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

Narasimhan, Vagheesh M and Hunt, Karen A and Mason, Dan and Baker, Christopher L and Karczewski, Konrad J and Barnes, Michael R and Barnett, Anthony H and Bates, Chris and Bellary, Srikanth and Bockett, Nicholas A and Giorda, Kristina and Griffiths, Christopher J and Hemingway, Harry and Jia, Zhilong and Kelly, M Ann and Khawaja, Hajrah A and Lek, Monkol and McCarthy, Shane and McEachan, Rosie and O'Donnell-Luria, Anne and Paigen, Kenneth and Parisinos, Constantinos A and Sheridan, Eamonn and Southgate, Laura and Tee, Louise and Thomas, Mark and Xue, Yali and Schnall-Levin, Michael and Petkov, Petko M and Tyler-Smith, Chris and Maher, Eamonn R and Trembath, Richard C and MacArthur, Daniel G and Wright, John and Durbin, Richard and van Heel, David A (2016) Health and population effects of rare gene knockouts in adult humans with related parents. Science (New York, N.Y.), 352 (6284). pp. 474-7. ISSN 1095-9203.

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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.

Item Type: Article
Subjects: QZ Pathology. Oncology
Divisions: Ambulatory Care > Diabetes
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Depositing User: Miss Adele Creak
Date Deposited: 31 Jan 2017 11:04
Last Modified: 31 Jan 2017 11:04

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