Faced with the scientific facts of modern veterinary medicine, many of us are caught between a fascination of the subject matter and a layman’s exasperation over its complexities.
Nowhere is this more true than in the average breeder’s struggles with genetics, but it has become more important than ever that we make the effort to understand at least the basics.
This will enable us to follow the research now taking place in the field of inherited health problems. Great strides have already been made in the detection and treatment of genetic faults in humans, providing a fund of information that is aiding directly in the research for dogs.
Dog Genetic Research Coalition Formed
In mid-summer of 1990, OFA Project Director, Dr. E. A. Corley sent the following bulletin to all OFA Representatives:
“The Orthopedic Foundation for Animals (OFA), Morris Animal Foundation (MAF), and the American Kennel Club (AKC) have formed a unique coalition to sponsor a molecular genetic research project conducted at the University of Michigan and Michigan State University.
The project is under the direction of George Brewer, M.D., a human geneticist, who will be working with veterinarians at Michigan State University College of Veterinary Medicine. The project will attempt to identify at least 400 molecular markers for problem genes that cause a variety of inherited diseases in the dog.”
When this goal is achieved, it will be possible to learn from a few drops of a young puppy’s blood exactly what genetic programming he is carrying the inherited diseases, present and potential, the joint and bone abnormalities, chemical imbalances that cause a variety of problems – all these and more will be obvious to the trained eye.
The possibilities are breath-taking, both for treatment and prevention, but all this will not take place in the immediate future. The molecular genetic research Dr. Brewer is directing is initially scheduled as a five-year project. It may take longer and it may cost more than the estimated $750,000 the three sponsors have pledged to fund.
In the meantime, the more we learn about the fundamentals of how characteristics are passed from one generation to another, the better we will be able to use the information when it is offered to us
Traits Established
As an atom is the smallest particle of matter, the cell is the smallest form of a living animal. This is the beginning, the life derived from lives before it, because a single cell is created from the union of one sperm and one egg at fertilization.
This process is actually close to the end of the story since the individual’s future traits are completely mapped at that moment of conception. How this mapping takes place, and with what materials, is at the heart of genetics. It is an incredibly complicated subject, but perhaps the barest bones will simplify it.
It should be understood, as a sort of “given” that the descriptions that follow are of normal, simplified processes offered to explain the outline of genetic mechanics.
There are countless exceptions to these normals, many of which affect heredity: too few genes or chromosomes, or too many; misshapen genetic material, some of which break into pieces and some of which fuses with other bits. All sorts of accidents occur during the various stages of development, but normally this is the picture.
Figure 1 – Basic Body Cell:
An outer membrane encloses the entire cell in which the nucleus, in its own membrane, is encased. Other small bodies tend to the upkeep of the cell. It is within the nucleus that chromosomes are formed.
Figure 2 – Nucleus Manufactures Chromosomes:
The cell at rest has few interesting features but is preparing to divide (the only way it can multiply), it develops grains of chromatin. the stuff of which chromosomes are made.
These granules draw out into fine threads
which turn into small rods of odd lengths and shapes. These are the chromosomes.
Figure 3 – Chromosome Pairs:
Under a powerful microscope, heavily stained for visibility, chromosomes in a cell’s nucleus are shown to be strewn carelessly
but scientists match them carefully for study. This orderly ranking by size and weight is called a karyotype.
and so forth, down to the last row
where the last two are the sex chromosomes, a large X and a much smaller Y, indicating that these chromosomes belong to a male dog.
Figure 4 – One Pair Of Chromosomes:
Same size, same shape, carrying paired (but not necessarily identical) genes.
Position, or locus, of paired genes on paired chromosomes, is the same in each chromosome. For instance, the gene for tail length (see text). Technically, these pairs of genes identically located are known as alleles, one allele to a chromosome.
But, back to the cell, .which may be imagined as an oval blob with a nucleus within it, surrounded by a membrane. (Fig. 1) There are several other bits and pieces floating inside this membrane, but we don’t need them now.
