Selection against Amino Acid Replacements in Human Proteins

Abstract

The vast majority of mutations occurring in the coding regions of human genes alter the encoded amino acids of proteins. A significant proportion of these mutations are known to disrupt the structure and/or function of human proteins. The similarity of a large fraction of amino acid residues of human protein sequences with that of other species implies that the amino acid altering mutations were purged through natural selection during the evolution of the human lineage. In contrast, due to the effects of genetic drift, amino acid replacement mutations are present within human populations at low frequencies and a high proportion of such mutations are harmful to humans. Therefore, understanding the contrasting patterns of long‐term and short‐term evolutionary histories of human proteins are vital in identifying the amino acid mutations associated with human genetic diseases.

Key Concepts:

  • Natural selection eliminates a high proportion of amino acid changing mutations over time.

  • Selection against amino acid replacement mutations can be quantified at the level of whole proteome, specific protein or individual amino acid residue.

  • The intensity of selection is high for proteins performing essential housekeeping functions.

  • Selection intensity not only varies between proteins but also between amino acid residues within a protein.

  • Mutations involving changes between biochemically dissimilar amino acids are under high selection pressure.

  • Amino acid polymorphisms are abundant in human population due to genetic drift.

  • Evolutionary history, structure and functional properties of human proteins are useful to identify amino acid mutations associated with genetic diseases.

Keywords: natural selection; protein evolution; genetic drift; polymorphisms; human genetic diseases

Figure 1.

Hierarchical levels of selection.

Figure 2.

Histogram of the average ω (KA/KS) of human proteins under different magnitudes of selection. Divergence at synonymous (KS) and nonsynonymous (KA) positions were estimated for the human–chimpanzee species pair (13 454 protein‐coding genes) using the data obtained from Mikkelsen et al..

Figure 3.

Median ω (KA/KS) of human proteins belonging to different biological processes (Ashburner et al., ). The vertical dashed line represents the median ω estimated for the complete human–chimpanzee proteomes. Data obtained from Mikkelsen et al..

Figure 4.

Proportion of amino acid positions and their relative evolutionary conservation. The proteins of the genes IVD and CRB1 were used in this analysis. The relative conservation of amino acid positions was estimated using multiple sequence alignments consisting of human proteins and their orthologous counterparts from mouse, chicken, puffer fish and fruit fly. The evolutionary rate of the amino acid positions was estimated using the maximum likelihood method with a discrete gamma function (Yang, ), and the rate estimates were normalised to a 0–1 scale. The shape parameters (α) of the gamma functions are 0.6 and 1.5 for IVD and CRB1, respectively.

Figure 5.

Temporal patterns of amino acid polymorphisms (or substitutions) in the human lineage. (a) An illustration showing the decline of amino acid polymorphisms over time. (b) Phylogeny of chimpanzee and humans from different populations. A–F denotes the branches of the tree in the ascending order of time. (A) and (F) are the oldest and youngest branches of the tree, respectively. (c) ω (KA/KS) estimates obtained for each branch of the tree (data from Subramanian, ). The ωs were estimated using the nonsynonymous and synonymous polymorphisms that were specific to a single European (F), those shared between the two Europeans (E), Europeans and Asian (D), Eurasians and Yoruban (West African) (C), Khoisan (an ancient African tribe) and other humans (B). The interspecies ω was estimated for the human–chimpanzee pair (A) using the divergence at nonsynonymous and synonymous sites.

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Yang Z (2006) Computational Molecular evolution. Oxford: Oxford University Press.

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How to Cite close
Subramanian, Sankar(Mar 2013) Selection against Amino Acid Replacements in Human Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020859.pub2]