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Is this the secret to a bigger brain? Wellcome Sanger Institute scientists and collaborators make genetic discovery

Some people have larger brains because of an inactivated gene, researchers have found.

While there is no detectable impact on health or disease, it is not yet clear what effect it has on cognitive powers.

A brain MRI scan
A brain MRI scan

Wellcome Sanger Institute scientists and their colleagues say it is an example of the positive selection of a mutated gene, in which the loss of function could provide potential advantages.

In mice, they found that when the gene Magee2 was inactivated, male mice had a 13 per cent larger brain, with no obvious impact on health or behaviour.

Then, studying MRI brain scans, they found a naturally-occurring loss-of-function mutation in the corresponding human gene, MAGEE2, led to a similarly enlarged brain in men.

However, there was a decrease in brain size in women with an inactivated MAGEE2 - a trend also seen in mice, although not at a statistically significant level.

The MAGEE2 variant is found with 84 per cent frequency in East Asia and the Americas, but only at low frequency elsewhere.

The study adds to the current genetic understanding of evolution and is an example of local adaptation, although the reason for the selection remains unknown.

Dr Michal Szpak, first author and postdoctoral fellow at the Wellcome Sanger Institute, said: “MAGEE2 inactivation has been recognised by its striking geographical distribution, suggestive of a strong positive selection in East Asia, yet with no understanding of its function. This is, to our knowledge, the first study that links the inactivation of MAGEE2 in humans and mice to the enlargement of brain structures.

“We now need to investigate this further to fully understand whether this variant affects cognition or behaviour, what the evolutionary advantage is, and why we see opposite effects in men and women.”

Dr Binnaz Yalcin, senior author and junior group leader at the French Institute of Health and Medical Research (Inserm), which collaborated on the work, said: “This study is a powerful example of how the mouse remains crucial as a model system beyond the field of medical genetics. We are pleased to see how findings in mice can translate to the biology of human genome evolution.”

Gene inactivation is often harmful and linked to disease, but if the gene that is lost is not responsible for an essential function, such a mutation may have no impact or might even provide evolutionary advantages.

This has been seen previously with some mutations being linked to malaria resistance or norovirus resistance.

Professor Huanming Yang, co-founder, director and chairman of the Beijing Genomics Institute Group in China, which was also involved, said: “Understanding the selection of genes in different populations can help build a more complete picture of genetic evolution and lead to a deeper understanding of the role of non-essential genes in the body. Investigating these non-essential genes and their impact on brain size could lead to insight on what drove the genetic changes in this group and the role of different genes on the function of the brain. The more we understand about the brain, the better we will be at being able to understand and treat brain diseases that are caused by genetic mutations.”

Dr Chris Tyler-Smith, senior author and former Senior Group Leader at the Wellcome Sanger Institute, said: “We could tell from previous genetic studies of MAGEE2 in the population that its loss was beneficial, at least in some parts of the world, but we had no idea why. Now we know from the current work starting in mice that loss has effects on brain size. In future research we need to go back to the human population to see how these brain changes, or others associated with MAGEE2 loss, have led to the beneficial effects that started off this work.”

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