The nucleus is the important part since it is filled with tiny, short rodlike structures called chromosomes, which occur in pairs. (Fig. 2) Though not necessarily close together, each will have a mate the same size and shape somewhere within the nucleus. (Fig. 3)
Along the length of the chromosomes are tiny segments, somewhat like spaces on a Parchesi board, which are the genes. Each gene is a hereditary unit and they too come in pairs. Every gene in one chromosome of a pair normally has a partner in the same position (locus) on the other chromosome. (Fig. 4)
These matching genes govern the same “character” or trait, but not necessarily in identical ways. (With two corresponding genes for tail length, one gene might produce a short tail, the other long.)
There is one other important ingredient in our cell called DNA, which stands for a tongue-twisting chemical compound, deoxyribonucleic acid. It is a chemical molecule, built as a long, slightly twisted, ladder-like structure that fills the length of the chromosome. The genes are part of this structure.
There are 39 pairs of chromosomes in the nucleus of every cell in the dog (of those cells which contain nuclei); 3 8 of them are similarly constructed, though slightly different in size and weight and reproduce with straightforward cell division. (Fig. 5)
That last pair of chromosomes is different from all the rest and controls the sex of the dog. Bitches normally have two X sex chromosomes and dogs have an X and a Y sex chromosome. The X chromosomes have genes on them but the Y has none.
Reduction of Cell Theory
The process that transforms a normal reproductive cell into a sperm or egg is called reduction cell division, and is not only different from normal body cell division, but the sequence of change is different for each sex.
When the division is completed, the male reproductive cell has produced four sperm (Fig. 6), but the female cell has produced a single proper egg and three non-functional duds. (Fig. 7)
The sperm and the egg each contain only half the normal number of chromosomes, not chosen haphazardly for the total, but carefully selected one chromosome from each pair. When a mating unites the two during fertilization, there will be a full complement of paired chromosomes again in the new individual.
This means that half the heritable traits of the parents are left on the cutting room floor, so to speak, so despite their best efforts, breeders are still playing roulette. It also explains why the same two parents will sometimes produce widely differing litters.
When the sperm and the egg unite, pure chance governs the combinations that result. To use the tail example again, if the mother is carrying two genes for a long tail and the father is carrying one long and one short, it is anybody’s guess which two of the four will combine for the new set that will be inherited by the embryo.
But only two genes will be used – one to each of that particular matched pair of chromosomes. This will be true all the way down the line, including the chromosomes for sex. Of the mother’s two X’s and the father’s X and Y, two will combine: XX is instantaneously a girl and XY a boy.
Just as sex is decided at conception, so are all the physical traits, both visible and hidden; all the potential for various diseases, some of which are immediately evident at birth – some to crop up later. But nothing results from this mating that was not contributed to it by the parents.
The trick is to know what they are carrying genetically. Up until now, the only way to discover even part of this answer has been with test breedings, with x-rays and blood tests, and by simple observation of the traits, we could see.
Dominant And Recessive Paths
There are two principal paths of inheritance. The term dominant describes the dominating of one gene in a pair over its partner. It is only necessary for one parent to carry this gene on a given pair of chromosomes. It hasn’t been destroyed, only “masked” or overcome for this particular breeding.
In order to pass on a recessive trait to a pup (spotted coat in Shar-Pei, for instance), it is necessary that both parents contribute one recessive gene each to each particular paired chromosome. Sometimes it takes several generations for one type of lone recessive gene to meet up with another one, which is why breeders sometimes get nasty surprises in their litters.
Figure 5 – Simple Cell Division:
The cell at rest, no activity at all beyond maintenance. It contains, among other things, a nucleus made up of protoplasm (the basic substance of plant and animal life) and a centrosome (not yet star-like).
When the cell reaches the point in its life when reproduction is scheduled, the nucleus develops webs of chromatin, a substance from which chromosomes are made. The centrosome is unchanged.
