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

By Vagheesh M. Narasimhan, K. Hunt, D. Mason, Christopher L. Baker, Konrad J. Karczewski, M. Barnes, A. Barnett, C. Bates, S. Bellary, N. Bockett and 26 more. 2015

282 citations recorded by the source corpus.

Rare gene knockouts in adult humans On average, most people's genomes contain approximately 100 completely nonfunctional genes. These loss-of-function (LOF) mutations tend to be rare and/or occur only as a single copy within individuals. Narasimhan et al. investigated LOF in a Pakistani population with high levels of consanguinity. Examining LOF alleles that were identical by descent, they found, as expected, an absence of homozygote LOF for certain protein-coding genes. However, they also identified many homozygote LOF alleles with no apparent deleterious phenotype, including some that were expected to confer genetic disease. Indeed, one family had lost the recombination-associated gene PRDM9. Science, this issue p. 474 The total loss of protein-coding genes, even those with the potential to confer genetic diseases, can be tolerated. 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.

Subfields: Genetics

Citations in the corpus

• High-throughput discovery of novel developmental phenotypes (2016, unknown): “Recent work has identified cases of homozygous loss-of-function in the human population 40,41 , complementing on-going efforts to discover disease genes in highly consanguineous populations, including mutations that are homozygous lethal 42,43 , (Salaheen et al.”
• Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity (2017, unknown): “We compared our results to three recent reports in which homozygous pLoF genes have been catalogued: in Pakistanis living in Britain 6 , in Icelanders 7 , and in the Exome Aggregation Consortium (ExAC) 8 .”