The genetic mutation that causes Huntington鈥檚 disease, a devastating brain condition, may have been selected for by evolution because it also leads to higher intelligence in people鈥檚 childhood and 20s.
This idea may not only lead to a rethink of strategies to treat Huntington鈥檚, but could also change our perspective on the genetics of intelligence. 鈥淭here are a lot of implications for our understanding of the biology of the brain,鈥� says at the University of Iowa, one of the authors of an analysis outlining the latest idea.
Huntington鈥檚 is a rare genetic condition that usually strikes in middle age, beginning with unusual jerking movements and cognitive problems before progressing inexorably to death. The condition is especially cruel because those affected often witness a parent becoming increasingly disabled, knowing they have a 50-50 chance of the same fate. A genetic test is available, but many refuse it as there are no effective treatments.
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The mutation responsible for Huntington鈥檚 affects a gene called huntingtin, which encodes a protein made in the brain. The longer, mutated form of the gene may have from 40 to more than 100 repeats of the same three DNA 鈥渓etters鈥�, but even in the standard version of the gene, there are usually between nine and 35 of these triplet repeats.
It isn鈥檛 yet known exactly how the longer form of the gene causes Huntington鈥檚 symptoms. The leading idea is that the mutated protein is somehow toxic to neurons, mainly based on post-mortem studies looking at the brain cells of those affected.
Recently, though, an alternative idea has been gaining ground. This says that the mutated huntingtin protein exerts its chief effects by altering brain development in the uterus and during infancy, making the brain more vulnerable to the normal degenerative processes of ageing. But in early life, these brain changes may cause higher intelligence quotient (IQ).
Much of the recent evidence for this idea comes from a study led by Schultz鈥檚 University of Iowa colleague , a co鈥慳uthor of the new paper. She has been following the health of children from Huntington鈥檚-affected families since 2006.
Brain scans show that in those children with the Huntington鈥檚 mutation, certain areas of their brains are slightly larger than usual in childhood, but become smaller from about their late 20s, presumably due to cells beginning to die. In 2019, , in the centre of the brain. This area, which is involved in controlling movements as well as many other cognitive functions, is an established site of cell death in Huntington鈥檚 disease.
The team has also shown that the mutation causes an increase in the size of the cortex, the outer layer of the brain more commonly linked with cognitive abilities, although this data hasn鈥檛 yet been published, says Nopoulos.
The same group of children also underwent a range of cognitive tests, , a children鈥檚 version of the standard IQ scale.
In this study of 316 children, the team didn鈥檛 just class the children as having the mutation or not, but also counted the number of triplet repeats in the gene. The researchers found the highest cognitive ability was about 113 points 鈥� well above the average of around 100 points 鈥� being seen in children with 40 or 41 repeats, which means they would develop Huntington鈥檚. This is compared with a score of 105 for those with 15 to 19 repeats who haven鈥檛 inherited the mutated gene.
It is impossible to prove that the Huntington鈥檚 mutation was selected for by evolution, but greater intelligence presumably helps people to survive and reproduce. And as the condition鈥檚 first symptoms tend to start only in people鈥檚 30s or later, they could have had several children by then.
Intriguingly, other researchers studying people without Huntington鈥檚, who all have 35 or fewer triplet repeats, found that it is more common to have higher numbers of repeats than would be expected by chance, .
If the new idea is right, it would change how we think about intelligence, as no other single gene has been discovered with such a large positive effect on IQ. But more evidence may be needed to convince brain geneticists. 鈥淚t would be very exciting if it were true,鈥� says at King鈥檚 College London.
To be convinced, Plomin wants to see the finding replicated in larger studies, mainly because all intelligence-related genetic research to date has found that, while it is highly heritable, the trait is generally influenced by hundreds of genes, each with a tiny effect 鈥� of much less than 0.1 of an IQ point.
On the other hand, these studies haven鈥檛 counted the number of repeats in the Huntington鈥檚 gene, says Nopoulos. Instead, they focus on the more common kinds of genetic variation, such as when one DNA letter is replaced by another. 鈥淭his is a whole different way of looking at the genetic code,鈥� she says.
Whether or not the Huntington鈥檚 mutation boosts IQ, other kinds of evidence support the idea that the normal function of the huntingtin protein is to help build a developing brain. For instance, the brain cells that die first have a higher level of activity for genes involved in the organ鈥檚 development.
If altered brain development is the root cause of the condition鈥檚 symptoms, that could be bad news for efforts to develop a treatment, as many therapies in the works are designed to lower levels of the huntingtin protein.
However, the toxicity idea has support from animal studies, says at University College London, who was involved in the young adults study. He says it is possible that the mutation has dual effects: altering early brain development and inducing later-life toxicity. 鈥淚t is reasonable to think that lowering it in the adult brain has the potential for benefit.鈥�
So far, three huntingtin-lowering strategies have failed in clinical trials, including a drug called tominersen, which didn鈥檛 improve Huntington鈥檚 symptoms despite cutting levels of the protein in cerebrospinal fluid.
It is too soon to know if the whole strategy is flawed, but one thing most researchers agree on聽is聽that we need to know more about the natural functions of the聽non-mutated form of the huntingtin protein. 鈥淭hat will be聽a聽very, very important piece of聽the puzzle,鈥� says Schultz.
Brain
Article amended on 23 November 2023
This article has been changed to correct information about the young adult study and the research that supports the toxicity idea.
