Population-genetic methods for inferring recent histories and targets of selection in the biobank era

PROJECT SUMMARY. The PI’s research program in human population genetics focuses on the coalescent-based inference of popula- tion histories from whole genomes, and identifying the genetic basis of adaptation and disease at multiple bio- logical scales—from mutations to genes to gene subnetworks. Global investments made in biobanks sampling millions of people around the world are revealing new challenges for human genetics. Biobanks demonstrate how ubiquitous genetic admixture—gene flow between previously isolated populations resulting in a population that is descended from multiple sources—has been throughout human history, yet methods for detecting genetic targets of natural selection are not calibrated for admixture. Relatives are increasingly sampled in biobanks, but are routinely discarded in population-genetic analyses, thereby limiting understanding of both recent population histories and complex trait architecture. Biobank participants are affected by heterogeneous environmental ex- posures, which confound our understanding of genetic influences on complex traits. Addressing these challenges requires new methods in human population genetics, the study of the evolutionary forces that produce and main- tain human genetic variation. This renewal application describes a series of projects motivated by three open questions in human population genetics: : (1) How do we infer the detailed histories and selection pressures that shape admixed populations? (2) How can we gain new insights into recent histories and complex traits from relatives’ genomes? (3) How can biobanks help us understand the role of environments in shaping human com- plex traits? The future research plans draw on the PI’s expertise in coalescent theory, Bayesian inference, pop- ulation genetics, and statistical genetics combined with scalable, efficient algorithms for analyzing biobank da- tasets such as the UK Biobank and All of Us Research Program. The proposed research in this MIRA renewal application will have wide-ranging impact, from characterizing how natural selection interacts with population histories to shape human genetic variation, to gaining new insights into complex traits and histories through the genomes of relatives, to countering the misuse of genetics research.