Selection Operating on Protein‐coding Genes in the Human Genome


The dominant selective force acting on protein‐coding regions throughout the human genome is purifying selection, which removes deleterious mutations. The fraction of substitutions that were positively selected, and can therefore be considered to be adaptive, can be estimated using methods based on comparisons of the relative amounts of change at two classes of sites – sites which if changed produce amino acid changes and sites which if changed do not lead to amino acid changes. Current estimates find very low estimates of adaptive evolution in protein‐coding regions during human evolution.

Keywords: purifying selection; adaptive evolution; human evolution; negative selection; positive selection


Arbiza L, Dopazo J and Dopazo H (2006) Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome. PLoS Computational Biology 2(4): e38.

Bakewell MA, Shi P and Zhang J (2007) More genes underwent positive selection in chimpanzee evolution than in human evolution. Proceedings of the National Academy of Sciences of the USA 104(18): 7489–7494.

Bustamante CD, Fledel‐Alon A, Williamson S et al. (2005) Natural selection on protein‐coding genes in the human genome. Nature 437(7062): 1153–1157.

Chen FC and Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. American Journal of Human Genetics 68(2): 444–456.

Clark AG, Glanowski S, Nielsen R et al. (2003) Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science 302(5652): 1960–1963.

Eyre‐Walker A (2006) The genomic rate of adaptive evolution. Trends in Ecology and Evolution 21(10): 569–575.

Fay JC, Wyckoff GJ and Wu CI (2001) Positive and negative selection on the human genome. Genetics 158(3): 1227–1234.

Gojobori J, Tang H, Akey JM and Wu CI (2007) Adaptive evolution in humans revealed by the negative correlation between the polymorphism and fixation phases of evolution. Proceedings of the National Academy of Sciences of the USA 104(10): 3907–3912.

Hughes AL (2007) Looking for Darwin in all the wrong places: the misguided quest for positive selection at the nucleotide sequence level. Heredity 99(4): 364–373.

Hughes AL, Packer B, Welch R et al. (2003) Widespread purifying selection at polymorphic sites in human protein‐coding loci. Proceedings of the National Academy of Sciences of the USA 100(26): 15754–15757.

Keightley PD, Lercher MJ and Eyre‐Walker A (2005) Evidence for widespread degradation of gene control regions in hominid genomes. PLoS Biology 3(2): e42.

Kimura M (1968) Evolutionary rate at the molecular level. Nature 217(5129): 624–626.

Kimura M (1983) The Neutral Theory of Molecular Evolution. Cambridge: Cambridge University Press.

King MC and Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188(4184): 107–116.

McDonald JH and Kreitman M (1991) Adaptive protein evolution at the Adh locus in Drosophila. Nature 351(6328): 652–654.

Mikkelsen TS, LaDeana WH, Eichler EE et al. (Chimpanzee Sequencing and Analysis Consortium) (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437(7055): 69–87.

Nielsen R and Yang Z (1998) Likelihood models for detecting positively selected amino acid sites and applications to the HIV‐1 envelope gene. Genetics 148(3): 929–936.

Nielsen R, Bustamante C, Clark AG et al. (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biology 3(6): e170.

Ohta T (1973) Slightly deleterious mutant substitutions in evolution. Nature 246: 96–98.

Prabhakar S, Noonan JP, Paabo S and Rubin EM (2006) Accelerated evolution of conserved noncoding sequences in humans. Science 314(5800): 786.

Sabeti PC, Schaffner SF, Fry B et al. (2006) Positive natural selection in the human lineage. Science 312: 1614–1620.

Subramanian S and Kumar S (2006) Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates. Molecular Biology and Evolution 23(12): 2283–2287.

Zhang L and Li WH (2005) Human SNPs reveal no evidence of frequent positive selection. Molecular Biology and Evolution 22(12): 2504–2507.

Further Reading

Fay JC and Wu CI (2001) The neutral theory in the genomic era. Current Opinions in Genetics and Development 11(6): 642–646.

Fay JC and Wu CI (2003) Sequence divergence, functional constraint, and selection in protein evolution. Annual Review of Genomics and Human Genetics 4: 213–235.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Meyer, Diogo, and Harris, Eugene E(Mar 2008) Selection Operating on Protein‐coding Genes in the Human Genome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020791]