Health and population effects of rare gene knockouts in adult humans with related parents
Vagheesh Narasimhan, Karen Hunt, Dan MasoniD, Christopher L Baker, Konrad Karczewski, Michael Barnes, Anthony Barnett, Chris Bates, Srikanth Bellary, Nick Bockett, Kristina Giorda, Chris GriffithsiD, Harry HemingwayiD, Zhilong Jia, Ann Kelly, Hajrah Khawaja, Monkol LekiD, Shaun McCarthy, Rosie McEachan, Kenneth PaigeniD, Costas Parisinos, Eamonn Sheridan, Laura Southgate, Louise Tee, Mark Thomas, , David van Heel
Abstract
AbstractComplete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9-dependent hotspots, demonstrating PRDM9 redundancy in humans.
02 /Specification & Classification
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