An inactivated gene found naturally in some people leads to a difference in brain size, without having a detectable impact on health or disease, new research has found.
The work, from the Wellcome Sanger Institute, the French Institute of Health and Medical Research (Inserm), the University of Bourgogne Franche-Comté, and Beijing Genomics Institute (BGI)-Shenzhen, found that when there was a loss-of-function mutation in the mouse gene Magee2, it led to adult male mice having slightly enlarged brains. When the researchers investigated human brains using scans, they found the same effects in people who have a naturally-occurring loss-of-function mutation in the corresponding human gene, MAGEE2.
The paper, published in Molecular Biology and Evolution, provides an example of beneficial, positive selection of a mutated gene, in this case where the loss of function could provide potential advantages.
This MAGEE2 variant, found mainly in East Asia and the Americas, adds to the current genetic understanding of evolution and is an example of local adaptation, even though the exact reason behind this selection is so far unknown. More studies are needed to fully understand the role of MAGEE2 when it is intact and the impact, if any, of its loss on cognitive function.
Gene inactivation, where a gene is mutated and therefore no longer works, is often considered harmful and linked to the development of disease. However, if the gene that is lost isn’t responsible for an essential function, the mutation could have no impact on the individual, or in some cases might provide evolutionary advantages. This has been documented previously with some mutations being linked to malaria resistance*, or norovirus resistance**.
In earlier work, the mutated MAGEE2 gene was identified as one of the strongest examples of positive selection in East Asia, being found at 84 per cent frequency across the region and in the Americas, but only at low frequency elsewhere. While this has been known for some time, there is little understanding about the function of the gene or the reasons behind its selection.***
The new research, from the Wellcome Sanger Institute and collaborators, used CRISPR-Cas9 genome editing to create knockout mouse models to investigate the impact of MAGEE2 inactivation, and then compare these findings to humans by analysing the brain scans of those who carry the inactivated gene.
They found that in mice, inactivation of Magee2 led to an increase of 13 per cent in size of the brain in male mice, with no obvious impact on health or behaviour. This was mimicked in humans, where MRI brain scans showed an enlarged brain in men with an inactivated MAGEE2. In humans, there was a decrease in brain size in women with an inactivated MAGEE2, a trend also seen in mice, although not statistically significant.
Source: Sanger Institute