The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

Abstract

The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe 20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe ,4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations.

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

“…Importantly, GERP scores are often used to assign selection coefficients to individual variants (Henn et al 2016(Henn et al , 2015Wang et al 2017;Pedersen et al 2017) . Figure 1A shows that a GERP score >4 can be generated by nearly neutral mutations ( N e s =-1) to very strongly deleterious mutations ( N e s <-8).…”

“…Here we leveraged this summary statistic to compare different models of turnover of selected sequence to each other. We do this by fitting evolutionary models to the empirical GERP score distribution computed from commonly used sequence alignment of data from 35 mammalian species to the human genome (e.g., Henn et al 2016Henn et al , 2015Pedersen et al 2017;Davydov et al 2010;Schubert et al 2014) . Because the number of species for which there is data in the multi-sequence alignment varies across the genome, we partitioned the genome into multiple bins.…”

“…A neutral tree of 46 vertebrate species was downloaded from the UCSC genome browser ( http://hgdownload.cse.ucsc.edu/goldenPath/hg19/multiz46way/46way.nh ). A subset of species was then selected to arrive at the tree of 36 mammalian species that is commonly used for GERP analysis (e.g., Henn et al 2016Henn et al , 2015Pedersen et al 2017;Davydov et al 2010;Schubert et al 2014) . The length of a branch reflects the neutral substitution rate along the branch, i.e.…”

Estimating narrow-sense heritability from genome-wide data in admixed populations

“…Greenlanders are an isolate with many unique characteristics, such as small population size, high degree of relatedness and extensive population structure with ancestry from both the Inuit and Europeans. 19,20 Our goal is to find a way to estimate and understand narrow-sense heritability in such populations, thus gaining valuable insights into the genetic architecture of complex traits in such populations. (v) the ADDITION study 29 All studies were conducted in compliance with the Helsinki Declaration II and all participants gave their written consent after being informed about the study orally and in writing.…”

Polymorphism of the trehalase gene (TREH) in native populations of Siberia

“…Так, у канадских эскимосов частота этой делеции составляет 17 % (Marcadier et al, 2015), у эскимосов Гренландии -39 % (Pedersen et al, 2017). По нашим данным, частота делеции AG в локусе rs781470490 у чукчей составляет 14.3 %, у коряков -7.3 % и у охотских эвенов -3.5 % (Малярчук и др., 2017).…”