Most Rare Missense Alleles Are Deleterious in Humans: Implications for Complex Disease and Association Studies
Open accessAbstract
The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, of human-chimpanzee divergence, and of systematic data on human genetic variation and found that ~20% of new missense mutations in humans result in a loss of function, whereas ~27% are effectively neutral. Thus, the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new data set of 37 genes sequenced in >1,500 individual human chromosomes. Surprisingly, up to 70% of low-frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in candidate genes or pathways in individuals with extreme values of quantitative phenotypes. These studies would be unlikely to yield results if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate-gene (pathway) association studies and imply that mutation-selection balance may be a feasible evolutionary mechanism underlying some common diseases.
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Whole-exome sequence data show non-synonymous substitutions are even more skewed toward low frequencies, almost certainly reflecting purifying selection.
“the finding from whole-exome sequence data that non-synonymous substitutions are even more significantly skewed towards low frequencies almost certainly reflects the operation of purifying selection32–34.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [33]
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- Authors
- Kryukov, G. V., Pennacchio, L. A., & Sunyaev, S. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Sunyaev, Shamil R.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 80
- Issue
- 4
- Pages
- 727-739
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1852724
- OpenAlex
- W2078663610
- Cited by
- 598
- References
- 70
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 15 · 2023: 11 · 2022: 26 · 2021: 20 · 2020: 20 · 2019: 20 · 2018: 35 · 2017: 28 · 2016: 29 · 2015: 35 · 2014: 43 · 2013: 42 · 2012: 58
- FWCI
- 24.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genome Canada
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM071852)
- U.S. National Library of Medicine (U54LM008748)
- 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
- missense mutations, deleterious alleles, rare variants, loss of function, human-chimpanzee divergence, allele frequency, mutation-selection balance, complex diseases, candidate gene association, human genetic variation
- MeSH terms
- Gene Frequency, Genetics, Population, Humans, Models, Genetic, Genetic Variation, Evolution, Molecular, Genetic Predisposition to Disease, Mutation, Missense, Genetic Diseases, Inborn
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