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

作者：Vagheesh M. Narasimhan, Karen A. Hunt, Dan Mason, Christopher L. Baker, Konrad J. Karczewski, Michael R. Barnes, Anthony H Barnett, Chris J Bates, Srikanth Bellary, Nicholas A. Bockett, Kristina Giorda, Chris Griffiths, Harry Hemingway, Zhilong Jia, Melissa A. Kelly, Hajrah A. Khawaja, Monkol Lek, Shane McCarthy, Rosie McEachan, Anne O’Donnell‐Luria, Kenneth Paigen, Constantinos A. Parisinos, Eamonn G. Sheridan, Laura Southgate, Louise J. Tee, Mark Robert Thomas, Yali Xue, Michael Schnall-Levin, Petko M. Petkov, Chris Tyler‐Smith, Eamonn Richard Maher, Richard C. Trembath, Daniel G. MacArthur, John Wright, Richard M. Durbin, David A. van Heel · 发表于：Science · 年份：2016 · DOI：10.1126/science.aac8624 · 被引用次数：320 · 研究领域：Genomics and Rare Diseases、Genetics and Neurodevelopmental Disorders、Genomic variations and chromosomal abnormalities

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.