Human physical performance is strongly influenced by genetic factors. A variation in the structure of the human angiotensin I-converting enzyme (ACE) gene has been reported in which the insertion (I) variant is associated with lower ACE levels than the deletion (D) gene. We have previously reported that the I variant was associated with improved endurance performance in high-altitude mountaineers and British Army recruits. We now examine this genotype distribution in 91 British Olympic-standard runners (79 Caucasians). DNA was extracted from the buccal cells contained in 10 ml of saline mouthwash donated by the subjects, and the I and D variants of the ACE gene were identified by PCR amplification of the polymorphic region. There was an increasing frequency of the I allele with distance run [0.35, 0.53, and 0.62 for /=5,000 m (n = 34), respectively; P = 0.009 for linear trend]. Among 404 Olympic-standard athletes from 19 other mixed sporting disciplines (in which endurance performance was not necessarily a key factor), the I allele did not differ significantly from that found in control subjects: 0.50 vs. 0.49 (P = 0.526). These results support a positive association of the I allele with elite endurance performance.

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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...