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December 16, 2013
The clichéd and controversial idea that male and female brains differ fundamentally has enjoyed mounting support in recent years. Research shows gender-based variation in brain structure and neurochemistry, as well as differences in overall behavior andsusceptibility to neurodegenerative and neuropsychiatric diseases, such as autism (more likely in males) and multiple sclerosis (more likely in females). But the molecular basis of this gender variation is unknown, and whether these differences mean brains are differently capable is unclear.
A new paper in the journal Nature Communications is the first large-scale study to investigate the genetic underpinnings of sex-based brain variation, reporting significant gender differences in expression and RNA splicing of genes in certain brain regions.
“The differences in gene expression between the sexes is much more widespread, both in terms of the number of genes involved and number of brain regions involved, than we had necessarily guessed,” said study co-author Mina Ryten of University College London. “The most interesting part is whether that gives any insight into neurological disorders, particularly because there are very well-known sex differences in many neurological diseases. Might some existing treatments be more effective in men or women?”
Previous studies have looked at fewer than 20 brains and in most cases only a handful of different brain regions. Here, investigators examined 12 regions (such as the frontal cortex, occipital cortex, thalamus, hippocampus) from each of 137 healthy brain samples (101 male, 36 female) derived from the UK Brain Expression Consortium. The team isolated total RNA from the brain tissues and analyzed it using Affymetrix Exon Arrays.
Ryten and her group found 448 genes that were expressed differently by gender (2.6% of all genes expressed in the CNS). All major brain regions showed some gender variation, and 85% of these variations were due to RNA splicing differences in male and female brains. Interestingly, “What’s key here is that there are an awful lot of autosomal genes that are involved in generating sex-biased expression patterns,” said Ryten.
Many of these genes play a role in disease. For example, the study identified expression differences in NRXN3, a gene linked to autism. NRXN3 has two major isoforms produced by alternate RNA splicing: one, alpha-neurexins, was expressed similarly in men and women, but the other, beta-neurexins, was expressed significantly less in women, but only in the thalamus. The authors speculate that this could help explain the higher incidence of autism in males, though to confirm this they would need to examine whether this difference in splicing occurs in young people as well.
Casting a wider net, the team next looked at entire gene networks using gene set enrichment analysis. They tested 71 CNS-related gene sets and found significant differences between the sexes. In one example, females had enhanced expression of two immune-related pathways in their white matter, perhaps providing a clue to why multiple sclerosis, an immune-related white matter disease, is more prevalent in women.
So, do these gender-based genetic differences have any greater meaning? “My perspective is not so much to make social commentary about these issues, but more whether it gives us insight into disease or not,” said Ryten.
Ryten hopes this work will improve basic neurological research. “This is a problem generally in neuroscience,” she said. “It’s not necessarily the case that people report sex differences in their studies, or whether they’ve analyzed, for example, male or female rodents, or whether they’ve cultured male or female cells, or even whether male or female skin cells are used as the starting point for developing induced pluripotent stem cells to make neurons.” With this work, she said, “sex should be a greater consideration in the design and analysis of neurological experiments.”
Trabzuni D, Ramasamy A, Imran S, Walker R, Smith C, Weale ME, Hardy J, Ryten M; North American Brain Expression Consortium. Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun. 2013 Nov 22;4:2771.
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