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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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![Figure 1 The standard random effects approach and samples. A) The standard random effects approach, in which the rates vary randomly over sites but are constant over branches. Different values of are showed in different colors. B) Samples from our new random effects approach [20], used by MEME, in which the rate on each branch is drawn independently of the rate on any other branch. All possible assignments of rates to sites are considered.](/paper-figures/7c0c11683f47469f9d5d29a91ca0dd06/detecting-individual-sites-subject-to-episodic-diversifying-selection-figure-1.jpg)
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“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]
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“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
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“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
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“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]
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“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
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“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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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482
Evolutionary trees from DNA sequences: A maximum likelihood approach.
Felsenstein, J. (1981) · Journal of Molecular Evolution · doi:10.1007/bf01734359 · Cited by 14,571
Evolutionary Rate at the Molecular Level
KIMURA, M. (1968) · Nature · doi:10.1038/217624a0 · Cited by 3,747
Adaptive protein evolution at the Adh locus in Drosophila
McDonald, J. H., & Kreitman, M. (1991) · Nature · doi:10.1038/351652a0 · Cited by 3,313
Self, S., & Liang, K.-Y. (1987) · Journal of the American Statistical Association · doi:10.1080/01621459.1987.10478472 · Cited by 2,861
Not So Different After All: A Comparison of Methods for Detecting Amino Acid Sites Under Selection
Pond, S. L. K., & Frost, S. D. W. (2005) · Molecular Biology and Evolution · doi:10.1093/molbev/msi105 · Cited by 2,320
Codon-substitution models for heterogeneous selection pressure at amino acid sites
Yang, Z., Nielsen, R., Goldman, N., & Pedersen, A.-M. K. (2000) · Genetics · doi:10.1093/genetics/155.1.431 · Cited by 2,286
Hughes, A. L., & Nei, M. (1988) · Nature · doi:10.1038/335167a0 · Cited by 1,976
A codon-based model of nucleotide substitution for protein-coding DNA sequences.
(1994) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040153 · Cited by 1,960
Nielsen, R., & Yang, Z. (1998) · Genetics · doi:10.1093/genetics/148.3.929 · Cited by 1,622
A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees
Nielsen, R., Bustamante, C. D., Clark, A. G., Glanowski, S., Sackton, T. B., Hubisz, M. J., Fledel-Alon, A., Tanenbaum, D. M., Civello, D., White, T. J., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030170 · Cited by 998
(1994) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040152 · Cited by 920
Sawyer, S. L., Wu, L. I., Emerman, M., & Malik, H. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409853102 · Cited by 688
Episodic adaptive evolution of primate lysozymes
Messier, W., & Stewart, C. (1997) · Nature · doi:10.1038/385151a0 · Cited by 476
A random effects branch-site model for detecting episodic diversifying selection
Kosakovsky Pond, S. L., Murrell, B., Fourment, M., Frost, S. D. W., Delport, W., & Scheffler, K. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr125 · Cited by 400
Self-citationModeling the covarion hypothesis of nucleotide substitution
Tuffley, C., & Steel, M. (1998) · Mathematical Biosciences · doi:10.1016/s0025-5564(97)00081-3 · Cited by 368
Statistical Properties of the Branch-Site Test of Positive Selection
Yang, Z., & dos Reis, M. (2010) · Molecular Biology and Evolution · doi:10.1093/molbev/msq303 · Cited by 353
Brault, A. C., Huang, C. Y. ‐., Langevin, S. A., Kinney, R. M., Bowen, R. A., Ramey, W. N., Panella, N. A., Holmes, E. C., Powers, A. M., & Miller, B. R. (2007) · Nature Genetics · doi:10.1038/ng2097 · Cited by 341
Site-to-Site Variation of Synonymous Substitution Rates
Pond, S. L. K., & Muse, S. V. (2005) · Molecular Biology and Evolution · doi:10.1093/molbev/msi232 · Cited by 283
Yokoyama, S., Tada, T., Zhang, H., & Britt, L. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802426105 · Cited by 272
Hotz, C. S., Loechl, C., de Brauw, A., Eozenou, P., Gilligan, D., Moursi, M., Munhaua, B., van Jaarsveld, P. J., Carriquiry, A. L., & Meenakshi, J. V. (2011) · British Journal Of Nutrition · doi:10.1017/s0007114511005174 · Cited by 261
Yang, Z. (2000) · Journal of Molecular Evolution · doi:10.1007/s002390010105 · Cited by 255
Harmsen, M. M., Ruuls, R. C., Nijman, I. J., Niewold, T., Frenken, L. G. J., & de Geus, B. (2000) · Molecular Immunology · doi:10.1016/s0161-5890(00)00081-x · Cited by 218
Positive darwinian selection observed at the variable-region genes of immunoglobulins.
