Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Abstract

ABSTRACTGenetic association studies have detected two trans-acting quantitative trait loci (QTL) on chromosomes 2, 6 and one cis-acting QTL on chromosome 11 that were associated with fetal hemoglobin (HbF) levels. In these studies, HbF was expressed as a percentage of total hemoglobin or the number of erythrocytes that contain HbF (F-cells). As theγ-globin chains of HbF are encoded by two non-allelic genes(HBG2, HBG1)that are expressed at different levels we used normalized gene expression and genotype data from The Genotype-Tissue Expression (GTEx)-project to study the effects of cis- and trans-acting HbF expression or eQTL. This allowed us to examine mRNA expression ofHBG2and HBG1individually. In addition to studying eQTL for globin genes we examined genes co-expressed withHBG1, studied upstream regulators ofHBG1co-expressed genes and performed a correlation analysis betweenHBG2andHBG1and known HbF regulators. Our results suggest differential effect of cis and trans-acting QTL onHBGandHBG1expression. Trans-acting eQTLs have the same magnitude of effect on the expression of bothHBG2andHBG1while the sole cis-acting eQTL affected onlyHBG2. Furthermore, the analysis of upstream regulators and the correlation analysis suggested thatBCL2L1might be a new potential trans-acting HbF activator. HbF is the major modulator of the phenotype of sickle cell anemia and β thalassemia. Depending on the effect size, modification of trans-acting elements might have a greater impact on HbF levels than cis-acting elements alone.