TY - JOUR T1 - Health and population effects of rare gene knockouts in adult humans with related parents JF - bioRxiv DO - 10.1101/031641 SP - 031641 AU - V. Narasimhan AU - K.A. Hunt AU - D. Mason AU - C.L. Baker AU - K.J. Karczewski AU - M.R. Barnes AU - A.H. Barnett AU - C. Bates AU - S. Bellary AU - N.A. Bockett AU - K. Giorda AU - C.J. Griffiths AU - H. Hemingway AU - Z. Jia AU - M.A. Kelly AU - H.A. Khawaja AU - Monkol Lek AU - S. McCarthy AU - R. McEachan AU - K. Paigen AU - C. Parisinos AU - E. Sheridan AU - Laura Southgate AU - L. Tee AU - M. Thomas AU - Y. Xue AU - M. Schnall-Levin AU - P.M. Petkov AU - C. Tyler-Smith AU - E.R. Maher AU - R.C. Trembath AU - D.G. MacArthur AU - J. Wright AU - R. Durbin AU - D.A. van Heel Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/11/14/031641.abstract N2 - Complete 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. ER -