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Effects of variable mutation rates and epistasis on the distribution of allele frequencies in humans

Arbel Harpak, Anand Bhaskar, Jonathan K. Pritchard
doi: https://doi.org/10.1101/048421
Arbel Harpak
1Department of Biology, Stanford University, Stanford, California, United States of America
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  • For correspondence: arbelh@stanford.edu
Anand Bhaskar
2Department of Genetics, Stanford University, Stanford, California, United States of America
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Jonathan K. Pritchard
1Department of Biology, Stanford University, Stanford, California, United States of America
2Department of Genetics, Stanford University, Stanford, California, United States of America
3Howard Hughes Medical Institute
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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 “phylogeneticaNy-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. We additionally find evidence for epistatic effects on the cSFS; namely, that parallel primate substitutions are more informative about constraint in humans when the local sequence context is similar than when there are other nearby substitutions. In summary, we show that variable mutation rates and local epistatic effects are important determinants of the SFS in humans.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 13, 2016.
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Effects of variable mutation rates and epistasis on the distribution of allele frequencies in humans
Arbel Harpak, Anand Bhaskar, Jonathan K. Pritchard
bioRxiv 048421; doi: https://doi.org/10.1101/048421
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Effects of variable mutation rates and epistasis on the distribution of allele frequencies in humans
Arbel Harpak, Anand Bhaskar, Jonathan K. Pritchard
bioRxiv 048421; doi: https://doi.org/10.1101/048421

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