22/04/2016 Biology Medicine
DOI: 10.1126/science.aac8624 SemanticScholar ID: 29600304 MAG: 2294521862

Health and population effects of rare gene knockouts in adult humans with related parents

Publication Summary

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.

CAER Authors

Avatar Image for John Wright

Prof. John Wright

Bradford Institute for Health Research - Chief Investigator Born in Bradford

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