Multiple-testing corrections in selection scans using identity-by-descent segments

Abstract

Failing to correct for multiple testing in selection scans can lead to false discoveries of recent genetic adaptations. The scanning statistics in selection studies are often too complicated to theoretically derive a genome-wide significance level or empirically validate control of the family-wise error rate (FWER). By modeling the autocorrelation of identity-by-descent (IBD) rates, we propose a computationally efficient method to determine genome-wide significance levels in an IBD-based scan for recent positive selection. In whole genome simulations, we show that our method has approximate control of the FWER and can adapt to the spacing of tests along the genome. We also show that these scans can have more than fifty percent power to reject the null model in hard sweeps with a selection coefficient s >= 0.01 and a sweeping allele frequency between twenty-five and seventy-five percent. A few human genes and gene complexes have statistically significant excesses of IBD segments in thousands of samples of African, European, and South Asian ancestry groups from the Trans-Omics for Precision Medicine project and the United Kingdom Biobank. Among the significant loci, many signals of recent selection are shared across ancestry groups. One shared selection signal at a skeletal cell development gene is extremely strong in African ancestry samples. HighlightsO_LIWe propose a method to address multiple testing when scanning along the genome for excess identity-by-descent rates. C_LIO_LIIn whole genome simulations, we calculate that the family-wise error rates of our method are close to the desired family-wise significance level. C_LIO_LIWe perform six selection scans in two consortium datasets covering different ancestry groups and reference genome builds. C_LIO_LIFor a genomic region on chromosome 16, we report extremely high identity-by-descent rates in African ancestry groups and replication in European and South Asian ancestry groups. C_LI