Deleterious Alleles in the Human Genome Are on Average Younger Than Neutral Alleles of the Same Frequency
Open accessAbstract
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.
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Disorder-specific lead SNPs and pleiotropic SNPs did not differ in minor allele frequencies, average heterozygosity, or predicted allele ages.
“Neither did we find differences between disorder-specific lead SNPs and pleiotropic SNPs with respect to their minor allele frequencies, average heterozygosity, or predicted allele ages (Kiezun et al., 2013).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Kiezun et al., 2013
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Self-citationThe Standing Pool of Genomic Structural Variation in a Natural Population of Mimulus guttatusPreprint
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- Authors
- Kiezun, A., Pulit, S. L., Francioli, L. C., van Dijk, F., Swertz, M., Boomsma, D. I., van Duijn, C. M., Slagboom, P. E., van Ommen, G. J. B., Wijmenga, C., Genome of the Netherlands Consortium, de Bakker, P. I. W., & Sunyaev, S. R.
- Affiliations
- Broad Institute (US)
- University Medical Center Utrecht (NL)
- University Medical Center Groningen (NL)
- Vrije Universiteit Amsterdam (NL)
- Leiden University Medical Center (NL)
- Corresponding author
- Sunyaev, Shamil R.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-02-28
- Volume
- 9
- Issue
- 2
- Pages
- e1003301
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3585140
- OpenAlex
- W2110857221
- Cited by
- 72
- References
- 29
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 9 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 9 · 2014: 10 · 2013: 6
- FWCI
- 6.86
- 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)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- VU Research Portal (publishedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- National Institute of Mental Health (R01MH084676)
- National Institute of General Medical Sciences (R01GM078598)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- deleterious alleles, natural selection, neutral alleles, allele frequency, non-synonymous variants, synonymous mutations, non-coding variants, human genetic variation, protein structure-function relationship
- MeSH terms
- Alleles, Gene Frequency, Genetics, Population, Humans, Models, Theoretical, Selection, Genetic, Genetic Variation, Genome, Human, Sequence Deletion, Evolution, Molecular, Genetic Drift
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