Rate, molecular spectrum, and consequences of human mutation
Open accessAbstract
Although mutation provides the fuel for phenotypic evolution, it also imposes a substantial burden on fitness through the production of predominantly deleterious alleles, a matter of concern from a human-health perspective. Here, recently established databases on de novo mutations for monogenic disorders are used to estimate the rate and molecular spectrum of spontaneously arising mutations and to derive a number of inferences with respect to eukaryotic genome evolution. Although the human per-generation mutation rate is exceptionally high, on a per-cell division basis, the human germline mutation rate is lower than that recorded for any other species. Comparison with data from other species demonstrates a universal mutational bias toward A/T composition, and leads to the hypothesis that genome-wide nucleotide composition generally evolves to the point at which the power of selection in favor of G/C is approximately balanced by the power of random genetic drift, such that variation in equilibrium genome-wide nucleotide composition is largely defined by variation in mutation biases. Quantification of the hazards associated with introns reveals that mutations at key splice-site residues are a major source of human mortality. Finally, a consideration of the long-term consequences of current human behavior for deleterious-mutation accumulation leads to the conclusion that a substantial reduction in human fitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.
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Relaxed selection in modern humans may favor accumulation of deleterious rare alleles and greatly increase disease prevalence hundreds of generations in the future.
“The argument has been made that relaxed selection in modern humans may favor the accumulation of deleterious rare alleles, greatly increasing the prevalence of disease hundreds of generations into the future30.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [30]
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- Authors
- Lynch, M.
- Affiliations
- Indiana University Bloomington (US)
- Corresponding author
- Lynch, Michael
- ORCID
- Lynch, Michael
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-01-04
- Volume
- 107
- Issue
- 3
- Pages
- 961-968
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2824313
- OpenAlex
- W1989298969
- Cited by
- 792
- References
- 1
- Citations by year
- 2026: 17 · 2025: 32 · 2024: 23 · 2023: 31 · 2022: 52 · 2021: 70 · 2020: 37 · 2019: 55 · 2018: 58 · 2017: 59 · 2016: 54 · 2015: 71 · 2014: 60 · 2013: 55 · 2012: 62
- FWCI
- 30.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0827411)
- Eli Lilly and Company
- National Institutes of Health
- National Institute of General Medical Sciences (GM 36827, R01GM036827)
- 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 › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- de novo mutations, monogenic disorders, germline mutation rate, mutation spectrum, genetic drift, splice site mutation, deleterious mutation accumulation, eukaryotic genome evolution
- MeSH terms
- Humans, Introns, Mutation
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