Niemi, M. E. | Search bioRxiv

bioRxiv2020

Sex-biased reduction in reproductive success drives selective constraint on human genes

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. 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 known2. Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.

genetics↗

bioRxiv2018

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2-4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

genetics↗