DLA diversity
DLA diversity test to follow and maintain heterozygosity at MHC II locus
Much of the genetic diversity of dogs is dimished or lost in many breeds due to aggressive breeding programs and closed inbred populations. Loss of genetic diversity threatens the welfare and vitality of dogs and may predispose them to various diseases.
An important part of this genetic diversity is related to genes, which are responsible for the effective and functional immune defense against viruses, parasites and other foreign pathogens in dogs. There are probaly hundreds if not thousands of genes involved in the functionality of the immune system in mammalian genome. One of the most important such gene cluster is called major histocompatibility complex (MHC) in the dog’s genome. MHC complex includes a large number of genes and lies in canine chromosome 12.
This MHC complex includes genes that are responsible for the recognition of the species own tissues from foreign material. Recognition is related to the genetic diversity and some of the genes in this region contain particulary hypervariable areas in their coding regions to maintain them as diverse as possible. The loss of diversity in the MHC region or inheritace of particular allele combinations may result in increased susceptibility to autoimmune diseases such as diabetes, atopia, hypothyroiditis and different forms of inflammatory disorders. Many canine autoimmune disorders have been already associated with risk haplotypes in the MHC locus and homozygosity to risk alleles or haplotypes seems to increase the disease risk. Heterozygosity is preferred in the MHC locus in wild population too. Several studies in both natural and domesticated populations underline the importance of heterozygosity rather than the numer of different haplotypes in the MHC region.
We have now tools to type your dog’s MHC II genes (DLA typing) so that you can follow the diversity of your dogs and lines and use this information while planning new breedings. It is useful to have a DLA-profile from your breed in differnet countries since the frequency of the alleles in the MHC genes may vary a lot between populations. Once the DLA-profile is established you could compare your dog's profile for the overall breed' or line's profile and take it into account while planning new breedings. The aim is to maintain the heterozygosity of the MHC region as much as possible in the breeding lines. This should reduce the risk for autoimmune or other diseases.
As a general rule it may be wise to avoid increasing homozygosity in the MHC locus containing a large number of important genes. There is a growing body of evidence that homozygosity in the MHC locus increases the risk for autoimmune disorders. Many of the published studies include rather small sample numbers. This has effects on the strength of the risk factors and significance levels. Larger studies in future should give more accurate risk estimates not available yet. However, it may be wise to choose a breeding partner that has different haplotypes to maintain heterozygosity and diversity in your litters and lines.
Since MHC locus is functionally important it is not a neutral locus and lies under a selective pressures. Certain MHC haplotypes may not be allowed at all or may lead to inviablity. DLA-typing analyzes only the MHC locus in one chromosome, and although it provides important data that may also reflect the overall diversity of the breed, it is recommended for breeders to test also other markers from other chromosomes for comparison to better reflect the overall diversity of the breed. Due to selective pressures the diversity of the MHC locus may turn out to be more heterozygous than other part of the dog's genome.
It is important to remember that several factors needs to be considered in breeding decisions and DLA-results are only one thing among many others. Breeding plans should never be based on only DLA-types or any other genetic tests. Breeding decisions needs to be made case by case. This is an increasing challenge in future with the growing number of genetic tests. Breeding against one locus may cause troubles in the other loci which are not known yet. Maintenance of the genetic diversity in the breed should be the key consideration in breeding plans. A good choice for this is to avoid inbreeding and keep the inbreeding coefficient as low as possible. This should also maintain the MHC locus heterozygous.
DLA test can be only made from blood sample due to the complexity of the analysis that requires high quality DNA.
DLA profiling service for Breed Clubs
Before typing individual dog's it would be useful to have a public DLA-profile from the breed. Different breeds have different numbers of MHC II haplotypes based on the origin and history of the breeds and used breeding practices. The current DLA-profile of the breed can be known only by DLA typing. We provide DLA-profiling services for Breed Clubs. We suggest to type about 50-100 unrelated dogs provided by the owners or the Club. After the analysis, the Breed Club will get haplotype profiles and frequencies. This information can be used to advise better and healthier breeding habits. The DLA-profile service takes usually at least 2-3 months to complete.
If your Club is interested in this service, please contact our Customer service. Several Clubs have already successully profiled their breeds with us.
References:
Wilbe ym. 2010. Increased genetic risk or protection for canine autoimmune lymphocytic thyroiditis in Giant Schnauzers depends on DLA class II genotype. Tissue Antigens 75(6): 712-719.
Bedford PG, Longstaffe JA. Corneal pannus (chronic superficial keratitis) in the German shepherd dog. J Small Anim Pract 1979: 20: 41-56.
Wilbe M, Jokinen P, Hermanrud C, et al. MHC class II polymorphism is associated with a canine SLE-related disease complex. Immunogenetics 2009: 61: 557-64.
Kennedy LJ, O'Neill T, House A, et al. Risk of anal furunculosis in German shepherd dogs is associated with the major histocompatibility complex. Tissue Antigens 2008: 71: 51-6.
Hughes AM, Jokinen P, Bannasch DL, Lohi H, Oberbauer AM. Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Tissue Antigens, 75(6):684-90, 2010.
K. A. Greer, A. K. Wong, H. Liu, T. R. Famula, N. C. Pedersen, A. Ruhe, M. Wallace & M. W. Neff; Necrotizing meningoencephalitis of Pug Dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens, 76(2):110-8, 2010.
Kennedy, L. J., Randall, D. A., Knobel, D., Brown, J. J., Fooks, A. R., Argaw, K., Shiferaw, F., Ollier, W. E. R., Sillero-Zubiri, C., Macdonald, D. W. and Laurenson, M. K. (2011), Major histocompatibility complex diversity in the endangered Ethiopian wolf (Canis simensis). Tissue Antigens, 77: 118–125.
Dyggve, H., Kennedy, L. J., Meri, S., Spillmann, T., Lohi, H. and Speeti, M. (2011), Association of Doberman hepatitis to canine major histocompatibility complex II. Tissue Antigens, 77: 30–35.
It, V., Barrientos, L., López Gappa, J., Posik, D., Díaz, S., Golijow, C. and Giovambattista, G. (2010), Association of canine juvenile generalized demodicosis with the dog leukocyte antigen system, Tissue Antigens, 76: 67–70.
Seddon, J. M., Berggren, K. T. and Fleeman, L. M. (2010), Evolutionary history of DLA class II haplotypes in canine diabetes mellitus through single nucleotide polymorphism genotyping. Tissue Antigens, 75: 218–226.
Barnes, A., O’Neill, T., Kennedy, L. J., Short, A. D., Catchpole, B., House, A., Binns, M., Fretwell, N., Day, M. J. and Ollier, W. E. R. (2009), Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*. Tissue Antigens, 73: 218–224.
Jokinen P, Rusanen E, Kennedy L and Lohi H. MHC class II risk haplotype associated with canine chronic superficial keratitis in German Shepherd Dogs. Vet Immunol Immunopathol. 140(1-2):37-41, 2011.