The chromatin has formed into actual chromosomes. The centrosome has split and become two star-like bodies.
As the membrane of the nucleus dissolves away, the centrosomes position themselves as opposite poles. Fine fibers radiate from them which align the chromosomes down the center of the cell.
The same force that causes the alignment now pulls each chromosome apart lengthwise so that each becomes one of an identical pair.
The mother cell splits in half, creating daughter cells whose chromosomes move to the center
The nucleus forms around the chromosomes which are converted back into the thread line. Eventually, these two will become mother cells exactly like the one which produced them. The process will be repeated.
Figure 6 – Male Reproductive Cell Becoming Sperm:
The first phases are similar to mitosis but: As the membrane around the nucleus disappears and the centrosomes go to opposite sides of the cell, the chromosomes do not line up down the center as they did in mitosis. They choose sides, by pairs, one chromosome from the father moving to position itself opposite the corresponding chromosome of the mother.
This is the first stage of the Reduction Division, which will provide each resulting cell with only HALF the chromosomes the parent cell started with. This only happens to reproductive cells, because when the sperm and egg are united, the total of their chromosomes must add up to only the normal 39 pair.
The reproductive cell splits to form two spermatocytes (male sex cells) which are not yet sperm but already carry their own genetic coding.
Two pairs of viable sperm, all four from the original cell but each pair carries a different inheritance.
Figure 7 – Female Reproductive Cell Becomes An Egg:
The process is similar to the sperm foundation right up to the last step.
Reduction split the same: Scientific theory surmises that these polar body duds provide extra food for a fertilized egg.
Figure 8 – Human Chromosome # 13:
Showing the location of the gene for Wilson’s disease (WND). Close by is the “Marker” ESD which always accompanies WND. From Dr. Brewer’s study on copper toxicosis.
How Do They Tell The Difference Between Dominant And Recessive?
There is nothing to distinguish these genes one from the other except their performance. Recorded results of test breedings have provided the list of traits and their mode of inheritance. Between these two modes, there are several complicated variations or shades of dominance and recessiveness, of interest mainly to full-fledged geneticists.
This rather simplified pictorial glossary gives us enough vocabulary to follow a very excellent article which appeared in the Pure-bred Dogs/ AKC Gazette (January 1989) under the title “Fighting Disease With Molecular Genetics”, written by George J. Brewer, M.D. and Vilma Yuzbasiyan-Gurkan, Ph.D. This is the same Dr. Brewer who is heading the five-year research project, recently announced, for which this older work was a preliminary study.
The article concerns a two-year project, funded by the Morris Animal Foundation, conducted by the same universities (Michigan State and the University of Michigan), plus a group of dog breeders who contributed their sick dogs suffering from a certain form of liver trouble.
In an inherited condition called copper toxicosis (CT), the liver accumulates copper and is poisoned by it. The problem doesn’t show up until the dog is over a year old and can only be detected reliably by an expensive liver biopsy.
This process identifies the victim and, since this disease is carried by recessive genes, it also damns both parents as carriers. These parents can appear quite healthy but still, carry the genetic seeds for disaster.
How To Find Other Possible Carriers BEFORE They Are Used As Breeding Stock?
The answer is only by breeding a sick dog to a well one in the breeds affected, chiefly the Bedlington Terrier and West Highland White Terrier. The dogs in question would already be over a year old since the disease doesn’t show up until then.
The entire litter born of this test breeding would have to be maintained for another year at which time biopsies could be performed on their livers to see if they had the disease. If the offspring (at least five or six puppies) are clear, the healthy-appearing half of this test breeding could be assumed free of any recessive genes carrying CT. But what a time consuming and expensive process!
If the same determination could be made in every young pup of the breeds afflicted with CT, breeders could sort out not only the carriers but the dogs already doomed to die of this disease by mid-life and remove them from their breeding programs.
From his work in human genetics, Dr. Brewerknew that canine CT had a human counterpart: Wilson’s disease. The gene carrying Wilson’s disease is known as WND. It exists on chromosome 13 along with hundreds of other genes.
These other genes vary from person to person, but always, ALWAYS, on the chromosome of a person with Wilson’s disease. The WND gene will have as a close neighbor an enzyme called esterase D (ESD). (Figure 8).
Now, genes that are close together on a chromosome are usually inherited as a block. They stick together. Because of this genetic linkage, ESD acts as a marker gene for Wilson’s disease.
If the same gene is involved in both people and dogs, there is hope that the marker for humans will flag the copper toxicity gene since this type of linkage has been shown to be the same from species to species. (Man and mouse share some of the same patterns of genetic markers.)
It has been established that the ESD gene is present in dogs and can be reliably located using a “probe” of human genetic material containing ESD. These probes can seek out a similar gene because of a sort of chemical attraction that exists between genetic substances with the same molecular structure.
So, an identified bit of DNA (in this case, human ESD) will bind to another similar bit of DNA material in the dog, showing where the target marker gene is located. If the marker is there, the gene for CT must be present, providing that further research proves that the canine gene for CT corresponds in every particular to the human gene for Wilson’s disease.
Detecting Harmful Genes
These same methods can be used to detect other harmful genes once a working system is organized. Dr. Brewer has been using what he calls the “shortcut” approach (matching markers from one species with those of another), but would like to “put in place a more generally applicable system, a long-range strategy”.
He would prefer to be able to locate the offending genes without “being dependent upon the luck of having (a similar disease) with linked marker genes in another species.”
This is what the five-year project just initiated is all about-establishing scientific routines for locating disease genes and their markers. In some cases these single genes are responsible for certain conditions, in others, there is more than one gene causing the problem.
Hip dysplasia (commonly affects larger breeds such as Labrador Retriever, BullDog, .etc), for instance, is the result of the action of multiple genes so it will take longer to track down but the same theory applies.
Concepts Within the Realm Of Possibilities
Amazing as this whole project seems, the concept is totally within the realm of possibility. At about the same time that Dr. Corley was announcing the new molecular genetic research program for dogs, the Associated Press released the news: Researchers Locate Gene Causing Elephant Man’s Disease (July 13, 1990).
Less than a month later (Aug. 10, 1990), another AP headline read Gene In Elephant Man’s Disease May Be (A) Link to Cancer, with new developments coming from a research program at the University of Utah.
As far back as 1985 (AP: November 29), another headline read Big Step Taken Toward Identifying Cystic Fibrosis Gene, with the lead sentence: Scientists report they have discovered two genetic ‘flags’ so close to the gene that causes cystic fibrosis that experts say new technologies should now find the gene relatively quickly. These are all processes that Dr. Brewer hopes to employ in his research on behalf of the dogs.
Once the project is begun, one discovery will lead to another, as it has for humans. At the least, we will prevent the birth of malformed and diseased pups.
At most, there also will be new cures and therapies for existing conditions. The savings in time and money are the practical aspects, but the heartwarming joy of healthy litters will make dog breeding and dog-owning an even greater pleasure than it is now.
References
- Brewer, George J. M.D., and Vilma Yuzbasiyan-Gurkan, Ph.D. “Fighting Disease with Molecular Genetics”, Pure-bred Dogs/AKC Gazette, Jan. 1989, pp. 66-75.
- Corley, E.A., D.V.M., Ph.D. “OFA Supports Molecular Genetic Research”, Communication to Breed Club Representatives. Columbia, MO. July 6, 1990.
- Foley, Charles W., John F. Lasley, and Gary D. Osweiler. “Fundamentals of Genetics”. Pure-bred Dogs/ AKC Gazette, Nov. 1979, pp. 34-49.
- Hutt, Frederick B., Genetics For Dog Breeders, W.H. Freeman & Co. San Francisco. 1979.
- Whitney, Leon F., D.V.M., How To Breed Dogs. Howell Book House, Inc., NY, 2nd Ed. 1972.
