The impact of identity-by-descent on fitness and disease in natural and domesticated Canid populations

Abstract

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and phenotype data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs, and that there remains an excess of understudied breeds that can reveal new disease-causing variation. Significance StatementDogs and humans have coexisted together for thousands of years, but it was not until the Victorian Era that humans practiced selective breeding to produce the modern standards we see today. Strong artificial selection during the breed formation period has simplified the genetic architecture of complex traits and caused an enrichment of identity-by-descent (IBD) segments in the dog genome. This study demonstrates the value of IBD segments and utilizes them to infer the recent demography of canids, predict case-control status for complex traits, locate regions of the genome potentially linked to inbreeding depression, and to identify understudied breeds where there is potential to discover new disease-associated variants.