| Literature DB >> 26940866 |
Vagheesh M Narasimhan1, Karen A Hunt2, Dan Mason3, Christopher L Baker4, Konrad J Karczewski5, Michael R Barnes6, Anthony H Barnett7, Chris Bates8, Srikanth Bellary9, Nicholas A Bockett2, Kristina Giorda10, Christopher J Griffiths2, Harry Hemingway11, Zhilong Jia6, M Ann Kelly12, Hajrah A Khawaja6, Monkol Lek5, Shane McCarthy1, Rosie McEachan3, Anne O'Donnell-Luria5, Kenneth Paigen4, Constantinos A Parisinos2, Eamonn Sheridan3, Laura Southgate2, Louise Tee12, Mark Thomas1, Yali Xue1, Michael Schnall-Levin10, Petko M Petkov4, Chris Tyler-Smith1, Eamonn R Maher13, Richard C Trembath14, Daniel G MacArthur5, John Wright3, Richard Durbin15, David A van Heel16.
Abstract
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.Entities:
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Year: 2016 PMID： 26940866 PMCID： PMC4985238 DOI： 10.1126/science.aac8624
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728