Natural selection on protein-coding genes in the human genome

• Published in: Nature (London) Vol. 437; no. 7062; pp. 1153 - 1157
• Main Authors: Bustamante, Carlos D., Fledel-Alon, Adi, Williamson, Scott, Nielsen, Rasmus, Todd Hubisz, Melissa, Glanowski, Stephen, Tanenbaum, David M., White, Thomas J., Sninsky, John J., Hernandez, Ryan D., Civello, Daniel, Adams, Mark D., Cargill, Michele, Clark, Andrew G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.10.2005; Nature Publishing; Nature Publishing Group
• Subjects: Amino Acid Substitution - genetics; Amino acids; Animals; Biological and medical sciences; Computational Biology; Cytoskeleton - metabolism; Deoxyribonucleic acid; Disease; DNA; Evolution; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Genes; Genes. Genome; Genetic Predisposition to Disease - genetics; Genome, Human; Genomics; Humanities and Social Sciences; Humans; letter; Male; Molecular and cellular biology; Molecular genetics; multidisciplinary; Pan troglodytes - genetics; Polymorphism, Genetic - genetics; Proteins; Proteins - genetics; Racial Groups - genetics; Science; Science (multidisciplinary); Selection, Genetic; Human; Molecular evolution; Gene; Genome; Protein; Polymorphism; Natural selection
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature04240

Go forth and evolve Are we still evolving? The simple answer is yes. A comparison of the sequences of over 11,000 genes from 39 human individuals and from chimpanzees reveals more than 1,139 genes that show evidence of either positive or weak negative selection. Certain gene types (such as transcription factors) show an excess of rapidly evolving genes and others (such as cytoskeletal proteins) show an excess of genes subject to weak negative selection. Genes associated with human disease tend to show a signature of past selection: this may be because complex common diseases are most likely to arise from genes that can tolerate mildly deleterious variation. Mutations that grossly affect gene function are likely to be kept at low frequencies by natural selection and thus contribute little to explaining variation in common disease. Comparisons of DNA polymorphism within species to divergence between species enables the discovery of molecular adaptation in evolutionarily constrained genes as well as the differentiation of weak from strong purifying selection 1 , 2 , 3 , 4 . The extent to which weak negative and positive darwinian selection have driven the molecular evolution of different species varies greatly 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , with some species, such as Drosophila melanogaster , showing strong evidence of pervasive positive selection 6 , 7 , 8 , 9 , and others, such as the selfing weed Arabidopsis thaliana , showing an excess of deleterious variation within local populations 9 , 10 . Here we contrast patterns of coding sequence polymorphism identified by direct sequencing of 39 humans for over 11,000 genes to divergence between humans and chimpanzees, and find strong evidence that natural selection has shaped the recent molecular evolution of our species. Our analysis discovered 304 (9.0%) out of 3,377 potentially informative loci showing evidence of rapid amino acid evolution. Furthermore, 813 (13.5%) out of 6,033 potentially informative loci show a paucity of amino acid differences between humans and chimpanzees, indicating weak negative selection and/or balancing selection operating on mutations at these loci. We find that the distribution of negatively and positively selected genes varies greatly among biological processes and molecular functions, and that some classes, such as transcription factors, show an excess of rapidly evolving genes, whereas others, such as cytoskeletal proteins, show an excess of genes with extensive amino acid polymorphism within humans and yet little amino acid divergence between humans and chimpanzees.