Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans.

Arbel Harpak,Anand Bhaskar,Jonathan K Pritchard,Adam Eyre-Walker

doi:10.1371/journal.pgen.1006489

Arbel Harpak, Anand Bhaskar + Show 2 more

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https://doi.org/10.1371/journal.pgen.1006489

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Abstract

The site frequency spectrum (SFS) has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the “phylogenetically-conditioned SFS” or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans.

Highlights

The distribution of allele frequencies across segregating sites, commonly referred to as the Site Frequency Spectrum (SFS), is a central focus of population genetics research as it can reflect a wide range of evolutionary processes, including demographic history as well as positive and purifying selection [1,2,3,4,5,6,7,8]
The site frequency spectrum (SFS) has long been used to study demographic history and natural selection. We extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the “phylogenetically-conditioned SFS” or cSFS
Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates

Summary

Introduction

The distribution of allele frequencies across segregating sites, commonly referred to as the Site Frequency Spectrum (SFS), is a central focus of population genetics research as it can reflect a wide range of evolutionary processes, including demographic history as well as positive and purifying selection [1,2,3,4,5,6,7,8]. The Exome Aggregation Consortium (ExAC) recently released high quality, exome-wide allele counts for over 60,000 people [12]. Large samples enable the detection of deleterious variants that are held at very low frequencies by purifying selection [18,19,20,21,22]

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