The Genetic Cul-de-sac Dogs as an endangered species Part 1

by Susan Thorpe-Vargas Ph.D., John Cargill MA, MBA, MS, D. Caroline Coile, Ph.D.

Why the dog opted to share his fate with men, may never be known, we suspect it had something to do with filling his stomach, but when he did, mankind took on a moral and ethical obligation. When we started to selectively breed dogs for our own ends, our responsibility only increased. How have they done under our stewardship? We will let you and your conscience answer that, but from our perspective it seems we have "improved" Canis familaris into a genetic nightmare. We have created designer dogs which cannot whelp freely or even breathe correctly. Concern for cosmetic attributes have selected for dogs who get lost at the end of the leash. Every year billions of veterinary dollars are spent ameliorating the effects of our tampering. Is it too late? For some breeds it may indeed be too late. If they were a wild species certain breeds of dogs would be on the endangered list. That is why this series of genetic articles is so important. If you are a breeder, you need to pay your intelectual dues. Every breeder who professes to love his breed needs to know more than rudimentary genetics. At a recent genetics conference hosted by the Canine Health Foundation, auther Susan Thorpe-Vargas cringed to hear "What you see is what you get" at the dinner table, from a parent club representative.

This is the first, in a reference series of six breeding-related articles by a special task force of four authors. The learning curve is apt to get steep at times and if your eyes start to glaze over then put the paper down for a bit, but it is your obligation to pick it up again. Under discussion will be such diverse subjects as the origin and domestication of the dog, a mini primer on Population Genetics, the techniques being used to discover the causes of genetic disease at the molecular level and tests currently available to breeders for genetic screening. We will be providing both general and technical information to a level one expects of a serious breeder. We hope to make this an exciting journey and if you are a breeder, a very necessary one. The authors will presume some knowledge of the subject as we will draw on previous articles published during 1996 and 1997 in Dog World. They start with A Genetic Primer for Breeders ; The Mapping of the Canine Genome ; Open Registries Promote Honesty in Breeding, , Canine Genetic Disease: is the situation changing? Part 1-4 , and Tipping the Genetic Scales , For those of you on-line, some sites will be mentioned and a glossary of genetic terminology will be available by e-mailing the authors. Words throughout this series in bold-faced type, other than headings, are included in the glossary.

Some of you may question the need for such a series and may ask yourself why it should concern you. This quote by Jay Russell Ph.D. perhaps explains that WHY far better than we can.

"Every breeder has the ability in a free society to "determine their own stopping point." But, a single breeder's actions may have consequences that are far-reaching. A breed is necessarily maintained by a society of breeders. As such, the actions of each breeder affects the actions of every breeder who dips their brush in the gene pool and every buyer -- present and future -- who buys one of these "works of art." Pragmatically (and ethically), a breeder loses his/her right to independence and his/her ability to be independent the minute he/she puts up a shingle that says "Puppies for Sale."


About 60 million years ago a small weasel-like animal lived in the part of the world that is now called Asia. This ancestor of all modern day canids (dogs, jackals, wolves and foxes) was called Miacis, and although they did not leave any direct descendants, Cynodicis, the first true dog-like canid did descend from them. Cynodictis appeared about 30 million years ago. This line eventually split off into two branches, one in Africa and the other in Eurasia. The Eurasian branch was called Tomarctus and is the progenitor of wolves, dogs, and foxes. Until recently, it was thought that wolves and jackals were both the ancestors of the domestic dog , but a recent paper appears to demonstrate that the wolf is the only ancestral species. This somewhat controversial paper also asserts that the first domestication of wolves, seems to have taken place about 100,000 years ago. Whether or not it happened that long ago is still in dispute as the fossil records do not support this, however, different domestication events did most likely occur from multiple populations. This makes sense as both wolves and humans coexisted over a wide geographical area and so multiple domestication opportunities would have arisen. As a hunter-gatherer, humans would have found these animals very useful, but then about 8,000 years ago humans turned to a more settled way of life. This is when severe selection for specific behaviors and traits became important and 'modern' breeding practices started. And so it begins.....

Evolution, by definition, is change and diversification over time in a species. However, if there is no genetic variability, there can be no evolution. Genetic variability is the result of naturally-occuring mutations and a genetic process called recombination.



Mutations can be caused by a variety of mechanisms. Some of the most common are mistakes made when the organism's DNA is replicated prior to a cell dividing. Although there are body system safe-guards in place to prevent this from happening, nothing is fool-proof, and eventually over time, failure to replicate DNA accurately will occur. Likewise, errors can occur all along the pathway that leads to the translation of messenger RNA into a specific protein. These errors can occur spontaneously or be the result of exposure to natural and man-made mutagens. Certain chemicals can cause genetic changes or exposure to certain types of radiation. What is important to remember is that these mutations are random events with respect to their adaptive potential. In other words, they will happen independently of whether they have beneficial or harmful consequences. More often then not these mutations are harmful as they are changes to the make up of a living organism. Just how harmful depends upon the type of mutation that occurs and the environment in which they occur. Most mutations fail to thrive, reproduce or survive and thus are not passed on to successive generations.

