Journal
SCIENCE
Volume 352, Issue 6284, Pages 474-477Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aac8624
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Funding
- Wellcome Trust [WT102627, WT098051, WT101597, WT099769]
- Barts Charity [845/1796]
- UK Medical Research Council [MR/M009017/1]
- NIHR under its Collaboration for Applied Health Research and Care for Yorkshire and Humber
- NIH National Institute of General Medical Sciences [R01GM104371]
- NIHR Cambridge Biomedical Research Centre
- UK Medical Research Council
- Arthritis Research UK
- British Heart Foundation
- Cancer Research UK
- Chief Scientist Office
- Economic and Social Research Council
- Engineering and Physical Sciences Research Council
- NIHR
- National Institute for Social Care and Health Research
- Wellcome Trust
- NIH [GM 099640]
- AstraZeneca
- Pfizer
- Medical Research Council [MR/K006584/1, MR/M009017/1, MC_PC_13042, MR/K006665/1] Funding Source: researchfish
- National Institute for Health Research [ACF-2013-19-001] Funding Source: researchfish
- MRC [MR/M009017/1, MR/K006665/1] Funding Source: UKRI
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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.
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