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A Positively Selected MAGEE2 LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size and Shows Similar Phenotypes in Magee2 Null Mice

Published version
Peer-reviewed

Type

Article

Change log

Authors

Lelliott, Christopher 
Szpak, Michal 
Collins, Stephan 
Li, Yan 
Ayub, Qasim 

Abstract

A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. 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 (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, 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=3.4x10-6). 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.

Description

Keywords

MRI, brain size, loss of function, mouse knockout, positive selection, sexual dimorphism, Alleles, Animals, Antigens, Neoplasm, Brain, Female, Humans, Male, Mice, Mice, Knockout, Organ Size, Phenotype, Proteins, Sex Characteristics

Journal Title

Molecular Biology and Evolution

Conference Name

Journal ISSN

0737-4038
1537-1719

Volume Title

Publisher

Oxford University Press (OUP)
Sponsorship
Wellcome Grant WT098051 French National Research Agency (ANR-18-CE12-0009) ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02