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3 Transcriptomic Evidence for Sex Differences in Neurodevelopmental and Neurodegenerative Disorders
Pages 15-28

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From page 15...
... . • In the human brain, differential gene expression among males and females implicates molecular pathways related to epig enome regulation, chromosome X inactivation, hormonal regulation, and synaptic transmission (Roussos)
From page 16...
... AUTISM The pervasive neurodevelopmental disorders known collectively as autism spectrum disorders (ASDs) have about a four-fold higher prevalence in males than in females, although the phenotypic presentation and overall severity are largely similar across both sexes, said Donna Werling, assistant professor of genetics at the University of Wisconsin–Madison (Baio et al., 2018)
From page 17...
... The first three of these studies analyzed co-expressed gene modules and showed that in the ASD frontal and temporal cortex there was decreased transcription of modules associated with neuronal and synaptic function and increased expression of modules associated with immune, ­astrocyte, and FIGURE 3-1  Characterizing genomic sex differences associated with autism spectrum disorders. The panel on the left illustrates how sex may modulate outcomes in response to risk factor exposure.
From page 18...
... Of these, only one cell type was proportionately more abundant in ASD samples than controls -- protoplasmic astrocytes. They also conducted differential expression analyses within specific cell types, which showed that many of the most strongly down-regulated genes in cells from patients diagnosed with ASD were primarily in layer two/three excitatory neurons and a class of interneurons called vasoactive intestinal polypeptide interneurons, while the genes that were most strongly upregulated were observed in protoplasmic astrocytes and microglia.
From page 19...
... Not surprisingly, the genes with the biggest effect sizes were located on the X and Y chromosomes, but there were also highly significant sex differences for many more genes residing on autosomes, said Roussos. Pathway analysis on these gene signatures identified molecular pathways related to 2  For more information, see http://commonmind.org (accessed October 26, 2020)
From page 20...
... dataset includes the original CMC cohort comprising brains from Mount Sinai, the University of Pennsylvania Brain Bank, and the University of Pittsburgh (the MSSM-Penn-Pitt cohort) , as well as the National Institute of Mental Health's Human Brain Collection Core (NIMH-HBCC)
From page 21...
... Many modules yielded robust signals, he said. In a study available in preprint format, pathway analysis indicated that these modules represent molecular functions such as metabolism, hormone synthesis, signaling pathways, and regulation of neuro­ transmission (Hoffman et al., 2020)
From page 22...
... Indeed, there are striking differences in cell-specific gene expression patterns that change in the male and female brain, even in mid-life. For example, with increased age, the male brain shows changes in genes expressed in neurons and genes involved in synaptic transmission and dendritic growth, while the aging female brain shows gene expression changes in many of the support cells of the brain -- microglia, endothelial cells, astrocytes, and o ­ ligodendrocytes (Sanfilippo et al., 2019)
From page 23...
... , show decreased gene expression in excitatory and inhibitory neurons. Men, but not women, show increased gene expression in oligodendrocytes.
From page 24...
... In neurodegenerative disease, microglia respond inappropriately, causing excessive synaptic pruning and release of neurotoxic cytokines and chemokines. To understand sex differences in how microglia respond to tau, Gan and colleagues used RNA sequencing to profile messenger RNA (mRNA)
From page 25...
... To understand the impact on the disease process of differential miRNA expression, they showed that in the absence of Dicer, an enzyme that regulates the maturation and function of miRNA, many more transcripts were modulated in male microglia than in female microglia. When they crossed the Dicer knockouts with tau transgenic mice, they identified a cluster of transcripts in male mice that were nearly absent in female mice.
From page 26...
... By sequencing nearly 85,000 nuclei with either the common variant or R47H, they showed differential expression of microglial genes in males and females with very little overlap. Gan noted that a subcluster of genes that are highly expressed in females but not males were highly enriched for interferon response.
From page 27...
... While most of the work on establishing DAM signatures has been done in mouse models, Roussos said his lab has shown that the DAM signature in human brain is very different from that in mouse brain. Nilüfer Ertekin-Taner, professor of neurology and neuroscience at Mayo Clinic Florida, added that while single-cell analysis can be very informative, analytic approaches that enable deconvoluting existing largescale, bulk brain RNA-sequencing data could also be useful.


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