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.
Highlights
The combination of quantitative trait locus (QTL) mapping and gene expression profiling allows for the identification of expression quantitative trait loci, which are loci associated with the expression of each transcript
We still found that many expression QTLs (eQTLs) are sex specific, and remarkably, that 30% of expressed genes were differentially expressed in female vs. male macrophages, suggesting that a large extent of sexually dimorphic gene expression may be directly dependent on X and Y chromosome dosage, rather than on the hormonal environment
We have identified eQTLs separately from male and female bone marrow derived macrophages derived from F2 mice from an AKR x DBA/2 strain intercross
Summary
The combination of quantitative trait locus (QTL) mapping and gene expression profiling allows for the identification of expression quantitative trait loci (eQTLs), which are loci associated with the expression of each transcript This method was first applied to a yeast strain intercross, where both cis-acting and trans-acting loci were identified associated with the expression level of hundreds of transcripts [1]. These 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 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
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