The presence of genetic sex differences in the adult human brain is now recognized.1 We hypothesized that the basis of this sex bias is already established in the brain before birth. Here, we show that several genes encoded in the Y-chromosome are expressed in many regions of the male prenatal brain, likely having functional consequences for sex bias during human brain development.
The marked sex differences in age at onset, prevalence and symptoms for numerous neuropsychiatric disorders2 indicate the importance to study the emergence of a sex bias during human brain development. A recent article includes for the first time comprehensive data on the human brain transcriptome before birth.3 This elegant work reveals a large number of gene and alternative splicing differences specific to certain regions of the brain during development. A total of 12 regions in the midgestation human brain were analyzed in both male and female human fetal brain specimens. This data set provides for the first time the opportunity to evaluate the existence of embryonic sex bias in the human brain. To do this, we re-analyzed human fetal brain expression data from the Gene expression Omnibus (GEO accession GSE 13344, Human Exon 1.0 ST Array) according to sex. The database included 95 array hybridizations, of which 72 corresponded with different brain regions from three midgestation female fetuses and 23 were from equivalent brain regions from a male. The largest sex differences observed were in genes encoded on the Y-chromosome, showing the existence of prenatal gender bias in brain expression. Figure 1a shows the expression levels of 11 Y-chromosome-encoded genes, including RPS4Y1, PCDH11Y, DDX3Y, USP9Y, NLGN4Y, EIF1AY, UTY, ZFY, TMSB4Y, CYorf15B and PRKY. For 10 genes out of these 11, expression was detected in all the 12 brain regions analyzed (Supplementary Figure 1), suggesting that they may be present throughout the whole brain during development. PRKY on the other hand was expressed in a more restricted manner in the cortex samples, with low expression in cerebellum and basal ganglia. Some evidence of specific splice variant expression was found. For example, only one out of three ZFY transcripts produced positive signals in cortex, striatum and thalamus (Supplementary Figure 1).
The expression of more than one-third of the genes encoded on the Y-chromosome in prenatal human brain indicates their importance for sex-biased brain development. These genes are not only expressed in the brain before birth but some of them are also known to have sex differences in adult brain,1, 4 whereas others are expressed during infancy, but reduced later on during their lifetime.5
Intriguingly, SRY, a well-known determinant of testicle development during midgestation,6 showed no evidence of expression in any of the brain regions analyzed (Figure 1b, and Supplementary Figure 1), suggesting that the main somatic sex determinants may be different for the brain and gonads during human gestation.
In humans, all 11 genes described here are encoded in the male-specific region of the Y-chromosome,7 with RPS4Y1 and ZFY located in the p-arm very close to SRY and most of the remaining genes located in the q-arm. Interestingly, the expression of Y-linked genes in prenatal brain is only partially conserved between rodents and humans. USP9Y, DDX3Y and UTY have known orthologous genes in the mouse Y-chromosome, and their expression is conserved in terms of sex bias prenatally in both groups.8 Other genes with prenatal sex bias in humans, such as RPS4Y1 and EIF1AY, have rodent homologs encoded in somatic chromosomes and are not known to be sexually dimorphic. PCDH11Y and CYorf15B only have known mouse homologs in the X-chromosome and are not known to have sex differences in the brain. TMSB4Y and NLGN4Y lack known homologous in rodents. Finally, ZFY, which encodes for a transcription factor in the Y-chromosome in both groups, is expressed in human brain before birth, but absent in prenatal mouse brain.8 The differences in prenatal expression of Y-linked genes mentioned above suggest that parts of the programming of gender biases in the brain are human-, or at least, primate-specific.
Although the importance of X-chromosome-encoded genes for mental function has been well established,9 the relevance of Y-chromosome genes on brain function is less known. The results presented here, together with the well-known rapid evolution of Y-chromosomes,10 clearly point to the importance of future investigation on Y-linked gene function in the developing human brain.
Conflict of interest
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)