There are several kinds of gene mutations, each having a unique range of potential effects. This is important to recognize because many genetically transmitted diseases result from a specific kind of mutation. Each of these forms of mutation is the result of the organism failing to reproduce its DNA accurately all of the time and subsequently passing these genetic changes to successive generations


Base-Pair Substitutions

The result of this type of mutation can range from a null effect to one that has severe consequences to the affected organism. DNA is made up of four different nucleic acids: thymine (T), adenine (A), guanine (G) and cytosine (C). Thymine always pairs up with adenine and guanine always pairs up with cytosine. Hence the name base-pair. Sometimes when the DNA strand is being replicated the wrong base is inserted. This can result in a different amino acid being added to the protein being made. If the essential biological function of that protein is not changed then there is no detectable effect. However, if the substitution affects the active site of an important enzyme or changes its three dimensional shape, then it modifies the fundamental nature of the protein. If this occurs along an essential metabolic pathway the results can be disastrous.

The most unfortunate result of a base-pair substitution is when this mutation codes for a stop codon. A codon is that portion of the messenger RNA that codes for a specific amino acid. A start codon (AUG) serves rather like a capital letter indicating the start of a sentence. A stop codon is a codon that does not specify an amino acid, and serves much as a comma or a period punctuating the genetic message. The Genetic Code is composed of sixty-four different arrangements of three nucleotides each (codons). This set of combinations codes for a total of twenty different amino acids and the stop codon. Some of the combinations code for the same amino acid and three of them signal for termination.

This redundancy is why some base-pair substitutions have no effect, because the change results in the same amino acid being produced. If, by chance, a mutation produces one of the stop codons, than the process of making the protein is terminated. This is not good.

"An example of this type of mutation is the one that leads to a form of progressive retinal atrophy (PRA) in the Irish setter. A substitution of an A for a G produces the stop codon (TAG) that replaces the normal codon for the amino acid tryptophan (TGG). This prevents a protein called PDEB (phosphodiesterase beta) from being produced in its full length form. The shortened protein is unstable and is degraded by the retinal cells in which it is needed. The lack of this protein causes the retina to degenerate, resulting in blindness in those Irish setters that have two copies of the mutant gene, and no normal copy."


Frameshift Mutations

In the normal cell replication process, DNA is transcribed into messenger RNA, which in turn is translated into a series of amino acids. This always occurs in a specific manner, i.e., it always begins at a definite spot and it is 'read' in multiples of three (codon) and in a particular orientation along the length of the strand of DNA . This is called a reading frame. If there is an addition or deletion of one or two base-pairs, then the result is often a very altered sequence of amino acids in the final protein product. This is definitly not good.

"An example of this is the mutation that leads to an inherited form of anemia in Basenjis. A deletion of a single nucleotide in the 433rd codon of the gene encoding a protein called PK (pyruvate kinase) causes a shift in the reading frame. The misformed and shortened protein (a new stop


Splice-site mutations

Molecular geneticists used to think that all of the DNA coding for a particular protein was continuous, that is, until they started to look at more complex organisims. What they found, in these types of cells, is that the DNA that makes up a gene is often distributed in discontinuous sections called exons, interspersed with long segments of non-coding DNA known as introns. These sections are transcribed into messenger RNA along with the exons, but before the RNA is translated into a protein they are 'edited' or 'spliced' out. A change of even a single nucleotide in one of the exons of the gene can cause a shift or alteration of the splice-site.

A genetic disease that affects Dobermans is a perfect illustration of this type of mutation. Von Willebrand disease is a bleeding disorder that effects the animals ability to form blood clots. Other breeds also have this disease, but what had perplexed those doing vWD research , was that Dobermans appeared to have a milder form of the disease. The discovery of a splice-site mutation that codes for von Willebrand factor has cleared up their mystery. George Brewer MD of the University of Michigan suggests that one use the following analogy in order to explain how the mutation functions.

Imagine that a freight train is supposed to go from point A to point B along a railroad track. Somewhere between A and B is a spot where a sidetrack goes to point C. Normally, the train never goes to point C because the switch, that connects the two tracks, is never thrown. Then the switch is broken (the mutation) and the lock that prevents the track from connecting to point C is no longer effective. The switch can now toggle back and forth, sending some trains to point B and sometimes to point C. In affected Dobermans, the defective switch sends the train to the wrong destination and about 95% of the time, the train rumbles over the cliff and is never heard from again. (and the proper protein is never made) However, sometimes the switch jiggles the right way and the train ends up at the normal destination and the proper protein is made.

Continued on Next Page.

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