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  Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing

Xue, Y., Chen, Y., Ayub, Q., Huang, N., Ball, E. V., Mort, M., et al. (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, 91(6), 1022-1031.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-E4FE-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-E4FF-E
Genre: Journal Article

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© 2012 The American Society of Human Genetics. Published by Elsevier Ltd.
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 Creators:
Xue, Yali, Author
Chen, Yuan , Author
Ayub, Qasim , Author
Huang, Ni, Author
Ball, Edward V. , Author
Mort, Matthew , Author
Phillips, Andrew D. , Author
Shaw, Katy, Author
Stenson, Peter D. , Author
Cooper, David N. , Author
Tyler-Smith, Chris , Author
The 1000 Genomes Project Consortium, Author
Timmermann, Bernd1, Author              
Lehrach, Hans2, Author              
Herwig, Ralf3, Author              
Affiliations:
1Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
3Bioinformatics (Ralf Herwig), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479648              

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 Abstract: 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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Language(s): eng - English
 Dates: 2012-12-07
 Publication Status: Published in print
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 Identifiers: PMC: 3516590
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 91 (6) Sequence Number: - Start / End Page: 1022 - 1031 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893_1