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.
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 (www.ebi.ac.uk/ega) under accession numbers EGAS00001000462, EGAS00001000511, EGAS00001000567, EGAS00001000717 and EGAS00001001301.
Materials and Methods
Figures S1 to S8
Tables S1 to S8
Data S1 to S3