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

Abstract

Abstract:Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani heritage adults with high parental relatedness, discovering 1,111 rare variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription or doctor consultation rate, and no disease related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9 dependent hotspots, demonstrating PRDM9 redundancy in humans. Main Text:The study of gene function by correlating genotype with phenotype has provided profound biological insights for several decades. In particular, complete gene knockouts, typically caused by homozygous loss of function (LOF) genotypes, have been used to identify the function of many genes, predominantly through studies in model organisms and of severe Mendelian inherited diseases in humans. However, information on the consequences of knocking out most genes in humans is still missing. Naturally occurring complete gene knockouts, whilst exceptional in outbred populations, offer the opportunity to study directly the lifelong effects of systemic gene inactivation in a living human. They provide a key entry point into human biology that can then be tested in other systems, and can lead to direct validation of specific biological hypotheses. The first large survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1). As expected almost all these homozygous genotypes were common (allele frequency) variants, and were concentrated in genes likely to have weak or neutral effects on fitness and health, for instance olfactory receptors. In contrast, rare predicted LOF genotypes in these outbred . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/031641 doi: bioRxiv preprint first posted online Nov. 14, 2015; samples were usually heterozygous and thus of uncertain overall impact on gene function. Several approaches have been described recently to identify naturally occurring human knockouts. A large exome sequencing aggregation study (ExAC), of predominantly outbred individuals, identified 1,775 genes with homozygous predicted LOF genotypes in 60,706 individuals(2). In population isolates, 1,171 genes with complete predicted LOF were identified in 104,220 Icelandic individuals(3), and modest enrichment for homozygou...

The evolutionary turnover of recombination hot spots contributes to speciation in mice

“…We previously hypothesized that inefficient DSB repair at default hot spots may cause sterility in Prdm9 −/− mice ; however, since gametogenesis can proceed without Prdm9, at least in one documented case in humans (Narasimhan et al 2015), it remains to be seen whether DSB repair at default hot spots is indeed compromised.…”

Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions

“…These studies have served as small‐scale “proof‐of‐concept” experiments (with the traditional inclination towards disease phenotypes and/or other distinct traits), and therefore have largely gone unnoticed; thus, much larger studies with deep phenotyping are needed to understand the importance of consanguineous populations for human genetics. Very recently, two papers were made available in BioRxiv which carried out similar studies to the one proposed in this review (Narasimhan et al., ; Saleheen et al., ). Although the studies should be commended for their potential contributions to the literature, the criteria used by the authors to define “LoF” mutations are based on strong assumptions; and there is not much functional evidence provided by the authors that the variants identified do indeed cause LoF (i.e.…”

Growing up in Bradford: protocol for the age 7–11 follow up of the Born in Bradford birth cohort

“…Follow-up since then has included growth and blood pressure measures by primary school nurses at age 5-6, [4,5] whole cohort record-linkage to health and educational data, e.g. [6,7], detailed bespoke data collection with sub-samples [8][9][10], and addition of biomarker data using stored biological samples, including genome-wide data, metabolomic data and Deoxyribonucleic acid (DNA) methylation [11,12]. A summary of data collected can be seen in Fig.…”

“…Analysis of BiB data has provided insights into the factors that affect health and wellbeing in pregnancy and early childhood, including on social and ethnic inequalities in health [14][15][16], the relationships between maternal gestational adiposity, gestational diabetes mellitus (GDM) and maternal circulating glucose concentrations and fetal growth, birth outcomes, infant and childhood health in South Asian and White European families [4,5,[17][18][19], the associations of environmental stressors such as green space and air pollution on health e.g. [20][21][22], exposures that may influence development of asthma and allergies [23] and the role of genetic variation in human health [12]. BiB data have underpinned more than 100 journal publications; a full list can be found at https://borninbradford.nhs.uk/.…”