Geschlechtsspezifische genetische Effekte in der Genregulation bei Menschen

Eine Studie beschäftigt sich mit geschlechtsspezifischen genetischen Effekten:

Human regulatory variation, reported as expression quantitative trait loci (eQTLs), contributes to differences between populations and tissues. The contribution of eQTLs to differences between sexes however has not been investigated to date. Here we explore regulatory variation in females and males and demonstrate that 12-15% of autosomal eQTLs function in a sex-biased manner. We show that genes possessing sex-biased eQTLs are expressed at similar levels across the sexes and highlight cases of genes controlling sexually dimorphic and shared traits that are under the control of distinct regulatory elements in females and males. This study illustrates that sex provides important context that can modify the effects of functional genetic variants.

Quelle: Sex-biased genetic effects on gene regulation in humans (Full Text/PDF)

Zur Einordnung noch ein Zitat aus der Wikipedia zu expression quantitative trait loci (eQTLs):

Expression quantitative trait loci (eQTLs) are genomic loci that regulate expression levels of mRNAs or proteins[1]. Expression traits differ from most other classical complex traits in one important respect—the measured mRNA or protein trait almost always is the product of a single gene with a specific chromosomal location. eQTLs that map to the approximate location of their gene-of-origin are referred to as cis eQTLs. In contrast, those that map far from the location of their gene-of-origin gene, often on different chromosomes, are referred to as trans eQTLs. The first genome-wide mapping studies of gene expression were initiated in the late 1980s and early 1990s by Damerval and de Vienne [2][3]. They exploited then innovative 2D protein separation methods and introduced the term „protein quantity locus“ or PQL (now sometimes pQTL). The advent of high-throughput array-based methods to measure mRNA abundance in the early 2000s catalyzed an impressive number of expression QTL studies in plants and animals, including humans.

Some cis eQTLs are detected in many tissue types but the majority of trans eQTLs are tissue-dependent (dynamic).[4] eQTLs may act in cis (locally) or trans (at a distance) to a gene.[5]. The abundance of a gene transcript is directly modified by polymorphism in regulatory elements. Consequently, transcript abundance might be considered as a quantitative trait that can be mapped with considerable power. These have been named expression QTLs (eQTLs)[6] The combination of whole-genome genetic association studies and the measurement of global gene expression allows the systematic identification of eQTLs. By assaying gene expression and genetic variation simultaneously on a genome-wide basis in a large number of individuals, statistical genetic methods can be used to map the genetic factors that underpin individual differences in quantitative levels of expression of many thousands of transcripts.[7] Studies have shown that single nucleotide polymorphisms (SNPs) reproducibly associated with complex disorders [8] as well as certain pharmacologic phenotypes [9] are significantly enriched for eQTLs relative to frequency-matched SNPs.

Das Ziel der Studie wird in der Einleitung noch einmal dargestellt:

The majority of traits that distinguish the two sexes develop secondarily to the development of the ovaries and testes (WILLIAMS and CARROLL 2009). Most studies of sexual dimorphism have focused on the impact of hormones or on the genetic contribution of sex chromosomes. However there is growing evidence that genetic variation on the autosomes contributes to sexual dimorphism (HEID et al. 2010; OBER et al. 2008). Sex-specific QTLs for sexually dimorphic traits such as lifespan and HDLcholesterol have been detected respectively in Drosophila (NUZHDIN et al. 1997) and mouse (KORSTANJE et al. 2004). Sex-specific eQTLs have also been detected in mice (YANG et al. 2006), but whether such effects on expression regulation are also seen in humans has not been explored to date.

Aus der Studie:

Although almost all shared eQTL-genes detected in the sex-stratified study were also detected in the whole sample analysis, we identified five cases of female-male shared eQTL-genes that were not discovered when pooling the two sexes into a single analysis (Fig. 2A-E, Table S2). In these cases, although the eQTL-gene is shared, there are independent regulatory elements in each sex. These eQTL-SNPs have negligible significance in the non-discovery sex (Table S2, Fig. S4-8) explaining why such signals are likely to be diluted when both sexes are analyzed simultaneously. These cases include genes (see below, Figures 2A-E created using the UCSC Genome Browser (KENT et al. 2002), http://genome.ucsc.edu) with a role in gamete formation, fertility and sexual dimorphism, but also genes involved in processes that are not linked to perceived sex-related traits. This suggests that there may be a sex-biased dimension for traits that, to date, are considered to have similar biology across sexes. SPO11 (CEU, Fig. 2A, Fig. S4) is involved in meiotic recombination (BELLANI et al. 2010), spermatocyte formation, it is expressed in oocytes, and both female and male knockout mice are infertile (BELLANI et al. 2010). CKLF (JPT, Fig. 2B, Fig. S5) is a chemokine with a role in muscle development and neuronal migration (WANG et al. 2010). Its expression is increased in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA), diseases that are nine and three times more common in women respectively. MRFAP1L1 (JPT, Fig. 2C, Fig. S6) is thought to have a role in spermatogenesis through its interaction with TSNAX (RUAL et al. 2005), a gene involved in spermatogenesis, neuronal regulation and genome stability (JAENDLING and MCFARLANE 2010). ODF2L (YRI, Fig. 2D, Fig. S7) interacts with PRSS23 (STELZL etal. 2005), a serine protease involved in proteolytic degradation of extracellular matrix components, an essential process for ovulation (WAHLBERG et al. 2008). Finally, PSAP (YRI, Fig. 2E, Fig. S8) is a conserved glycoprotein involved in the development of the reproductive and nervous systems (HU et al. 2010). It has a developmental role in prostate cancer, its inactivation in mice leads atrophy of the male reproductive system and its down-regulation decreases metastatic prostate cancer cell adhesion, migration and invasion (HU et al. 2010).

Hier scheint sich also noch einiges an weiteren möglichen Ursachen von Geschlechterunterschieden aufzutun.