title: Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans.
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.
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Arbel
authors.identifier: http://orcid.org/0000-0002-3655-748X
authors.initials: A
authors.lastname: Harpak
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.|Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Anand
authors.initials: A
authors.lastname: Bhaskar
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.|Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D019175:DNA Methylation / Q000235:genetics; D059472:Exome / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D005828:Genetics, Population; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D010802:Phylogeny; D057079:Pongo / Q000235:genetics; D011323:Primates / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics*