The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing
Open accessAbstract
We have assessed the numbers of potentially deleterious variants in the genomes of apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals in the 1000 Genomes Pilot Project and (2) current predictions and databases of deleterious variants. Each individual carried 281-515 missense substitutions, 40-85 of which were homozygous, predicted to be highly damaging. They also carried 40-110 variants classified by the Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3-24 variants in the homozygous state, and many polymorphisms putatively associated with disease. Whereas many of these DMs are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0-1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance. These analyses emphasize the need for improved annotation of disease alleles both in mutation databases and in the primary literature; some HGMD mutation data have been recategorized on the basis of the present findings, an iterative process that is both necessary and ongoing. Our estimates of deleterious-allele numbers are likely to be subject to both overcounting and undercounting. However, our current best mean estimates of ~400 damaging variants and ~2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively and as additional disease alleles are discovered.
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Cites
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Cited by
A global reference for human genetic variation
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Self-citationAnalysis of protein-coding genetic variation in 60,706 humans
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Self-citationGuidelines for investigating causality of sequence variants in human disease
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From the genetic architecture to synaptic plasticity in autism spectrum disorder
Bourgeron, T. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3992 · Cited by 975
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
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Metadata
- Authors
- Xue, Y., Chen, Y., Ayub, Q., Huang, N., Ball, E. V., Mort, M., Phillips, A. D., Shaw, K., Stenson, P. D., Cooper, D. N., & Tyler-Smith, C.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 91
- Issue
- 6
- Pages
- 1022-1032
- ISSN
- 0002-9297 (ISSN-L)
- OpenAlex
- W1967010300
- Cited by
- 274
- References
- 45
- FWCI
- 18.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Xue, Y., Chen, Y., Ayub, Q., Huang, N., Ball, E. V., Mort, M., Phillips, A. D., Shaw, K., Stenson, P. D., Cooper, D. N., & Tyler-Smith, C. (2012). Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing. The American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2012.10.015
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