PgmNr 83: Building genealogies for tens of thousands of individuals genome-wide identifies evidence of directional selection driving many complex human traits.
Authors:S.R. Myers 1,2; L. Speidel 1
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Affiliations:
1) Department of Statistics, University of Oxford, Oxford, United Kingdom; 2) Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
For a variety of species, large-scale genetic variation datasets are now available. All observed genetic variation can be traced back to a genealogy, which records historical recombination and coalescence events and in principle captures all available information about evolutionary processes. However, the reconstruction of these genealogies has been impossible for modern-scale data, due to huge inherent computational challenges. As a consequence, existing methods usually scale to no more than tens of samples. We have developed a new, computationally efficient method for inferring genome-wide genealogies accounting for varying population sizes and recombination hotspots, robust to data errors, and applicable to thousands of samples genome-wide in many species. This method is >10,000 times faster than existing approaches, and more accurate than leading algorithms for a range of tasks including estimating mutational ages and inferring historical population sizes. Application to 2,478 present-day humans in the 1000 Genomes Project, and wild mice, provides dates for population size changes, merges, splits and introgressions, and identifies changes in underlying evolutionary mutation rates, from 1000 years, to more than 1 million years, ago. Using our mutational age estimates, we developed an approach quantifying evidence of natural selection at each SNP. We compared resulting p-values to existing GWAS study results, finding widespread enrichment (>2.5-fold in Europeans and East Asians) of GWAS hits among individual SNPs with low selection p-values (Z>6), stronger than the 1.5-fold increase observed at nonsynonymous mutations, and with enrichment increasing with statistical significance. We found evidence that directional selection, impacting many SNPs jointly, has shaped the evolution of >50 human traits over the past 1,000-50,000 years, sometimes in different directions among different groups. These include many blood-related traits including blood pressure, platelet volume, both red and white blood cell count and e.g. monocyte counts; educational attainment; age at menarche; and physical traits including skin colour, body mass index and (particularly in South Asian populations) height. Our approach enables simultaneous testing of recent selection, ancient natural selection, and changes in the strength of selection on a trait through time, and is applicable across a wide range of organisms.