Reduced reproductive success is associated with selective constraint on human genes

Gardner, Eugene J.; Neville, Matthew D. C.; Samocha, Kaitlin E.; Barclay, Kieron J.; Kolk, Martin; Niemi, Mari; Kirov, George; Martin, Hilary C.; Hurles, Matthew

doi:10.1101/2020.05.26.116111

Cited by 5 publications

(4 citation statements)

References 83 publications

(93 reference 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. Our findings are consistent with similar studies 4,[20][21][22][23][24] showing reduced penetrance of rare damaging variants in monogenic forms of DD in clinically unselected population cohorts.…”

Section: Discussionsupporting

confidence: 93%

Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population

Kingdom

Tuke

Wood

et al. 2021

Preprint

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Many rare diseases are known to be caused by deleterious variants in Mendelian genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci that are known to cause monogenic developmental disorders (DD) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 dominant DD genes using whole exome sequencing data from ∼200,000 individuals, and rare copy number variants overlapping known DD loci using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, with a higher BMI and had significant socioeconomic disadvantages, being less likely to be employed or be able to work, and having a lower income and higher deprivation index. Our findings suggest that many monogenic DD genes routinely tested within paediatric genetics have intermediate penetrance and may cause lifelong milder, sub-clinical phenotypes in the general adult population.

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Section: Discussionsupporting

confidence: 93%

Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population

Kingdom

Tuke

Wood

et al. 2021

Preprint

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“…Admittedly, ancestral claims can be debated and, again, the mechanisms of selection may include those that are not competition-based. A more recent genome-wide association study, for example, found that men's, but not women's, propensity for childlessness was higher in the presence of harmful autosomal mutations (Gardner et al, 2020). These mutations were correlated with lower intelligence and higher incidence of mental illness, and their association with DOMAINS OF FEMALE CHOICE childlessness remained when physiological explanations (e.g., infertility) were ruled out.…”

Section: Evidence From Geneticsmentioning

confidence: 99%

Domains of female choice in human evolution.

Gorelik¹

2023

Evolutionary Behavioral Sciences

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The present article advances the view that women's mate preferences can be grouped into at least two overarching domains: competitiveness and fatherhood. Theoretical and empirical considerations suggest that female mate preferences evolve in contexts of male competitiveness and often amplify the effects of male-male competition. Evidence for the importance of malemale competition and female choice for competitiveness in humans is reviewed. Evidence is likewise offered for the importance of human fatherhood as an additional domain of female choice outside of male competitiveness. Implications of more inclusive mate preferences for the evolution of cognitive architecture are discussed.

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“…Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.Sexual dimorphism in lifespan is widely evident, including among humans, contemporaneously and historically 1,2 . Many reasons have been advanced for shorter life expectancy in men than women, from gendered health and health care seeking behavior 3 through sex-specific nutrient metabolism and steroid hormones 4 to sex-specific sexual selection pressures 5,6 , but few of these have been explicitly exploited as a means of promoting healthy aging in both sexes. As the long-term trend of increasing life expectancy in the West now appears to be stagnating 7 , reconsidering overlooked targets and their implications for the design of interventions might bear consideration.An obvious modifiable difference between men and women is levels of sex hormones.…”

mentioning

confidence: 99%

Investigating the association of testosterone with survival in men and women using a Mendelian randomization study in the UK Biobank

Schooling

Zhao

2021

Sci Rep

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Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI − 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

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Reduced reproductive success is associated with selective constraint on human genes

Cited by 5 publications

References 83 publications

Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population

Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population

Domains of female choice in human evolution.

Investigating the association of testosterone with survival in men and women using a Mendelian randomization study in the UK Biobank

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