title: Darwinian and demographic forces affecting human protein coding genes.
abstract: Past demographic changes can produce distortions in patterns of genetic variation that can mimic the appearance of natural selection unless the demographic effects are explicitly removed. Here we fit a detailed model of human demography that incorporates divergence, migration, admixture, and changes in population size to directly sequenced data from 13,400 protein coding genes from 20 European-American and 19 African-American individuals. Based on this demographic model, we use several new and established statistical methods for identifying genes with extreme patterns of polymorphism likely to be caused by Darwinian selection, providing the first genome-wide analysis of allele frequency distributions in humans based on directly sequenced data. The tests are based on observations of excesses of high frequency-derived alleles, excesses of low frequency-derived alleles, and excesses of differences in allele frequencies between populations. We detect numerous new genes with strong evidence of selection, including a number of genes related to psychiatric and other diseases. We also show that microRNA controlled genes evolve under extremely high constraints and are more likely to undergo negative selection than other genes. Furthermore, we show that genes involved in muscle development have been subject to positive selection during recent human history. In accordance with previous studies, we find evidence for negative selection against mutations in genes associated with Mendelian disease and positive selection acting on genes associated with several complex diseases.
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark. Rasmus@binf.ku.dk
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Hubisz
authors.forename: Ines
authors.initials: I
authors.lastname: Hellmann
authors.forename: Dara
authors.initials: D
authors.lastname: Torgerson
authors.forename: Aida M
authors.initials: AM
authors.lastname: Andrés
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Ryan
authors.initials: R
authors.lastname: Gutenkunst
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.forename: Michele
authors.initials: M
authors.lastname: Cargill
authors.forename: Adam
authors.initials: A
authors.lastname: Boyko
authors.forename: Amit
authors.initials: A
authors.lastname: Indap
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
mesh_terms: D001741:Black or African American / Q000235:genetics; D003710:Demography; D019143:Evolution, Molecular; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012641:Selection, Genetic; D044465:White People / Q000235:genetics
chemical_list: D035683:MicroRNAs; D011506:Proteins