A Plea for Help

A Plea for Help
By Leos Kral

Background Information

There are several ways in which specific genes can be identified that cause genetic diseases. One way is to follow the candidate gene approach. With this approach, a particular gene is hypothesized as the cause of the disease. The gene sequence is then determined in both healthy individuals and in affected individuals and the sequences compared. If a difference in sequence is detected, then this DNA sequence in an additional number of individuals with the disease and without the disease is examined in order to determine if the correlation holds up. While this technique does not require extensive pedigree analysis of affected individuals, it is also not guaranteed to identify the gene. For example, there are about 45 genes known to produce cataracts in the mouse that would be reasonable candidates for genes that may cause cataracts in the Australian Shepherd. Analysis of any one of these genes in normal and cataract affected dogs may take a year or more at a cost of tens of thousands of dollars or more. While one may get lucky with the first few genes examined, one can also waste a lot of time and money. Furthermore, there is no guarantee that that any one of the 45 cataract causing genes known in the mouse is responsible for the cataracts afflicting the Australian Shepherd.

An other way to identify a disease causing gene is to first map the gene to a particular chromosome and to a region in that chromosome. The region can then be studied more closely to identify the gene that is likely responsible for the genetic disease. This gene or, perhaps, a small number of genes in this region, can then be sequenced as described above to find a difference between normal and affected dogs.

Gene mapping is carried out by comparing the inheritance of 200 to 300 DNA markers with the inheritance of the genetic disease. Since the chromosomal locations of the DNA markers are known, then the chromosomal location of any gene that is inherited in the same pattern as a particular DNA marker can be deduced. Essentially, if a DNA marker and a particular gene are located in the same region of a particular chromosome, then they would be inherited together. For example, in the pedigree below, the inheritance of two DNA markers is compared to the inheritance of a dominant trait (filled in symbols). The DNA markers are the A marker and the B marker. The A marker has 4 alleles (A5, A7, A9 and A1) and the B marker has 4 alleles (B2, B3, B4 and B6). Note that there is no correlation in the inheritance of the A markers with the trait. However, All affected individuals have inherited the B3 marker. Therefore, we can conclude that the gene for this trait is located in the same part of a particular chromosome that the DNA marker B is located at.

This approach is almost guaranteed to work if there is a large enough set of DNA markers available, and if DNA is available from a large enough number of related dogs that include both normal and affected individuals. Currently, the dog genome project has identified a large enough number of DNA markers throughout the canine genome to make this kind of project a likely success. The only thing missing is knowledge of how cataracts in Australian Shepherds are inherited and families of dogs with cataracts from whom DNA can be obtained. This is where you, the Aussie owners and breeders come in.

Actual Plea

Before any laboratory research can begin, pedigree analysis must be performed to determine how cataracts are inherited. Successful pedigree analysis requires complete pedigrees. (Please refer to the article Importance of Complete Pedigrees for more information). I can not obtain these complete pedigrees without your cooperation and I ask that you do the following:

Obviously, register your dog in the health database and encourage all other Aussie owners to do the same, especially those who own littermates and parents of your dog. However, to expedite the cataracts research project also do the following:
If you are an Aussie owner and your dog has cataracts that are not the result of some eye injury, please get in touch with your breeder. Ask the breeder for cooperation with this research and ask the breeder to contact me. If you know others who purchased a littermate of your dog, please ask them to send me a copy their dog's CERF exam form with a pedigree of the dog. Also, please send me a copy of your dog's CERF exam form and pedigree. Also, it is very important that I know about the status of littermates that test clear, so please have the owners of clear littermates send me a copy of those CERF forms and pedigrees. All information will be held in the strictest confidence.
If you are a breeder and a case of cataracts comes to your attention in your lines, please contact me. If you can tell me which matings have produced cataracts and which have not, I may be able to focus attention to the most relevant matings. Mainly what I will need from you are copies of CERF exam forms for as many dogs as you can obtain that are related to the affected dogs. Please note that the status of dogs that have been sold as pets is as important as the status of dogs sold to show homes. While you can ask individual owners to send copies of CERF forms and pedigrees directly to me, it would make it much easier if you would collect and forward to me CERF forms and pedigrees of related individuals as a single set.

Contact Information:

Dr. Leos Kral
Department of Biology
State University of West Georgia
Carrollton, GA 30118

E-Mail: lkral@westga.edu
Fax: (770) 836-6633
Phone: (770) 836-4546

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