1 in 100 Mutations: Why Carriers of Intellectual Disability Genes Are Evolving Out of Existence

We often think of our relationship with our biology as something settled. We accept our parents, our grandparents, the family tree we were handed at birth. But sometimes you look at the data and realize your family history is not the only story on the page. There is a quiet, evolutionary story playing out right now involving a surprising number of people who carry the invisible load of recessive genes for intellectual disability. Recent research from Radboudumc has uncovered that these carriers are statistically less healthy and have a reduced chance of having offspring. It is a shift happening at the level of the gene, but it feels deeply personal.

For a long time, textbooks taught us about inheritance in very clear lines. You get a gene from your dad and one from your mom. If one causes a problem, it is dominant. If it is recessive, you only see the problem if you get the bad gene from both sides. However, researchers led by the Department of Human Genetics at Radboudumc published a remarkable finding in a 2014 issue of Nature that challenged that simple view. They discovered that inherited variants in genes were rarely the cause of intellectual disability. Instead, the vast majority of cases came from a spontaneous mutation. This is a genetic surprise that happens during conception. It is a mutation that neither parent has, but suddenly appears in the child. It is a biological fact that about one hundred of these spontaneous mutations occur in the hereditary material of each child. Most of them do nothing. On average only one affects a gene. And of those, only a fraction affects the hundreds of genes known to cause intellectual disability. Despite the rarity, this is how most intellectual disabilities arise in the world today.

This discovery led researchers, including Christian Gilissen who is a professor of Genome Bioinformatics, to ask another question. If most disabilities come from these new, spontaneous mutations, what happens to the recessive genes we inherit from our parents? There are more recessive genes for intellectual disability than dominant ones. So, you might expect to see a lot of children with recessive disabilities. But the clinic data did not show that. The researchers found very few children with double mutations in recessive genes. They looked at the population data from the UK Biobank, which included more than 300,000 people. They found that each person carries on average two mutations in any one of 1,900 recessive genes. According to the old textbooks, carriers of such recessive genes should not experience any disadvantage. They should be perfectly healthy. But the data told a different story. As a group, they do have more medical diagnoses and a slightly lower chance of having offspring. In essence, they are less likely to pass on their genes for these recessive disorders.