Context Dependence, Ancestral Misidentification, and Spurious Signatures of Natural Selection
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Population genetic analyses often use polymorphism data from one species, and orthologous genomic sequences from closely related outgroup species. These outgroup sequences are frequently used to identify ancestral alleles at segregating sites and to compare the patterns of polymorphism and divergence. Inherent in such studies is the assumption of parsimony, which posits that the ancestral state of each single nucleotide polymorphism (SNP) is the allele that matches the orthologous site in the outgroup sequence, and that all nucleotide substitutions between species have been observed. This study tests the effect of violating the parsimony assumption when mutation rates vary across sites and over time. Using a context-dependent mutation model that accounts for elevated mutation rates at CpG dinucleotides, increased propensity for transitional versus transversional mutations, as well as other directional and contextual mutation biases estimated along the human lineage, we show (using both simulations and a theoretical model) that enough unobserved substitutions could have occurred since the divergence of human and chimpanzee to cause many statistical tests to spuriously reject neutrality. Moreover, using both the chimpanzee and rhesus macaque genomes to parsimoniously identify ancestral states causes a large fraction of the data to be removed while not completely alleviating problem. By constructing a novel model of the context-dependent mutation process, we can correct polymorphism data for the effect of ancestral misidentification using a single outgroup.
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High CpG mutation rates make these sites especially susceptible to ancestral state miscalls.
“This is not surprising given that high CpG mutation rates makes these sites especially susceptible to ancestral state miscalls (21).”
From Evidence for recent, population-specific evolution of the human mutation rate (2015) · cites this paper as [21]
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“Here, we develop and apply a computationally efficient diffusion-based approach to the problem of demographic inference, based on the multipopulation allele frequency spectrum (AFS) (i.e., the joint distribution of allele frequencies across SNPs) [10, 17, 18, 20, 21].”
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Boyko, A. R., Williamson, S. H., Indap, A. R., Degenhardt, J. D., Hernandez, R. D., Lohmueller, K. E., Adams, M. D., Schmidt, S., Sninsky, J. J., Sunyaev, S. R., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000083 · Cited by 628 · see citing works
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Harris, K. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418652112 · Cited by 165 · see citing works
A Population Genetics-Phylogenetics Approach to Inferring Natural Selection in Coding Sequences
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Self-citationPopulation history and gene divergence in native Mexicans inferred from 76 human exomes
Ávila-Arcos, M. C., McManus, K. F., Sandoval, K., Rodríguez-Rodríguez, J. E., Villa-Islas, V., Martin, A. R., Luisi, P., Peñaloza-Espinosa, R. I., Eng, C., Huntsman, S., et al. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msz282 · Cited by 50 · see citing works
Self-citation
- Authors
- Hernandez, R. D., Williamson, S. H., & Bustamante, C. D.
- Affiliations
- Cornell University (US)
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-18
- Volume
- 24
- Issue
- 8
- Pages
- 1792-1800
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- OpenAlex
- W2135576052
- Cited by
- 169
- References
- 44
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 4 · 2020: 6 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 8 · 2015: 8 · 2014: 31 · 2013: 9 · 2012: 8
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- transition-transversion bias, mutation rate heterogeneity, human-chimpanzee divergence, single nucleotide polymorphisms, neutrality tests
- MeSH terms
- Animals, Pan troglodytes, Genetics, Population, Humans, Macaca mulatta, Mutation, Selection, Genetic, Genetic Variation, Evolution, Molecular, Polymorphism, Single Nucleotide
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