Sex Specific Gene Regulation Figure 1. Genomic location of eQTLs. Bone marrow derived macrophage eQTLs with LOD$3.0 were mapped to partially overlapping 20 Mb bins in female (A) and male (B) F2 mice. The horizontal dotted line denotes the arbitrary cutoff for eQTL hotspots. eQTLs for sex biased transcripts with LOD$3.0 were mapped to partially overlapping 20 Mb bins in female (C) and male (D) F2 mice. doi:10.1371/journal.pone.0001435.g001 hotspot positions in females and males, near the distal ends of chromosome 1 and 4, and near the proximal end of chromosomes 7 and 13. Interestingly, there were only 46 eQTLs in the male cohort that mapped to the X chromosome (20 cis, 11 trans, and 15 ambiguous), showing an unexpectedly large difference compared to the female cohort where 861 eQTLs mapped to the X chromosome. In order to identify potential candidates responsible for the two male autosomal super hotspots, we examined cis eQTLs that mapped to these hotspots and had a LOD score of $5.5. We then correlated the expression levels of each of these cis eQTLs with the expression of the trans eQTLs that mapped precisely to the most common marker for trans eQTLs in these region. We found nine cis eQTLs probes on chromosome 1 whose expression had an average absolute value correlation coefficient .0.20 with 308 trans eQTLs at that locus; and, we found three chromosome 16 cis eQTLs whose expression had an average absolute value correlation coefficients .0.2 with 379 trans eQTLs at that locus. Each of these cis eQTLs, listed in Tables 2 and 3, respectively, are candidate genes whose expression is strain dependent that could be responsible for mediating the trans regulation of ,1000 other genes. Suggestive eQTL Sharing Between the Sexes We examined the suggestive eQTLs on the autosomes and the X chromosome to determine how many were shared between the female and male cohorts, thus the identical probe had an eQTL in both sexes that mapped within 20 Mb to the same locus (Table 4). 1,285 cis eQTLs were shared, representing 69% of the female and 65% of the male cis eQTLs (Supplemental Table S4). Among these sex-shared cis eQTLs, the LOD scores for the female eQTLs were highly correlated with the LOD scores in males (r2 = 0.71, p,0.0001), highlighting the similarity of these shared eQTLs. A very different picture emerged from the trans eQTLs, with only 71 being shared between the sexes, representing only 1.2% and 0.8% of the female and male trans eQTLs, respectively. Supplemental Table S5 details each of these 71 shared trans eQTLs that had mean LOD scores of 4.07 and 4.13 in the female and male cohorts, respectively. Among these sex-shared trans eQTLs, a correlation between female and male LOD scores was evident (r2 = 0.26, p,0.0001), but was weaker than that observed for the sex shared cis eQTLs (r2 = 0.71). There was some clustering of these sex-shared trans eQTLs, with 7 mapping to the proximal end of chromosome 1, 11 mapping to the distal end of chromosome 1, and 7 mapping to the distal end of chromosome 4. The gene ontology associations of the sex-shared trans eQTLs were statistically compared against all of the trans eQTLs. This analysis yielded no apparent clustering based on known gene functions, or any particular pathway in the sex shared trans eQTLs. There were also 243 sex-shared ambiguous eQTLs with very high average LOD scores (11.35 and 12.7 in females and PLoS ONE | www.plosone.org 3 January 2008 | Issue 1 | e1435