Tanaka, T., & Nei, M. (1989) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040569 · Cited by 209
Purifying selection can obscure the ancient age of viral lineages
Wertheim, J. O., & Kosakovsky Pond, S. L. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr170 · Cited by 200
Self-citationModeling the site-specific variation of selection patterns along lineages
Guindon, S., Rodrigo, A. G., Dyer, K. A., & Huelsenbeck, J. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402177101 · Cited by 187
Investigating Protein-Coding Sequence Evolution with Probabilistic Codon Substitution Models
Anisimova, M. O., & Kosiol, C. (2008) · Molecular Biology and Evolution · doi:10.1093/molbev/msn232 · Cited by 173
Bonhoeffer, S., Holmes, E. C., & Nowak, M. A. (1995) · Nature · doi:10.1038/376125a0 · Cited by 162
Reliabilities of identifying positive selection by the branch-site and the site-prediction methods
Nozawa, M., Suzuki, Y., & Nei, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901855106 · Cited by 155
Structural Basis of a Flavivirus Recognized by Its Neutralizing Antibody
Wu, K., Wu, C.-W., Tsao, Y.-P., Kuo, T.-W., Lou, Y., Lin, C., Wu, S., & Cheng, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307776200 · Cited by 133
For the PROMISE EBF study group, Doherty, T., Sanders, D., Jackson, D. J., Swanevelder, S. A., Lombard, C. J., Zembe‐Mkabile, W., Chopra, M., Goga, A. E., Colvin, M., et al. (2012) · BMC Pediatrics · doi:10.1186/1471-2431-12-105 · Cited by 105
Pond, S. L. K., Poon, A. F. Y., Brown, A., & Frost, S. D. W. (2008) · Molecular Biology and Evolution · doi:10.1093/molbev/msn123 · Cited by 99
Weight loss interventions for chronic asthma
Adeniyi, F. B., & Young, T. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009339.pub2 · Cited by 97
Ramsoomar, L., & Morojele, N. K. (2012) · South African Medical Journal · doi:10.7196/samj.5766 · Cited by 86
Models of coding sequence evolution
Delport, W., Scheffler, K., & Seoighe, C. (2008) · Briefings in Bioinformatics · doi:10.1093/bib/bbn049 · Cited by 82
Self-citationJewkes, R. K., Morrell, R. G., Sikweyiya, Y. M., Dunkle, K., & Penn‐Kekana, L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040821 · Cited by 70
Carey, P., Suliman, S., Ganesan, K., Seedat, S., & Stein, D. J. (2012) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2238 · Cited by 70
Feeley, A. B., Musenge, E., Pettifor, J. M., & Norris, S. A. (2012) · Nutrition · doi:10.1016/j.nut.2011.11.025 · Cited by 69
Diacon, A. H., Maritz, J. S., Venter, A., van Helden, P. D., Dawson, R., & Donald, P. R. (2011) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2011.03626.x · Cited by 68
Evolutionary Fingerprinting of Genes
Pond, S. L. K., Scheffler, K., Gravenor, M. B., Poon, A. F. Y., & Frost, S. D. W. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msp260 · Cited by 64
Self-citationKatale, B. Z., Mbugi, E. V., Kendal, S., Fyumagwa, R., Kibiki, G. S., Godfrey‐Faussett, P., Keyyu, J. D., van Helden, P. D., & Matee, M. I. (2012) · Onderstepoort Journal of Veterinary Research · doi:10.4102/ojvr.v79i2.463 · Cited by 61
Katerere, D. R., Gray, A. I., Nash, R. J., & Waigh, R. D. (2012) · Fitoterapia · doi:10.1016/j.fitote.2012.04.011 · Cited by 61
Parker, W., Steyn, N. P., Levitt, N. S., & Lombard, C. J. (2012) · BMC Public Health · doi:10.1186/1471-2458-12-503 · Cited by 57
A total ban on alcohol advertising: Presenting the public health case
Parry, C. D. H., Harker, N., & London, L. (2012) · South African Medical Journal · doi:10.7196/samj.5945 · Cited by 56
Adaptive Evolution of Variable Region Genes Encoding an Unusual Type of Immunoglobulin in Camelids
Chen, S., Nguyen, V. K., & Nei, M. (2002) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a004073 · Cited by 55
Frequent Toggling between Alternative Amino Acids Is Driven by Selection in HIV-1
Delport, W., Scheffler, K., & Seoighe, C. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000242 · Cited by 54
Self-citationCorrecting the Bias of Empirical Frequency Parameter Estimators in Codon Models
Kosakovsky Pond, S., Delport, W., Muse, S. V., & Scheffler, K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011230 · Cited by 51
Self-citationImproved and standardized method for assessing years lived with disability after injury
Haagsma, J. A., Polinder, S., Lyons, R. A., Lund, J., Ditsuwan, V., Prinsloo, M., Veerman, L. J., & Beeck, E. V. (2012) · Bulletin of the World Health Organization · doi:10.2471/blt.11.095109 · Cited by 50
Channa, K., Röllin, H. B., Nøst, T. H., Odland, J. Ø., & Sandanger, T. M. (2012) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2012.03.073 · Cited by 42
Chen, J., & Sun, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019996 · Cited by 42
A Model of Directional Selection Applied to the Evolution of Drug Resistance in HIV-1
Seoighe, C., Ketwaroo, F., Pillay, V., Scheffler, K., Wood, N. T., Duffet, R., Zvelebil, M., Martinson, N. A., McIntyre, J. A., Morris, L., et al. (2007) · Molecular Biology and Evolution · doi:10.1093/molbev/msm021 · Cited by 36
Self-citation‘One Health’ infectious diseases surveillance in Tanzania: Are we all on board the same flight?
