PT - JOURNAL ARTICLE AU - Raul Torres AU - Zachary A. Szpiech AU - Ryan D. Hernandez TI - Human demographic history has amplified the effects of background selection across the genome AID - 10.1101/181859 DP - 2018 Jan 01 TA - bioRxiv PG - 181859 4099 - http://biorxiv.org/content/early/2018/01/09/181859.short 4100 - http://biorxiv.org/content/early/2018/01/09/181859.full AB - Natural populations often grow, shrink, and migrate over time. Demographic processes such as these can impact genome-wide levels of genetic diversity. In addition, genetic variation in functional regions of the genome can be altered by natural selection, which drives adaptive mutations to higher frequencies or purges deleterious ones. Such selective processes impact not only the sites directly under selection but also nearby neutral variation through genetic linkage through processes referred to as genetic hitch-hiking in the context of positive selection and background selection (BGS) in the context of purifying selection. While there is extensive literature examining the impact of selection at linked sites at demographic equilibrium, less is known about how non-equilibrium demographic processes impact the effects of hitchhiking and BGS. Utilizing a global sample of human whole-genome sequences from the Thousand Genomes Project and extensive simulations, we investigate how non-equilibrium demographic processes magnify and dampen the consequences of selection at linked sites across the human genome. When binning the genome by inferred strength of BGS, we observe that, compared to Africans, non-African populations have experienced larger proportional decreases in neutral genetic diversity in such regions. We replicate these findings in admixed populations by showing that non-African ancestral components of the genome have also been impacted more severely in these regions. We attribute these differences to the strong, sustained/recurrent population bottlenecks that non-Africans experienced as they migrated out of Africa and throughout the globe. Furthermore, we observe a strong correlation between FST and inferred strength of BGS, suggesting a stronger rate of genetic drift. Forward simulations of human demographic history with a model of BGS support these observations. Our results show that non-equilibrium demography significantly alters the consequences selection at linked sites and support the need for more work investigating the dynamic process of multiple evolutionary forces operating in concert.Author summary Patterns of genetic diversity within a species are affected at broad and fine scales by population size changes (“demography”) and natural selection. From both population genetics theory and observation of genomic sequence data, it is known that demography can alter genome-wide average neutral genetic diversity. Additionally, natural selection can affect neutral genetic diversity regionally across the genome via selection at linked sites. During this process, natural selection acting on adaptive or deleterious variants in the genome will also impact diversity at nearby neutral sites due to genetic linkage. However, less is well known about the dynamic changes to diversity that occur in regions impacted by selection at linked sites when a population undergoes a size change. We characterize these dynamic changes using thousands of human genomes and find that the population size changes experienced by humans have shaped the consequences of linked selection across the genome. In particular, population contractions, such as those experienced by non-Africans, have disproportionately decreased neutral diversity in regions of the genome inferred to be under strong background selection (i.e., selection at linked sites that is caused by natural selection acting on deleterious variants), resulting in large differences between African and non-African populations.