Detecting Individual Sites Subject to Episodic Diversifying Selection
Open accessAbstract
The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.
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Positively selected sites were identified using two different methods: BEB from MA with a cutoff of 0.90 and MEME with the default cutoff of 0.1.
“Positively selected sites were identified using two different methods: the Bayes Empirical Bayes (BEB) analysis from MA (with a cutoff of 0.90) and the Mixed Effects Model of Evolution (MEME) (with the default cutoff of 0.1)34.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [34]
The Methods section, “The MEME test for episodic diversifying selection” (page unavailable), describes MEME as a method for identifying sites under positive selection. Our copy does not establish a default MEME cutoff of 0.1 or describe the cited sentence’s BEB analysis from MA with a 0.90 cutoff. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe partitioned lineages test can be misleading because estimates of ! can be increased by processes such as intensification of positive selection when selective pressures vary both along branches and sites.
“However, this test can be misleading because estimates of ! can be increased by processes such as intensification of positive selection when selective pressures vary both along branches and sites (Murrell et al. 2012).”
From RELAX: Detecting Relaxed Selection in a Phylogenetic Framework (2015) · cites this paper as Murrell et al. 2012
The Introduction (page unavailable) says tests that assume selection is constant across lineages can miss episodic positive selection, and the Discussion (page unavailable) describes positive selection on some branches being masked by purifying selection on others. These passages support the general warning that varying selective pressures can mislead a test, but they do not say that the partitioned lineages test yields increased ω estimates because positive selection intensifies. (LLM, conf=0.82)
Experimental — accuracy not yet measuredStandard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection.
“Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection.”
From RELAX: Detecting Relaxed Selection in a Phylogenetic Framework (2015) · cites this paper as Murrell et al. 2012
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredPositively selected sites along the mammalian or sauropsidan branches were considered only if they were also detected by the Mixed Effects Model of Evolution (MEME) method.
“To be conservative, we considered as positively selected only sites also detected by the Mixed Effects Model of Evolution (MEME) method34.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [34]
Branch-level resolution vastly increased the detectable instances of positive selection.
“This development vastly increased the detectable instances of positive selection (Murrell et al. 2012).”
From RELAX: Detecting Relaxed Selection in a Phylogenetic Framework (2015) · cites this paper as Murrell et al. 2012
Random effects and mixed effects branch-site models allow detection of individual branches on which only a subset of sites are under positive selection or, conversely, individual sites which are under positive selection on only a subset of branches.
“Our random effects (Kosakovsky Pond et al. 2011) and mixed effects (Murrell et al. 2012) branch-site models allow detection of individual branches on which only a subset of sites are under positive selection or, conversely, individual sites which are under positive selection on only a subset of branches.”
From RELAX: Detecting Relaxed Selection in a Phylogenetic Framework (2015) · cites this paper as Murrell et al. 2012
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- Authors
- Murrell, B., Wertheim, J. O., Moola, S., Weighill, T., Scheffler, K., & Kosakovsky Pond, S. L.
- Affiliations
- Stellenbosch University (ZA)
- University of California San Diego (US)
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-12
- Volume
- 8
- Issue
- 7
- Pages
- e1002764
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3395634
- OpenAlex
- W2118982822
- Cited by
- 1,811
- References
- 63
- Citations by year
- 2026: 147 · 2025: 135 · 2024: 169 · 2023: 162 · 2022: 161 · 2021: 183 · 2020: 172 · 2019: 123 · 2018: 115 · 2017: 99 · 2016: 87 · 2015: 100 · 2014: 83 · 2013: 66 · 2012: 9
- FWCI
- 49.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- TUScholarShare (Temple University) (submittedVersion, cc-by)
- SUNScholar (Stellenbosch University) (submittedVersion)
- Funders
- National Science Foundation (0714991)
- European Commission
- National Research Foundation
- National Institutes of Health (AI47745, AI74621, AI-36214, AI57167, GM093939)
- Center for AIDS Research, University of Washington
- University of California, San Diego
- National Institute of General Medical Sciences (GM093939, R01GM093939)
- National Institute of Allergy and Infectious Diseases (R01AI057167, AI-74621, AI-47745, AI57167, R21AI047745, AI 43638, R24AI106039, R56AI047745, AI-36214, R01AI047745, U01AI043638, P01AI074621, P30AI036214, T32AI007384)
- 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 › Genetics › Genetic diversity and population structure
- Keywords
- episodic selection, positive selection, memes, protein-coding genes, natural selection
- MeSH terms
- Amino Acids, Animals, Computer Simulation, Models, Theoretical, Phylogeny, Rhodopsin, Selection, Genetic, Vertebrates, Open Reading Frames, Evolution, Molecular, Computational Biology
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