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The Population Genetics of dN/dS

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  • Sergey Kryazhimskiy
  • Joshua B Plotkin

Abstract

Evolutionary pressures on proteins are often quantified by the ratio of substitution rates at non-synonymous and synonymous sites. The dN/dS ratio was originally developed for application to distantly diverged sequences, the differences among which represent substitutions that have fixed along independent lineages. Nevertheless, the dN/dS measure is often applied to sequences sampled from a single population, the differences among which represent segregating polymorphisms. Here, we study the expected dN/dS ratio for samples drawn from a single population under selection, and we find that in this context, dN/dS is relatively insensitive to the selection coefficient. Moreover, the hallmark signature of positive selection over divergent lineages, dN/dS>1, is violated within a population. For population samples, the relationship between selection and dN/dS does not follow a monotonic function, and so it may be impossible to infer selection pressures from dN/dS. These results have significant implications for the interpretation of dN/dS measurements among population-genetic samples.Author Summary: Since the time of Darwin, biologists have worked to identify instances of evolutionary adaptation. At the molecular scale, it is understood that adaptation should induce more genetic changes at amino acid altering sites in the genome, compared to amino acid–preserving sites. The ratio of substitution rates at such sites, denoted dN/dS, is therefore commonly used to detect proteins undergoing adaptation. This test was originally developed for application to distantly diverged genetic sequences, the differences among which represent substitutions along independent evolutionary lineages. Nonetheless, the dN/dS statistics are also frequently applied to genetic sequences sampled from a single population, the differences among which represent transient polymorphisms, not substitutions. Here, we show that the behavior of the dN/dS statistic is very different in these two cases. In particular, when applied to sequences from a single population, the dN/dS ratio is relatively insensitive to the strength of natural selection, and the anticipated signature of adaptive evolution, dN/dS>1, is violated. These results have implications for the interpretation of genetic variation sampled from a population. In particular, these results suggest that microbes may experience substantially stronger selective forces than previously thought.

Suggested Citation

  • Sergey Kryazhimskiy & Joshua B Plotkin, 2008. "The Population Genetics of dN/dS," PLOS Genetics, Public Library of Science, vol. 4(12), pages 1-10, December.
  • Handle: RePEc:plo:pgen00:1000304
    DOI: 10.1371/journal.pgen.1000304
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    Cited by:

    1. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Vivak Soni & John W. Terbot & Jeffrey D. Jensen, 2024. "Population genetic considerations regarding the interpretation of within-patient SARS-CoV-2 polymorphism data," Nature Communications, Nature, vol. 15(1), pages 1-5, December.
    3. Jingqiu Liao & Liat Shenhav & Julia A. Urban & Myrna Serrano & Bin Zhu & Gregory A. Buck & Tal Korem, 2023. "Microdiversity of the vaginal microbiome is associated with preterm birth," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Caitlin S Pepperell & Amanda M Casto & Andrew Kitchen & Julie M Granka & Omar E Cornejo & Eddie C Holmes & Bruce Birren & James Galagan & Marcus W Feldman, 2013. "The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations," PLOS Pathogens, Public Library of Science, vol. 9(8), pages 1-14, August.
    5. Cassia Wagner & Kathryn E. Kistler & Garrett A. Perchetti & Noah Baker & Lauren A. Frisbie & Laura Marcela Torres & Frank Aragona & Cory Yun & Marlin Figgins & Alexander L. Greninger & Alex Cox & Hann, 2024. "Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Andrea Fulgione & Célia Neto & Ahmed F. Elfarargi & Emmanuel Tergemina & Shifa Ansari & Mehmet Göktay & Herculano Dinis & Nina Döring & Pádraic J. Flood & Sofia Rodriguez-Pacheco & Nora Walden & Marcu, 2022. "Parallel reduction in flowering time from de novo mutations enable evolutionary rescue in colonizing lineages," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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