As a group, carriers of recessive disorders are slightly less healthy and have a reduced chance of having offspring. This disadvantage is greatest for carriers of a recessive gene for intellectual disability, and reflected in a shorter school career and increased childlessness, according to research from Radboudumc published in Nature human behavior. Time to rewrite the textbooks?
Dominant mutation
Researchers from Radboudumc, Department of Human Genetics, demonstrated something remarkable in a 2014 publication in Nature . Contrary to expectations, inherited variants in genes were rarely responsible for intellectual disability. In the vast majority, the disability arose from a spontaneous mutation: a mutation that neither parent has, but suddenly appears in the child. It is a biological fact that about one hundred spontaneous mutations occur in the hereditary material of each child. Mutations that therefore do not originate from the parents. On average, only one of these one hundred mutations affects a gene. And only a fraction of those affects one of the hundreds of genes that can cause intellectual disability. But rare events still happen. Most intellectual disabilities arise in this way.
From dominant to recessive
"There was something else going on," said Christian Gilissen, professor of Genome Bioinformatics and first author of the 2014 article. "Children receive a gene from both father and mother by default. When a single mutation in the child leads to intellectual disability, this is called a mutation in a dominant gene. Other mutations affect recessive genes. Having a single mutation in a recessive gene, in principle, has no effect on the carrier. A handicap only arises if the mutation is in both copies of the recessive gene. In our clinic we found very few of these double mutations in recessive genes in children with intellectual disabilities. Strange, because there are more recessive than dominant genes for this. So we wondered: where did all those recessive mutations go?"
More medical diagnoses
The question led to a long and extensive search, the results of which have now been published in Nature human behavior [link]. "We first investigated how often these recessive mutations occur in the population," says Han Brunner professor of clinical genetics and, like Gilissen, involved in both publications. To do so, the data of more than 300,000 people included in the UK Biobank were examined. "We found that each person carries on average two mutations in any one of 1,900 recessive genes. According to textbooks, carriers of such recessive genes should not experience any disadvantage. However, we found that, as a group, they do have more medical diagnoses, and slightly less offspring. Thus, they are less likely to pass on their genes for recessive disorders."
Less education
Compared to other recessive genes, genes for intellectual disability were the most absent. Apparently, there is another aspect at play here. The UK Biobank data provide a clue. Gilissen: "Carriers of a recessive gene for intellectual disability go to school for a shorter time, which suggests that they have a lower level of education. Mind you, these are carriers, according to existing theory, are not affected at all by their recessive gene."
More likely to be childless
Thus, carriers of recessive genes for intellectual disability have reduced reproductive success and a shorter school career. Brunner: "In 1859, Darwin published On the Origin of Species by Means of Natural Selection. It was mainly about survival, about genes that make you strong and healthy, about natural selection. Twelve years later he wrote The Descent of Man, and Selection in Relation to Sex, in which he refined his theory. You can have fine genes, but if no one wants to have children with you, those genes will not be passed on. The principle of sexual selection. We're not demonstrating it rock solid here, but if I had to give a cause for these findings - based in part on a lot of sociological research - sexual selection is the most obvious explanation."
Rewriting textbooks
This research clearly shows that recessive carriers of diseases have a selection disadvantage at the group level. In the past, this has been pointed out for specific disorders. Here, for the first time this is demonstrated for recessive disorders in general. That may go into the textbooks. Brunner: "Our research indicates that our genes are still constantly changing, that the genetic landscape remains in motion, that evolution continues. The idea that in our modern age evolution has come to a creaking halt thanks to health care and other amenities is not true." Nor will it ever be, Gilissen suggests: "We will never be optimized for tomorrow's problem."
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Paper in Nature human behaviour: Reproductive and cognitive phenotypes in carriers of recessive pathogenic variants - Hila Fridman, Gelana Khazeeva, Ephrat Levy-Lahad, Christian Gilissen, Han G. Brunner
