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Cited by 95Evolution and Genetic DynamicsGenomics and Rare DiseasesRNA and protein synthesis mechanisms

Distribution of the strength of selection against amino acid replacements in human proteins.

Open access
Yampolsky, Lev Y., Kondrashov, Fyodor A., Kondrashov, Alexey S.·2005·Human Molecular Genetics
DOI 10.1093/hmg/ddi350
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Abstract

The impact of an amino acid replacement on the organism's fitness can vary from lethal to selectively neutral and even, in rare cases, beneficial. Substantial data are available on either pathogenic or acceptable replacements. However, the whole distribution of coefficients of selection against individual replacements is not known for any organism. To ascertain this distribution for human proteins, we combined data on pathogenic missense mutations, on human non-synonymous SNPs and on human-chimpanzee divergence of orthologous proteins. Fractions of amino acid replacements which reduce fitness by >10(-2), 10(-2)-10(-4), 10(-4)-10(-5) and <10(-5) are 25, 49, 14 and 12%, respectively. On average, the strength of selection against a replacement is substantially higher when chemically dissimilar amino acids are involved, and the Grantham's index of a replacement explains 35% of variance in the average logarithm of selection coefficients associated with different replacements. Still, the impact of a replacement depends on its context within the protein more than on its own nature. Reciprocal replacements are often associated with rather different selection coefficients, in particular, replacements of non-polar amino acids with polar ones are typically much more deleterious than replacements in the opposite direction. However, differences between evolutionary fluxes of reciprocal replacements are only weakly correlated with the differences between the corresponding selection coefficients.

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  • Because recessive lethal mutations are only a subset of all deleterious mutations, the estimate provides a lower bound on the burden of recessive deleterious mutations and information on the tail of the distribution of fitness effects.

    “Since recessive lethal mutations are only a subset of all deleterious mutations, our estimate provides a lower bound on the burden of recessive deleterious mutations, as well as information on the tail of the distribution of fitness effects of deleterious mutations ( e.g. , Yampolsky et al. 2005; Eyre-Walker et al. 2006; Boyko et al. 2008).”

    From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Yampolsky et al. 2005

  • Population genetic approaches find that 25-40% of all amino acid changes in humans are strongly deleterious (s > 1% in a genic selection model).

    “These methods find that 25 -40% of all amino acid changes in humans are strongly deleterious ( i.e. , have s . 1% in a genic selection model) (Yampolsky et al. 2005; EyreWalker et al. 2006; Boyko et al. 2008).”

    From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Yampolsky et al. 2005

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Authors
Yampolsky, L. Y., Kondrashov, F. A., & Kondrashov, A. S.
Affiliations
  • East Tennessee State University (US)
  • University of California San Diego (US)
  • National Institutes of Health (US)
Corresponding author
Yampolsky, Lev Y.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2005-09-20
Volume
14
Issue
21
Pages
3191-3201
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddi350
OpenAlex
W2139792356
Cited by
95
References
40
Citations by year
2025: 4 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 7 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 7
FWCI
5.93
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Human Molecular Genetics (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
amino acid substitutions, selection strength, human protein, non-synonymous SNPs, human-chimpanzee divergence, orthologous proteins, selection coefficients, deleterious mutations, protein evolution, fitness cost of mutations
MeSH terms
Amino Acids, Humans, Proteins, Regression Analysis, Selection, Genetic, Species Specificity, Evolution, Molecular, Amino Acid Substitution, Mutation, Missense, Polymorphism, Single Nucleotide, Genetic Diseases, Inborn

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