View Program - 2022 Population, Evolutionary, and Quantitative Genetics Conference

Runs of homozygosity are long stretches of identical-by-descent (IBD) haplotypes inherited from parents with a recent common ancestor. Their abundance and distribution within a population are affected by numerous factors such as population bottlenecks and isolation, founder effects, recent inbreeding, and natural selection, and it has been shown that long ROH are enriched for deleterious homozygotes. Although ROH abundance has been associated with increased risk for various complex traits, it remains unclear the extent to which population history and genetic architecture influence ROH associations with phenotypes. Here we take a simulation approach to characterize the relationship between demographic history, genetic architecture, and a generic complex phenotype. We perform forward-in-time simulations of a three-population human demographic history roughly representing African, European, and Asian continental populations. We simulate a 100 Mb chromosome region with exon structure and a variable recombination map based on the first 100 Mb of human chromosome 1 and allow deleterious mutations with selection coefficients drawn from a gamma distribution. Phenotype is modeled as a function of selection coefficients, with parameters that allow us to vary the relative importance of rare versus common variants in their contribution to the total phenotype. Our results show that demographic history, ROH length, and dominance coefficient are important factors contributing to how much variation in a trait are explained by ROH. We show that ROH influence the simulated phenotype most strongly when alleles are recessive and rare, and that, under these conditions, long ROH (comprised of IBD haplotypes inherited from a very recent ancestor) have more influence than short ROH. These results suggest that the role of ROH in contributing to complex phenotypes may be largely due to the pairing of rare alleles of recessive effect and that incorporating ROH into disease mapping approaches may help the identification of recessive effects.

The influence of demographic history and genetic architecture on complex phenotypes via runs of homozygosity