What's normal? Identifying harmful human gene inactivation.

28 February 2012

Researchers have launched a new catalogue of ‘loss-of-function’ (LoF) gene variants, which suggests that healthy individuals may have multiple completely inactive genes with no ill effects.

Part of the 1000 Genomes Project (see previous news) based at the Wellcome Trust Sanger Institute, the catalogue is intended to aid understanding of the function of human genes in health and disease; LoF variants (changes expected to completely disrupt normal gene function) can be associated with severe forms of inherited disease.
Analysis of 185 genomes from people of different ethnic origins suggested that of more than 3000 potential LoFs, more than a thousand were likely to have a genuinely severe effect on gene function; a typical person might have at least 20 such variants affecting both copies of the gene, effectively blocking the activity of that gene. Most of these LoF mutations were fairly common and did not appear to have harmful effects for the individual, although other more rare variants were identified that, if present on both gene copies, would cause significant disease.
Importantly, the researchers were able to develop algorithms to predict which mutations were most likely to be harmful, which could be of great value in searching for disease-associated genetic variants in the context of clinical whole genome sequencing.

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