1771: Defining the Unique Genetic Markers in Dogs That Define Immune Function, Disease Resistance and Tissue Transplantation

Grant Amount: $178,200

Beverly Torok-Storb, PhD; Fred Hutchinson Cancer Research Center

January 1, 2013 - June 30, 2018

Sponsor(s): American Lhasa Apso Club, American Miniature Schnauzer Club, Inc., American Shetland Sheepdog Association, Bedlington Terrier Club of America, Bernese Mountain Dog Club of America, Chihuahua Club of America, Collie Health Foundation, English Cocker Spaniel Club of America, Orthopedic Foundation for Animals, Soft Coated Wheaten Terrier Genetic Research Fund, TarTan Gordon Setter Club

Breed(s): -All Dogs

Research Program Area: Immunology and Infectious Disease

Abstract

The Major Histocompatibility Complex (MHC) genes encode proteins that are critical for a wide range of biological functions, from immune protection against infectious disease to the predisposition of an individual to develop diabetes and auto immune diseases. The MHC genes in the dog are incompletely characterized, thereby severely limiting our ability to full define the cause of many canine diseases. Dr. Ramakrishnan has developed improved methods for identifying the different forms of canine MHC genes in a large number of dogs of diverse breeds. In this study he will characterize the patterns of MHC genetic variation in over 1200 dogs from at least 50 breeds using a high throughput sequencing strategy. The distribution and frequency of different forms of each of these genes and their specific clustering among different breeds will greatly enhance our knowledge of the genetic diversity among breeds. The methodology and data gained from this study will enhance the power of association studies between MHC types and canine diseases. Such a database will also enable tissue transplantation from unrelated but matched donors as a treatment for advanced malignancies (stem cell transplants) and other diseases (tissue transplantation). Fully defining the canine MHC will have broad impact across canine health, including oncology, immunology and infectious disease.

Publication(s)

Pyo, C.-W., Harkey, M. A., Torok-Storb, B., Storb, R., Wang, R., Thomas, A. S., Nelson, W. C., & Geraghty, D. E. (2022). Genotyping of canine MHC gene DLA-88 by next-generation sequencing reveals high frequencies of new allele discovery and gene duplication. HLA. https://doi.org/10.1111/tan.14752

Harkey, M. A., Villagran, A. M., Venkataraman, G. M., Leisenring, W. M., Hullar, M. A. J., & Torok-Storb, B. J. (2017). Associations between gastric dilatation-volvulus in Great Danes and specific alleles of canine immune-system genes DLA88, DRB1, and TLR5. American Journal of Veterinary Research, 78(8), 12.

Hullar, M. A. J., Lampe, J. W., Torok-Storb, B. J., & Harkey, M. A. (2018). The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system. PLOS ONE, 13(6), e0197686. https://doi.org/10.1371/journal.pone.0197686

Tsai, K. L., Starr-Moss, A. N., Venkataraman, G. M., Robinson, C., Kennedy, L. J., Steiner, J. M., & Clark, L. A. (2013). Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs. Immunogenetics, 65(7), 501–509. https://doi.org/10.1007/s00251-013-0704-y

Venkataraman, G. M., Geraghty, D., Fox, J., Graves, S. S., Zellmer, E., Storer, B. E., … Storb, R. (2013). Canine DLA-79 gene: an improved typing method, identification of new alleles and its role in graft rejection and graft-versus-host disease. Tissue Antigens, 81(4), 204–211. https://doi.org/10.1111/tan.12094

Venkataraman, G. M., Kennedy, L. J., Little, M.-T. E., Graves, S. S., Harkey, M. A., Torok-Storb, B. J., & Storb, R. (2017). Thirteen novel canine dog leukocyte antigen-88 alleles identified by sequence-based typing. HLA, 90(3), 165–170. https://doi.org/10.1111/tan.13077