A new study, published in Molecular Biology and Evolution, has revealed that gene inactivation that naturally occurs in some individuals leads to a difference in brain size, with no detectable impact on health or disease. Despite being widely seen across East Asia, this mutation has been very poorly understood – until now.
Positively selected gene inactivation
Gene inactivation is often linked to the development of disease, and as such is usually considered harmful. Despite this, if loss-of-function variants occur in a non-essential gene, there is often no impact on an organism’s fitness. In some rare cases, however, gene inactivation can be beneficial. Whilst many putatively positively selected loss-of-function mutations have been identified, they are currently not well understood.
One such mutation is a premature stop codon in the human MAGEE2 gene, which results in a protein truncation. It is one of the strongest examples of mutations under local positive selection. Interestingly, previous studies have found this mutation at a 84% frequency across East Asia and the Americas, but at a very low frequency elsewhere. Despite this, the function of MAGEE2 and the reason for its strong positive selection is still unclear.
To uncover more about MAGEE2, the researchers behind this study generated gene knockout mice to investigate the functional consequences of losing this gene.
Sex-specific effects of gene inactivation
First, the team used CRISPR-Cas9 genome editing to generate Magee2 null mice. Magee2 is the corresponding mouse gene to MAGEE2. In terms of whole-body phenotypes, the Magee2 null mice appeared no different to normal mice. However, previous studies have shown that in humans, MAGEE2 expression is brain specific. Therefore, the researchers carried out further analyses of the mice brains.
The brain analyses revealed that male Magee2 null mice had 13% larger brains than normal mice. In addition, there was no obvious impact on health or behaviour. Interestingly, the brain region that increased most in size was the granular retrosplenial cortex. This region is responsible for memory, navigation and spatial information processing.
Intriguingly, female Magee2 null mice displayed different results. Their brains were actually found to be slightly smaller than normal, but this difference was not statistically significant. These results suggest sexual dimorphism in the neuroanatomy of Magee2 null mice.
Effect of MAGEE2 gene inactivation on human brain size
Next, the team set out to discover if their findings in mice were mimicked in humans. To do this, the researchers performed an association study between brain volume quantified from MRI scans and mutated MAGEE2 genotypes. The team carried out the analysis in a group of 141 Chinese volunteers.
The team found that males with an inactivated MAGEE2 gene had significantly larger brains, whilst females with the mutation had significantly smaller brains. These results replicate the sexual dimorphism observed in the mouse model. In humans, the volume of the posterior temporal lobe was significantly associated with MAGEE2 inactivation. This region has similarities to the granular retrosplenial cortex in mice. However, the segmentation of human and mouse brains is different, so specific comparisons could not be made.
Conclusions and future work
Until now, scientists knew very little about MAGEE2. This study is the very first to link the inactivation of MAGEE2 in both human and mice to sex-specific changes in brain size. Amazingly, the team also found no evidence of any accompanying effects on health.
Nonetheless, researchers still do not know why MAGEE2 inactivation is found at such high frequencies in East Asia and the Americas. Further studies will be needed to confirm whether or not the mutation affects cognition, what the evolutionary advantage is and why opposite effects are seen in men and women.
Senior author Dr Chris Tyler-Smith 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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