animal
appears, head lowered and tail down, and cautiously approaches the
group. The men reach for their spears, but the animal simply lies down
B far enough not to threaten but close enough to feel the fire. In the
morning, the animal follows the hunters and flushes game for them.
That night they reward their new partner with food from the fresh killed
game.
Is this an overly romanticized version of how the companionship
between human and dog began? Perhaps, but surely this early
relationship was driven by mutual necessity. Perhaps humans followed
wolf hunters instead B amazed by the cold efficiency of the pack=s
hunting skills and scavenging what the pack left behind or perhaps the
humans hunted alongside them. The domestication of wolf-like
creatures into the aboriginal Aproto-dogs@ and then into more
recognizable dog breeds was accompanied by a change in the way
humans and canids communicate B visual rather than verbal cues can be
used to direct the actions of a modern, well-trained dog. Perhaps this
stemmed from the need for prehistoric man to use those visual cues so as
not to startle herds of game animals as he directed his newly
domesticated hunting companion to round them up or chase them down.
So, today the dog is companion, co-worker, protector, therapist, and best
friend. ADOG@ is God spelled backward, as a reflection in a mirror. To
me this has always meant that dogs are reflections of our best selves,
loyal, tolerant, courageous, forgiving, loving us more than they love
themselves B they are the way God would want us all to be. Certainly
the human-canine relationship is, arguably, the most intense of any
except human-human relationships.
The poet John Davies, writing in the late 1500's, said:
AThou sayest thou art as weary as a dog,
As angry, sick, and hungry as a dog,
As dull and melancholy as a dog,
As lazy, sleepy, idle as a dog,
But why dost thou compare thee to a dog?
In that for which all men despise a dog,
I will compare thee better to a dog,
Thou are as fair and comely as a dog,
Thou art as true and honest as a dog,
Thou art as kind and liberal as a dog,
Thou are as wise and valiant as a dog.
I strive to be the person my dogs think I am. Our symposium today has
elucidated some of the newest and most important findings about the
canine genome and unique canine behaviors. It is our fervent hope that
this information will be used to enrich and expand the boundaries of that
relationship with a unique and remarkable species.
The organizers would like to express their deep gratitude to Nestle
Purina Pet Care for their generous support of both canine genetic
research and this symposium.
References
Budiansky, Stephen, The Truth About Dogs: An Inquiry Into the
Ancestry, Social Conventions, Mental Habits, and Moral Fiber of Canis
familiaris, Penguin Books (2000)
Jolly, R.D., et al., “Screening for Genetic Diseases: Principles and
Practices. ” Advances in Veterinary Science and Comparative Medicine.
25:245 (1981)
Van der Velden, N.A., et al., “An Abnormal Behavioural Trait in
Bernese Mountain Dogs (Berner sennenhund): A Preliminary Report.”
Tjidschrift voor Diergeneeskunde 101:403 (1976)