Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing.

By Yali Xue, Yuan Chen, Q. Ayub, N. Huang, Edward V. Ball, Matthew E. Mort, A. Phillips, Katy Shaw, Peter D. Stenson, David N. Cooper and 1 more. 2012

279 citations recorded by the source corpus.

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.

Subfields: Genetics

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

Citations in the corpus

Neutral and weakly nonneutral sequence variants may define individuality (2013, background): “At least one study suggests that healthy people carry hundreds of severely functionally damaging mutations, some of which are disease-associated (10).”
The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies (2017, unknown): “Further, population sequencing programmes (such as the 1000 Genomes Project and ExAC) are now identifying considerable numbers of “DM” mutations in apparently healthy individuals (MacArthur et al. 2012; Xue et al. 2012; Lek et al. 2016).”
Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations (2015, background): “However, many nonsynonymous SNPs predicted to have a deleterious effect are not clearly associated with a disease phenotype [10], either because they are rare [11] or because a deleterious effect in a single gene often results in no phenotype at the organismal level [12].”