The normal structure and regulation of human globin gene clusters

The genes encoding the different globin chains of hemoglobin are members of an ancient gene family. In this chapter we will review the structural features of the globin genes, with particular attention to the sequences needed for proper regulation of gene expression. Some of these have been well conserved during mammalian evolution and therefore are likely to provide a common function in many mammals. Others are only found in higher primates and may play roles in lineage-specific regulation. We will first describe the structural characteristics of the human globin genes and then provide a comparative analysis of the genomic contexts, regulatory regions, and evolutionary conservation of features present in the globin gene clusters. Number and Chromosomal Localization of Human Globin Genes: Hemoglobin is a heterotetramer that contains two polypeptide subunits related to the α-globin gene subfamily (referred to here as α-like globins) and two polypeptide subunits related to the β-globin gene subfamily (β-like globins). Globin polypeptides bind heme, which in turn allows the hemoglobin in erythrocytes to bind oxygen reversibly and transport it from the lungs to respiring tissues. In humans, as in all vertebrate species studied, different α-like and β-like globin chains are synthesized at progressive stages of development to produce hemoglobins characteristic of primitive (embryonic) and definitive (fetal and adult) erythroid cells (Fig. 3.1). Before precise knowledge of globin gene organization was gained by gene mapping and molecular cloning, a general picture of the number and arrangement of the human globin genes emerged from the genetic analysis of normal and abnormal hemoglobins and their pattern of inheritance.