Since the canine genome sequencing project we have made a lot of progress both in terms of developing strategies and tools for canine disease gene mapping and in actually finding disease genes for both monogenic and complex diseases. In recent years we have mapped genes for diseases as diverse as eye disease, epilepsy, cardiomyopathy, compulsive disorder, periodic fevers and cancer. Some mutations have been relatively easy to find and the genetics behind the disease can be easily explained by the identified mutation and therefore genetic tests are easy to offer. For other diseases, more complex inheritance or mutations make life a bit harder. For example, for SharPei Fever a regulatory copy number variant underlies both the desirable thickened wrinkled skin and the periodic fever disease, making both biological understanding, technical genetic test development and guidance to breeders more challenging.

Shar-Pei Fever Example

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei dogs have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p_raw = 2.3x10^-6, pgenome = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

Pathway Examples

For several of our complex traits such as cancer, the breeders' hopes might have been to find a single gene mutation that can be bred away. While we often find one or a few genes of major relevance the main findings in these studies appear to be the identification of pathways underlying the disease. For immune- mediated rheumatic disease, osteosarcoma, mast cell tumors, and canine compulsive disorders we have identified key pathways for the disease. These pathways are sometimes similar between breeds and sometimes unique. This information offers the potential of developing new more targeted drugs and applying with a personalized medicine approach where genetic susceptibility is taken into account.

Here I will discuss both the Shar-Pei Fever story as well as other challenges and success stories and try to relate these findings to how they can help breeders, pet owners and the dogs.