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Cited by 2,286Evolution and Genetic DynamicsGenomics and Phylogenetic StudiesRNA and protein synthesis mechanisms

Codon-substitution models for heterogeneous selection pressure at amino acid sites

Yang, Ziheng, Nielsen, Rasmus, Goldman, Nick, Pedersen, Anne-Mette Krabbe·2000·Genetics
DOI 10.1093/genetics/155.1.431
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Abstract

Comparison of relative fixation rates of synonymous (silent) and nonsynonymous (amino acid-altering) mutations provides a means for understanding the mechanisms of molecular sequence evolution. The nonsynonymous/synonymous rate ratio (ω = dN/dS) is an important indicator of selective pressure at the protein level, with ω = 1 meaning neutral mutations, ω < 1 purifying selection, and ω > 1 diversifying positive selection. Amino acid sites in a protein are expected to be under different selective pressures and have different underlying ω ratios. We develop models that account for heterogeneous ω ratios among amino acid sites and apply them to phylogenetic analyses of protein-coding DNA sequences. These models are useful for testing for adaptive molecular evolution and identifying amino acid sites under diversifying selection. Ten data sets of genes from nuclear, mitochondrial, and viral genomes are analyzed to estimate the distributions of ω among sites. In all data sets analyzed, the selective pressure indicated by the ω ratio is found to be highly heterogeneous among sites. Previously unsuspected Darwinian selection is detected in several genes in which the average ω ratio across sites is <1, but in which some sites are clearly under diversifying selection with ω > 1. Genes undergoing positive selection include the β-globin gene from vertebrates, mitochondrial protein-coding genes from hominoids, the hemagglutinin (HA) gene from human influenza virus A, and HIV-1 env, vif, and pol genes. Tests for the presence of positively selected sites and their subsequent identification appear quite robust to the specific distributional form assumed for ω and can be achieved using any of several models we implement. However, we encountered difficulties in estimating the precise distribution of ω among sites from real data sets.

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  • It became conventional to think in terms of the distribution of ! values over sites instead of a single gene-wide !.

    “Therefore, it became conventional to think in terms of the distribution of !values over sites instead of a single gene-wide !(Yang et al. 2000).”

    From RELAX: Detecting Relaxed Selection in a Phylogenetic Framework (2015) · cites this paper as Yang et al. 2000

    The Theory section models site-to-site variation in the dN/dS ratio using a statistical distribution, and the Results compare those models with a one-ratio model. This supports the conceptual contrast in the claim, but the paper does not establish that thinking in distributions became conventional across the field. (LLM, conf=0.82)

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Research works printed but not linked: 6

  1. Fitch, W. M., R. M. Bush, C. A. Bender and N. J. Cox, 1997 Long term trends in the evolution of H(3) HA1 human influenza type A. Proc. Natl. Acad. Sci. USA 94: 7712-7718.
  2. Gillespie, J. H., 1991 The Couses of Molecular Evolution. Oxford University Press, Oxford.
  3. Kimura, M., 1983 The Neutral Theory of Molecular Evolution. Cambridge University Press, Cambridge, United Kingdom.
  4. Mindell, D. P., 1996 Positive selection and rates of evolution in immunodeficiency viruses from humans and chimpanzees. Proc. Natl. Acad. Sci. USA 93: 3284-3288.
  5. Yamaguchi, Y., and T. Gojobori, 1997 Evolutionary mechanisms and population dynamics of the third variable envelope region of HIVwithin single hosts. Proc. Natl. Acad. Sci. USA 94: 1264-1269.
  6. Zanotto, P. M., E. A. Gould, G. F. Gao, P. H. Harvey and E. C. Holmes, 1996 Population dynamics of flaviviruses revealed by molecular phylogenies. Proc. Natl. Acad. Sci. USA 93: 548-553.

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Authors
Yang, Z., Nielsen, R., Goldman, N., & Pedersen, A.-M. K.
Affiliations
  • University College London (GB)
  • Harvard University (US)
  • University of Cambridge (GB)
  • Aarhus University (DK)
Corresponding author
Yang, Ziheng
ORCID
Venue
Genetics
Publisher
Oxford University Press (OUP)
Published
2000-05-01
Volume
155
Issue
1
Pages
431-449
ISSN
  • 0016-6731 (ISSN-L)
  • 1943-2631
DOI
10.1093/genetics/155.1.431
OpenAlex
W2160364329
Cited by
2,286
References
3
Citations by year
2026: 35 · 2025: 35 · 2024: 59 · 2023: 45 · 2022: 51 · 2021: 63 · 2020: 55 · 2019: 68 · 2018: 76 · 2017: 71 · 2016: 80 · 2015: 95 · 2014: 112 · 2013: 109 · 2012: 106
FWCI
31.47
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
codon substitution models, Omega ratio, positive selection, purifying selection, site-specific selection, adaptive molecular evolution, beta-globin, influenza hemagglutinin
MeSH terms
Amino Acids, Animals, Codon, Drosophila, Globins, Humans, Membrane Glycoproteins, Mitochondria, Models, Genetic, Peptide Fragments, Selection, Genetic, Vertebrates, Viral Envelope Proteins, HIV Envelope Protein gp120, Genes, pol, Gene Products, vif, Viral Nonstructural Proteins, Hemagglutinin Glycoproteins, Influenza Virus, Amino Acid Substitution

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