Why do we have the diseases we have? This is a question that we have been asking ourselves for the last 15 years. It all started when we found that spontaneous mutations that arise in the DNA are the major reason why children are born with severe neurodevelopmental disorders (NDDs).

This finding had a profound impact on the way we handle questions in the clinic about why the disorder occurs. Where previously we would focus heavily on possible adverse events in the pregnancy or delivery, we now know that problems in these stages are only rarely the major cause. New spontaneous mutations are a much more important factor determining severe intellectual disability. It is striking, and often quite moving, to see how grateful parents are to finally know what caused the problem in their child. Importantly, the fact that this was not anyone’s fault can help alleviate the guilt that many parents experience about the handicap of their child.

But why is dominant inheritance through spontaneous mutations so much more frequent for NDDs than recessive inheritance? There are more recessive genes than dominant genes in which mutations cause a neurodevelopmental disorder. Still, recessive inheritance accounts for just a few percent of all severe NDDs in individuals born to nonconsanguineous parents. So why do we not see recessive inheritance for NDDs, when this is so common for other conditions such as blindness, deafness or neuromuscular disease? We realized that in order to answer this question, we first needed to investigate the overall distribution of recessive disease variants in the general population.

For this, we examined the landscape of pathogenic (disease-causing) variants in healthy Dutch and Estonian individuals. Since the Dutch and Estonians do not share much demographic history we could compare the findings and derive some general concepts. This work, led by Hila Fridman, was published in 2021 in the American Journal of Human Genetics (Fridman et al. 2021). Hila found that although specific genetic variants differed between the populations, at the gene level the overall genetic landscapes were almost identical in both European populations, with each individual on average carrying 2 pathogenic variants in a recessive disease gene. Moreover, this landscape pointed towards possible selection against carrying a pathogenic variant in recessive NDD genes.

Common genetic practice says that being a carrier for a recessive pathogenic mutation increases the risk for having an affected child, but has no detrimental effects on the carrier. In the current study, Dr. Hila Fridman and PhD student Gelana Khazeeva asked whether the strikingly small contribution of recessive inheritance to NDDs could be due to negative selection impacting those who carry a pathogenic variant in a recessive gene? In other words: are we losing recessive pathogenic genetic variants, and is being a carrier associated with effects on health or cognition? Hila and Gelana explored these questions in the current study by looking at genetic variants in more than 300,000 British individuals from the UK Biobank. We indeed found that being a carrier has small negative effects of on reproduction and on cognitive traits. While increased childlessness was observed for heterozygous carriers for all types of recessive disorders, we detected an effect on years of schooling that appeared to be strongest for NDD genes.

These findings  support the growing evidence that recessive carriers may well be (very mildly) affected by the gene variant that they carry. Even though this small effect may not be immediately noticeable in any given individual, the selective effect on reproduction could still shape the overall genetic landscape for recessive disease. There is a considerable body of literature to suggest that there has been Darwinian selection on cognitive traits in humans. Our work is consistent with that hypothesis, because pathogenic variants in the genes that carry the strongest signature of historical selection in human evolution, are also associated with the strongest reproductive and cognitive effects in our study. Selection on cognitive traits has occurred throughout human history and is ongoing today.

How could this selection work? Our study unfortunately cannot answer this question. However, based on other studies, we can speculate that this evolutionary force works through what Darwin called sexual selection. In other words, if reduced reproductive success is not through issues with health or fertility, it may involve a lesser likelihood of being selected by the opposite sex.

Looking ahead, there are numerous questions relating to evolution and selection that may be explored in future work. Will we see similar selective effects in non-European populations? What other phenotypic features that do not involve cognitive traits induce negative selection on the recessive carriers? Is selection today the same or materially different from selection occurring in the Middle Ages or in the Palaeolithic? Can we detect and define whether positive selection causes recessive disease-causing variants in some genes to become more frequent in multiple populations? It would seem that our understanding of selection acting on carriers of recessive diseases is only just starting.

Article: https://www.nature.com/articles/s41562-025-02204-7

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