Sex Specific Gene Regulation and Expression QTLs in Mouse Macrophages from a Strain Intercross

Abstract

BackgroundA powerful way to identify genes for complex traits it to combine genetic and genomic methods. Many trait quantitative trait loci (QTLs) for complex traits are sex specific, but the reason for this is not well understood.Methodology/Principal FindingsRNA was prepared from bone marrow derived macrophages of 93 female and 114 male F2 mice derived from a strain intercross between apoE-deficient mice on the AKR and DBA/2 genetic backgrounds, and was subjected to transcriptome profiling using microarrays. A high density genome scan was performed using a mouse SNP chip, and expression QTLs (eQTLs) were located for expressed transcripts. Using suggestive and significant LOD score cutoffs of 3.0 and 4.3, respectively, thousands of eQTLs in the female and male cohorts were identified. At the suggestive LOD threshold the majority of the eQTLs were trans eQTLs, mapping unlinked to the position of the gene. Cis eQTLs, which mapped to the location of the gene, had much higher LOD scores than trans eQTLs, indicating their more direct effect on gene expression. The majority of cis eQTLs were common to both males and females, but only ∼1% of the trans eQTLs were shared by both sexes. At the significant LOD threshold, the majority of eQTLs were cis eQTLs, which were mostly sex-shared, while the trans eQTLs were overwhelmingly sex-specific. Pooling the male and female data, 31% of expressed transcripts were expressed at different levels in males vs. females after correction for multiple testing.Conclusions/SignificanceThese studies demonstrate a large sex effect on gene expression and trans regulation, under conditions where male and female derived cells were cultured ex vivo and thus without the influence of endogenous sex steroids. These data suggest that eQTL data from male and female mice should be analyzed separately, as many effects, such as trans regulation are sex specific.

Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts

“…All these phenotypic sex-related differences cannot be attributable to sex-specific hormonal differences but to genomic actions, which are not only restricted to the preimplantation period, as sexual dimorphism phenomena independent of hormonal interaction have been reported in adult tissues. Thus, a large sex effect on gene expression (30% of expressed genes) and trans-regulation was described in mouse macrophages that were cultured 2 weeks ex vivo, and thus were not influenced by endogenous sex steroids (22). Furthermore, the chromosomal sex of muscle-derived stem cells influences their ability to promote skeletal muscle regeneration by differential transcription of genes related to cell stress response (23).…”

Revealing the architecture of gene regulation: the promise of eQTL studies

“…Furthermore, transcriptional networks can be plastic [50,51] and, as a consequence, eQTLs can be extremely context dependent, differing because of a large number of factors, such as temperature [41], sex [38], developmental stage and tissues [44]. The task of mapping entire regulatory networks given these difficulties seems daunting [52].…”

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

“…Immune responses including those involving eosinophils might be modulated by steroid hormones [65, 66]. Moreover, some of the differences between females and males might be due to sex-specific genetic architecture, characterized by profound gene-sex interactions [67, 68]. This would mean that some genes controlling response to L. major might operate differently in the two sexes.…”