2022
DOI: 10.1038/s41586-022-04549-9
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Reduced reproductive success is associated with selective constraint on human genes

Abstract: Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants 1 . While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known 2 . Here we show that genetic variants that damage these genes are associated with markedly reduced reprod… Show more

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Cited by 53 publications
(43 citation statements)
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“…Gene panel association tests suggest a strong and consistent trend for increasing phenotypic effects with rarer and more damaging variants. Although it is impossible to disentangle incomplete penetrance and variable expressivity in a population study, our findings are consistent with similar studies in clinically unselected population cohorts 4 , 20 , 21 , 22 , 23 , 24 showing reduced penetrance of rare damaging variants in genes where similar variants cause rare monogenic forms of DD. Moreover, our results are robust to removal of individuals diagnosed with a childhood developmental disorder, suggesting that fully penetrant individuals are not driving the signal.…”
Section: Discussionsupporting
confidence: 91%
“…Gene panel association tests suggest a strong and consistent trend for increasing phenotypic effects with rarer and more damaging variants. Although it is impossible to disentangle incomplete penetrance and variable expressivity in a population study, our findings are consistent with similar studies in clinically unselected population cohorts 4 , 20 , 21 , 22 , 23 , 24 showing reduced penetrance of rare damaging variants in genes where similar variants cause rare monogenic forms of DD. Moreover, our results are robust to removal of individuals diagnosed with a childhood developmental disorder, suggesting that fully penetrant individuals are not driving the signal.…”
Section: Discussionsupporting
confidence: 91%
“…The reason is simple: sexual reproduction equalises autosomal allele frequencies between the sexes every generation, restricting genetic divergence and, in effect, preventing the use of common tests ( e.g ., McDonald-Kreitman tests for positive selection and F ST outlier tests for spatially-varying selection [6365]) to infer sex differences in selection. Published studies using human genomic data illustrate the challenges of studying polymorphisms with sex-differential fitness effects [32,40,41,43,44], including sample sizes that may be insufficient for detecting polygenic signals of sex-differential selection, lack of controls for population structure or technical artefacts, and/or absence of data concerning reproductive fitness components.…”
Section: Discussionmentioning
confidence: 99%
“…Published studies using human genomic data illustrate the challenges of studying polymorphisms with sex-differential fitness effects [32,40,41,43,44], including sample sizes that may be insufficient for detecting polygenic signals of sex-differential selection, lack of controls for population structure or technical artefacts, and/or absence of data concerning reproductive fitness components.…”
Section: Discussionmentioning
confidence: 99%
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“…Fourth, the UK Biobank is a relatively healthy population cohort 58 , which limits our power to analyze diseases. For the same reason, the UK Biobank sample might be depleted of deleterious genetic variation 37 , potentially causing decreased burden heritability in this population.…”
Section: Discussionmentioning
confidence: 99%