Mbugi, E. V., Kayunze, K. A., Katale, B. Z., Kendall, S. L., Good, L., Kibik, G. S., Keyyu, J. D., Godfrey‐Faussett, P., van Helden, P. D., & Matee, M. I. (2012) · Onderstepoort Journal of Veterinary Research · doi:10.4102/ojvr.v79i2.500 · Cited by 28
Miller, M. A., Joubert, J., Mathebula, N., de Klerk‐Lorist, L., Lyashchenko, K. P., Bengis, R. G., van Helden, P. D., Hofmeyr, M., Olea‐Popelka, F. J., Greenwald, R., et al. (2012) · Journal of Zoo and Wildlife Medicine · doi:10.1638/2011-0171.1 · Cited by 26
Griffiths, P. L., Sheppard, Z. A., Johnson, W., Cameron, N., Pettifor, J. M., & Norris, S. A. (2012) · Journal of Biosocial Science · doi:10.1017/s0021932012000107 · Cited by 25
Antibiotic Resistance of Pathogens Causing Community-Acquired Pneumonia
Feldman, C. H., & Anderson, R. (2012) · Seminars in Respiratory and Critical Care Medicine · doi:10.1055/s-0032-1315635 · Cited by 22
Sloan, D. J., Corbett, E. L., Butterworth, A. E., Mwandumba, H. C., Khoo, S., Mdolo, A., Shani, D., Kamdolozi, M., Allen, J., Mitchison, D. A., et al. (2012) · Journal of Clinical Microbiology · doi:10.1128/jcm.00043-12 · Cited by 20
Dewing, S., Mathews, C., Schaay, N., Cloete, A., Louw, J., & Simbayi, L. C. (2011) · AIDS and Behavior · doi:10.1007/s10461-011-0059-z · Cited by 19
Sorsdahl, K. R., Stein, D. J., Weich, L., Fourie, D. P., & MYERS, B. J. (2012) · South African Medical Journal · doi:10.7196/samj.5749 · Cited by 19
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Sheldon, W. R., Nhemachena, T., Blanchard, K., Chipato, T., Gita Ramjee, H., Trussell, J., McCulloch, C. E., Blum, M., & Harper, C. C. (2012) · Sexually Transmitted Diseases · doi:10.1097/olq.0b013e31824f9eaf · Cited by 15
Gangwar, R. S., Shil, P., Cherian, S., & Gore, M. M. (2011) · Virus Research · doi:10.1016/j.virusres.2011.03.030 · Cited by 14
Fatal violence among children under 15 years in four cities of South Africa, 2001–2005
Prinsloo, M., Laubscher, R., Neethling, I., & Bradshaw, D. (2011) · International Journal of Injury Control and Safety Promotion · doi:10.1080/17457300.2011.635211 · Cited by 9
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Hon, G. M., Hassan, M. S., van Rensburg, S. J., Abel, S., Erasmus, R. T., & Matsha, T. E. (2012) · European Journal of Lipid Science and Technology · doi:10.1002/ejlt.201100216 · Cited by 6
Nyembezi, A., Funani, I. N., Sifunda, S., Ruiter, R. A. C., van den Borne, B. H. P., & Reddy, P. S. (2011) · Journal of Health Psychology · doi:10.1177/1359105311424469 · Cited by 6
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“…in multiple epidemiologically unlinked lineages that have statistical support for non-neutral evolution (Mixed Effects Model of Evolution, MEME) 25 , (ii) sites where these polymorphisms have support for a greater than expected ratio of non-synonymous:synonymous nucleotide substitution rates…”
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Metadata
- 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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