Characterization of single-nucleotide polymorphisms in coding regions of human genes
Abstract
A major goal in human genetics is to understand the role of common genetic variants in susceptibility to common diseases. This will require characterizing the nature of gene variation in human populations, assembling an extensive catalogue of single-nucleotide polymorphisms (SNPs) in candidate genes and performing association studies for particular diseases. At present, our knowledge of human gene variation remains rudimentary. Here we describe a systematic survey of SNPs in the coding regions of human genes. We identified SNPs in 106 genes relevant to cardiovascular disease, endocrinology and neuropsychiatry by screening an average of 114 independent alleles using 2 independent screening methods. To ensure high accuracy, all reported SNPs were confirmed by DNA sequencing. We identified 560 SNPs, including 392 coding-region SNPs (cSNPs) divided roughly equally between those causing synonymous and non-synonymous changes. We observed different rates of polymorphism among classes of sites within genes (non-coding, degenerate and non-degenerate) as well as between genes. The cSNPs most likely to influence disease, those that alter the amino acid sequence of the encoded protein, are found at a lower rate and with lower allele frequencies than silent substitutions. This likely reflects selection acting against deleterious alleles during human evolution. The lower allele frequency of missense cSNPs has implications for the compilation of a comprehensive catalogue, as well as for the subsequent application to disease association.
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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 [32]
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- Authors
- Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., Lane, C. R., Lim, E. P., Kalyanaraman, N., Nemesh, J., Ziaugra, L., Friedland, L., Rolfe, A., Warrington, J., Lipshutz, R., Daley, G. Q., & Lander, E. S.
- Affiliations
- Massachusetts Institute of Technology (US)
- Affymetrix (United States) (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Lander, Eric S.
- ORCID
- Venue
- Nature Genetics
- Published
- 1999-07
- Volume
- 22
- Issue
- 3
- Pages
- 231-238
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W4254753097
- Cited by
- 1,547
- References
- 30
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 21 · 2023: 26 · 2022: 21 · 2021: 27 · 2020: 35 · 2019: 30 · 2018: 21 · 2017: 27 · 2016: 22 · 2015: 27 · 2014: 37 · 2013: 40 · 2012: 48
- FWCI
- 76.91
- Type
- journal article
- Language
- en
- Update notices
- correction (1999-11-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Alliance for Research on Schizophrenia and Depression
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- single nucleotide polymorphisms, synonymous substitutions, missense mutations, allele frequency, disease susceptibility, cardiovascular disease genes, natural selection, disease association studies
- MeSH terms
- Alleles, Biological Evolution, Gene Frequency, Genes, Humans, Polymorphism, Genetic, Proteins, Genetic Variation, Sequence Analysis, DNA
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