부산대학교 도서관

Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a ~10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs–the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity. Author summary: As a consequence of selective breeding, specific disease-causing mutations have become more frequent in certain dog breeds. Whether the breeding practice also resulted in a general increase in the overall number of disease-causing mutations per dog genome is however not clear. To address this question, we compare the amount of harmful, potentially disease-causing, mutations in dogs from eight common breeds that have experienced varying degrees of intense selective breeding. We find that individuals belonging to the breed affected by the most intense breeding—cavalier King Charles spaniel (cKCs)—carry more harmful variants than other breeds, indicating that past breeding practices may have increased the overall levels of harmful genetic variation in dogs. The most common disease in cKCs is myxomatous mitral valve disease (MMVD). To identify variants linked to this disease we next characterize mutations that are common in cKCs, but rare in other breeds, and then investigate if these mutations can predict MMVD in dachshunds. We find that variants that regulate the expression of the gene NEBL in papillary muscles may increase the risk of the disease, indicating that loss of papillary muscle integrity could contribute to the development of MMVD. [ABSTRACT FROM AUTHOR]