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

Vagheesh M. Narasimhan, Karen A. Hunt, Dan Mason, Christopher L. Baker, Konrad J. Karczewski, Michael R. Barnes, Anthony H. Barnett, Chris Bates, Srikanth Bellary, Nicholas A. Bockett, Kristina Giorda, Christopher J. Griffiths, Harry Hemingway, Zhilong Jia, M. Ann Kelly, Hajrah A. Khawaja, Monkol Lek, Shane McCarthy, Rosie McEachan, Anne O’Donnell-LuriaKenneth Paigen, Constantinos A. Parisinos, Eamonn Sheridan, Laura Southgate, Louise Tee, Mark Thomas, Yali Xue, Michael Schnall-Levin, Petko M. Petkov, Chris Tyler-Smith, Eamonn R. Maher, Richard C. Trembath, Daniel G. MacArthur, John Wright, Richard Durbin*, David A. van Heel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British Pakistani-heritage adults with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.

Original languageEnglish
Pages (from-to) 474-477
Number of pages8
Issue number6284
Early online date3 Mar 2016
Publication statusPublished - 1 Apr 2016

Bibliographical note

-Funding: Wellcome Trust (WT102627, WT098051,WT099769 and WT101597); Barts Charity (845/1796); Medical Research Council (MR/M009017/1); NIHR under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and NIHR Cambridge Biomedical Research Centre; National Institute of General Medical Sciences of the National Institutes of Health (R01GM104371); MRC; Arthritis Research UK; British Heart Foundation, Cancer Research UK; Chief Scientist Office; ESRC; EPSRC; National Institute for Social Care and Health Research.

Data reported in the paper are presented in the supplementary materials, and are available under a Data Access Agreement at the European Genotype-phenome Archive ( under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717 and EGAS00001001301.
Materials and Methods
Figures S1 to S8
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