Modelling Human Adaptations in Mice: A Positively Selected MAGEE2 LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size

Add to your list(s) Download to your calendar using vCal

• Dr Michał Szpak from the Wellcome Sanger Institute and the European Bioinformatics Institute
• Wednesday 17 November 2021, 12:00-13:00
• online .

If you have a question about this talk, please contact Jordan McCormick.

The focus of positive selection studies in humans needs to move from candidate locus discovery to pinpointing underlying causal variants and further investigation of their biological significance. We have developed a method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency and molecular functionality to prioritize positively-selected candidate variants for functional follow-up. We then used FineMAV to identify the best candidate variants driving local adaptations in the 1000 Genomes Project Phase 3 SNP dataset and begun studying 29 of them using mouse models. One of such variants was a nonsense allele at rs1343879 in human MAGEE2 on chromosome X. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas but rare elsewhere, suggesting a strong positive selection. We generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation, and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10−6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of grey matter in males (P = 0.00094), and smaller volumes of grey (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behaviour or cognition, but it might have been the driving force underlying the positive selection in humans.

This talk is part of the CCB seminars series.

This talk is included in these lists:

• online

Note that ex-directory lists are not shown.