In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in beta-thalassemia

Genome-wide association studies (GWAS) have identified numerous genetic variants linked to human diseases, mostly located in non-coding regions of the genome, particularly in putative enhancers. However, functional assessment of the non-coding GWAS variants has progressed at slow pace, since the functions of the vast majority of genomic enhancers have not been defined, impeding interpretation of disease-susceptibility variants. The HBS1L-MYB intergenic region harbors multiple SNPs associated with clinical erythroid parameters, including fetal hemoglobin levels, a feature impacting disease severity of beta-hemoglobinopathies such as sickle cell anemia and beta-thalassemia. HBS1L-MYB variants cluster in the vicinity of several MYB enhancers, altering MYB expression and globin switching. We and others have highlighted the conserved human MYB -84kb enhancer, known as the -81kb enhancer in the mouse, as likely candidate linked to these traits. We report here the generation of a Myb -81kb enhancer knock-out mouse model, and shed light for the first time on its impact on steady state erythropoiesis and in beta-thalassemia in vivo.