Deletion of the mouse α-globin regulatory element (HS −26) has an unexpectedly mild phenotype

Abstract

Natural deletions of the region upstream of the human α-globin gene cluster, together with expression studies in cell lines and transgenic mice, identified a single element (HS −40) as necessary and perhaps sufficient for high-level expression of the α-globin genes. A similar element occupies the corresponding position upstream of the mouse (m) α-globin genes (mHS −26) and was thought to have similar functional properties. We knocked out mHS −26 by homologous recombination and observed the surprising result that instead of the expected severe α-thalassemia phenotype, the mice had a mild disease. Transcription levels of the mouse genes were reduced by about 50%, but homozygotes were healthy, with normal hemoglobin levels and only mild decreases in mean corpuscular volume and mean corpuscular hemoglobin. These results may indicate differences in the regulation of the α-globin clusters in mice and humans or that additionalcis-acting elements remain to be characterized in one or both clusters.