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Sex Differences in Mouse Hippocampal Astrocytes after In-Vitro Ischemia
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Tissue-specific sex differences in human gene expression.

Irfahan Kassam1, Yang Wu1, Jian Yang1,2

  • 1Institute for Molecular Bioscience.

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Sex differences in gene expression vary by tissue. While sex chromosomes play a role, autosomal genes show complex, tissue-specific regulation influenced by hormone-binding sites and enhancers, impacting human traits and diseases.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Human Genetics

Background:

  • Human complex traits and diseases exhibit significant sex differences, yet the primary genetic difference lies only in sex chromosomes.
  • Most sex-differentiated traits are attributed to differential gene expression in genes common to both sexes.
  • The mechanisms underlying tissue-specific sex differences (TSSDs) in gene expression remain poorly understood.

Purpose of the Study:

  • To investigate the biological mechanisms of tissue-specific sex differences in gene expression.
  • To identify transcripts with heterogeneous sex difference effect sizes across multiple tissue types.

Main Methods:

  • Analyzed 30,640 autosomal and 1,021 X-linked transcripts for sex difference heterogeneity in 617 individuals across 40 tissue types using Genotype-Tissue Expression (GTEx) data.
  • Identified tissue-specific sex-differentiated (TSSD) transcripts using a stringent significance threshold.
  • Examined the location of cis-expression quantitative trait loci (eQTLs) relative to androgen/estrogen binding motifs and enhancers for TSSD and stable sex-differentiated transcripts.

Main Results:

  • Identified 65 autosomal and 66 X-linked TSSD transcripts.
  • X-linked TSSD transcripts showed largely consistent sex differences across tissues.
  • Autosomal TSSD transcripts exhibited predominantly discordant sex differences across tissues.
  • Top cis-eQTLs for autosomal TSSD transcripts were located near androgen/estrogen binding motifs and enhancers, similar to stable sex-differentiated transcripts.
  • Enhancer regions for TSSD cis-eQTLs were more dispersed across tissues.

Conclusions:

  • Hormone regulatory elements (androgen and estrogen) in cis regions may contribute generally to sex differences in gene expression.
  • Tissue-specific enhancer regions likely play a significant role in driving tissue-specific sex differences in gene expression.