Evolutionary pressures on genes associated with childlessness
New research suggests that genetic variants that damage the genome are associated with reduced reproductive success and an increased likelihood of not having children.
Researchers from the Wellcome Sanger Institute and their collaborators demonstrate that one mechanism of natural selection that is removing damaging genetic variation from the population is increased childlessness, likely linked to genetic influences on cognitive and behavioural traits1, which may mean that men and women with these genetic variants are less likely to form reproductive partnerships.
The study, published today (23 March) in Nature, shows that this genetic link may play a very minor role in the overall likelihood of being childless – less than one per cent – when compared to more influential factors such as sociodemographic factors and choice. However, despite this very small effect on individuals, researchers suggest these genetic variants may substantially influence how genes evolve over time.
While 99.9 per cent of the DNA in our genome is identical between any two humans, there are small differences known as genetic variants. New genetic variants arise through the process of mutation, and each child will have a small number of changes in their genome that are different from their biological mother and father.
In some cases, genetic variants can cause damage to the genome and can lead to diseases or disabilities. These damaging genetic variants2 are changes in a person’s DNA that interfere with the function of the protein the affected gene codes for.
Some of these damaging genetic variants can lead to neurodevelopmental disorders. Many patients with these disorders do not currently receive a diagnosis after genetic testing. There is strong evidence that some of these undiagnosed patients have damaging genetic variants in genes that increase the risk of a disorder, but these have not yet been linked to disease. The damaging genetic variants that are mostly likely to be linked to disease are in the minority of genes that exhibit a marked depletion of damaging genetic variation in the general population.
In this new study, researchers at the Wellcome Sanger Institute and their collaborators set out to pinpoint the evolutionary processes that might be leading to this depletion of damaging genetic variation in this subset of genes, with the hope of using this information to better inform their search for novel genetic causes of neurodevelopmental disorders. The team did not initially set out to study the genetic and non-genetic factors that influence childlessness or reproductive success, but rather to see if reproductive success might be an alternative mechanism, other than disease, leading to depletion of damaging genetic variation in these genes.
Using data from more than 340,000 UK Biobank participants, the researchers investigated whether damaging genetic variants were associated with lower reproductive success by calculating for each person, how much damaging genetic variation they carry across their entire genome, known as their ‘genetic burden’3. They tested whether genetic burden was associated with the number of children that UK Biobank participants had, and found it was associated with men with the highest genetic burden having an average 0.26 fewer children – but this was not seen in women. The team also found that increasing genetic burden was associated with a higher chance of being childless in both men and women, but much more so in men.
The researchers then investigated why genetic burden might be associated with childlessness by looking at whether it was associated with infertility – an inability to produce viable eggs or sperm – in men or women, and found it was not.
The team also looked at whether genetic burden might be associated with any other medical conditions that could impact on childlessness, and found it was unlikely that a damaged genome increased the risk of health conditions that could fully account for the reduced reproductive success.
However, the researchers did find that both men and women with a higher genetic burden were more likely to have mental health disorders. In addition, those with a higher genetic burden were less likely to perform well on cognitive tests, less likely to have a university degree, were more likely to have lower household income or were more likely to live in a deprived area.
The team found that those men with a higher genetic burden had an increased likelihood of not having a partner at home compared to women with a similar genetic burden.
By comparing these various factors and any associations with genetic burden, the researchers concluded that the association between genetic burden and childlessness in men may be more likely to be due to the effect of damaging genetic variants on cognitive and behavioural traits that may reduce their chances of finding a partner with whom to have children. Their results suggest that these damaging genetic variants are likely under negative selection partly in a manner that is consistent with Darwin’s theory of sexual selection, and specifically, due to a phenomenon known as mate choice4.
The researchers highlight that the genetic association with childlessness cannot be used to predict who will or won’t remain childless, as it explains less than one per cent of the overall likelihood of childlessness. Other factors, such as infertility, socioeconomic status and choice are much more likely to be associated with not having children.
