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Sex chromosomes and brain gender

Key Points

  • Differences between the brains of males and females are thought to arise largely through the actions of hormones secreted by the gonads. However, there is increasing evidence that X and Y chromosome-linked genes also act directly on the brain to cause sex-specific differences in both mammals and birds.

  • The sex chromosomes have evolved under sex-specific selection processes, so that the Y chromosome would be expected to harbour male-benefit sexually antagonistic alleles. The X chromosome would be expected to contain both male-benefit genes and female-benefit genes.

  • Because of the sex difference in the number of X chromosomes, mechanisms have evolved to compensate for the potential difference in dosage between expression of these genes in females and males. If dosage is not compensated, this could lead to sex-specific differences in gene expression.

  • Genes that control sexual dimorphisms in the brain would be expected to be enriched on the sex chromosomes, because brain function is important for reproductive function and behaviour.

  • The gonadal hormones can generate sexual dimorphisms in the brain, but sex differences can, in some cases, be detected before the gonads have differentiated. Further evidence for a direct role of the XX or XY genotype on the brain comes from mice in which the testis-determining Sry gene has been removed from the Y chromosome and replaced on an autosome. In this way, it is possible to generate 'female' mice with an XY genotype, and 'male' mice with an XXSry genotype. The brains of XX mice differ in several respects from those of XY mice, regardless of the presence or absence of the Sry gene.

  • Birds differ from mammals in that the female is heterogametic (with a Z and a W chromosome) and the male has two Z chromosomes. The forebrain song circuit shows marked sexual differentiation, which does not seem to be due solely to gonadal hormones, but rather might result from differences in neuronal sex chromosome genotype. Neuronal transplantation studies in quails also support a role for genetic sex in controlling sexual differentiation in the brain.

Abstract

In birds and mammals, differences in development between the sexes arise from the differential actions of genes that are encoded on the sex chromosomes. These genes are differentially represented in the cells of males and females, and have been selected for sex-specific roles. The brain is a sexually dimorphic organ and is also shaped by sex-specific selection pressures. Genes on the sex chromosomes probably determine the gender (sexually dimorphic phenotype) of the brain in two ways: by acting on the gonads to induce sex differences in levels of gonadal secretions that have sex-specific effects on the brain, and by acting in the brain itself to differentiate XX and XY brain cells.

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Figure 1: Genetic differences between XX and XY cells.
Figure 2: The implications of X mosaicism for brain gender.
Figure 3: Sex chromosome effect on dopamine neurons.
Figure 4: The case of the half-male, half-female finch.

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Acknowledgements

Thanks to Paul Burgoyne, Geert De Vries, Emilie Rissman, Robin Lovell-Badge, Amanda Swain, Eric Vilain, Robert Agate, Jun Xu, Xuqi Chen, Yuichiro Itoh, Barbara Finlay, Andrew Sinclair and Jennifer Graves for discussions of the ideas summarized here. Supported by the National Institutes of Health.

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DATABASES

Entrez Gene

MECP2

Sry

Trp53

OMIM

Rett syndrome

FURTHER INFORMATION

Encyclopedia of Life Sciences

chromosome function: sex differences

Y-chromosome-linked traits

Art Arnold's Laboratory

Glossary

AUTOSOME

Any chromosome in a cell that is not a sex chromosome.

GYNANDROMPORPHIC

Having both male and female morphological characteristics.

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Arnold, A. Sex chromosomes and brain gender. Nat Rev Neurosci 5, 701–708 (2004). https://doi.org/10.1038/nrn1494

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