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

• DOI: 10.1016/j.ajhg.2012.10.015
• Publication Date: 2012-12-06T17:50:40Z
• Authors: Yali Xue; Yuan Chen; Qasim Ayub; Ni Huang; Edward V. Ball; Matthew Mort; Andrew D. Phillips; Katy Shaw; Peter D. Stenson; David N. Cooper; Chris Tyler-Smith
• Keywords: 1000 Genomes Project

We have assessed the numbers of potentially deleterious variants in genomes apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals 1000 Genomes Pilot Project and (2) current predictions databases variants. Each individual carried 281–515 missense substitutions, 40–85 which were homozygous, predicted to be highly damaging. They also 40–110 classified Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3–24 homozygous state, many polymorphisms putatively associated with disease. Whereas these DMs are likely represent disease-allele-annotation errors, between 0 8 (0–1 homozygous) per damaging, some them provide information medical relevance. These analyses emphasize need for improved annotation disease alleles both mutation primary literature; HGMD been recategorized on basis present findings, an iterative process that is necessary ongoing. Our estimates deleterious-allele subject overcounting undercounting. However, our best mean ∼400 damaging ∼2 bona fide increase rather than decrease sequencing studies ascertain rare more effectively additional discovered.