“It’s important to emphasise that we have not found a ‘gene for childlessness’, as that implies a strong, causal effect of genetic variation on whether or not someone will have children. Instead we have shown that people with damaged genomes, particularly men, are slightly more likely to be childless. This is probably due to the effect of damaging genetic variants on cognitive and behavioural traits, which make these men less likely to find a partner to have children with. Similarly we cannot use these results to ‘predict’ whether or not these damaging genetic variants will be linked with childlessness, as both genetics and the environment influence our behaviour, cognitive abilities and personalities.”
Dr Eugene Gardner, first author previously from the Wellcome Sanger Institute, now based at the MRC Epidemiology Unit at the University of Cambridge
“Involuntary childlessness and an inability to find a partner can have profound psychological effects. We hope that our study will motivate more studies exploring the factors influencing childlessness, especially in men, which has been relatively under-studied compared to female childlessness, and more studies of the relationships between childlessness and mental health.”
Professor Matthew Hurles, lead author and Head of Human Genetics at the Wellcome Sanger Institute
More information
Notes to Editors:
For more information on this study, its implications and limitations, please read the FAQs within the publication’s supplementary information. https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-022-04549-9/MediaObjects/41586_2022_4549_MOESM1_ESM.pdf
It is important to note that association does not necessarily imply causation. In genetics, researchers often report that a particular genetic variant is associated with a certain trait.
The proportion of people who do not have biological children of their own varies over time, and from country to country. In the UK, approximately 20 per cent of adults over age 50 do not have children. Childlessness can be voluntary or involuntary, with associations including infertility, not meeting the right person, psychiatric disorders such as schizophrenia, and socio-demographic factors. For example, low socioeconomic status is more strongly associated with childlessness in men, and higher educational attainment in women is linked to not having children.
1 The researchers do not know the specific cognitive and behavioural factors that might be mediating the association between damaging genetic variation and childlessness. It is likely that there is not a single behavioural or cognitive trait that is playing a role, but rather a combined effect of several different traits. There are important behavioural traits that are known to be associated with reproductive success (e.g. personality traits), which they have not been able to evaluate in this study. Therefore, it would not be appropriate to speculate on the relative importance of the different cognitive and behavioural factors that could potentially be involved.
2 In this study, researchers investigated two types of damaging genetic variation: deletions and protein-truncating variants. Deletions are where a large piece of DNA is removed from a specific location in a genome. Protein-truncating variants (PTVs) are where there is a small change in the DNA sequence that is predicted to cut short the encoded protein and lead to a reduction in the amount of functional protein.
3 The researchers calculated for each person, how much damaging genetic variation they carry across their entire genome, known as their genetic burden. If a person has a high genetic burden, it means that the person’s genome contains at least one damaging genetic variant that disrupts a constrained gene – genes that contain many fewer damaging genetic variants than expected.
4 Natural selection is the process by which some individuals in a population that are better adapted to their environment have higher chances of surviving and producing (more) offspring. Negative selection is the selective removal of genetic variants that are deleterious, and thus reduce survival and reproduction. Sexual selection is a type of natural selection in which genetic variation influences reproduction, but not survival, and is not as a result of an inability to form viable sperm or eggs. One mechanism of sexual selection is when members of one biological sex choose partners of the other sex with particular characteristics to have offspring with (‘mate choice’). Hence, sexual selection directly impacts reproductive success within a species, rather than affecting the survival of the individual. The mechanism of sexual selection known as mate choice represents selection pressures that disproportionately affect one sex more than the other. Thus, genetic variants or traits that do not impact survival but that impact reproductive success differently in men versus women may be doing so via sexual selection.
Publication:
Eugene Gardner, Matthew Neville et al. (2022) Reduced reproductive success is associated with selective constraint on human genes. Nature. DOI: 10.1038/s41586-022-04549-9
https://www.nature.com/articles/s41586-022-04549-9
Funding:
This study was supported by Wellcome, the Medical Research Council and others. For full funding information please refer to the publication.
