Structural organization of the alpha and beta globin loci of the goat

Abstract

Goats switch their hemoglobins during development in a manner similar to humans and thus provide a useful model system for studying the control of hemoglobin synthesis. Initially, goats synthesize embryonic hemoglobin, zeta 2 epsilon 2, which is replaced by fetal hemoglobin, alpha 2 beta F 2, as erythropoiesis moves to the liver and bone marrow. At birth, the fetal hemoglobin is replaced by juvenile hemoglobin, alpha 2 beta C 2, which in turn is replaced by adult hemoglobin, alpha 2 beta A 2, during the first year of life. In order to understand these switches, we have cloned the alpha and beta globin loci of goats. The alpha globin locus is composed of three genes, an embryonic and two adult genes, zeta-I alpha-II alpha. The beta globin locus is composed of twelve genes arranged in the following order, epsilon I-epsilon II-psi beta X-beta C-epsilon III-epsilon IV-psi beta Z-beta A-epsilon V-epsilon VI-psi beta Y-beta F. Close inspection of the beta globin locus indicates that it has arisen from a triplication of a four-gene set, epsilon-epsilon-beta-beta. Interestingly, the fetal globin gene has originated from an adult beta globin gene rather than from a second position gene as it has in humans. The gene at the end of the first four gene set, beta C, is expressed during pre-adult life while the gene at the end of the second set is the adult beta A gene. The last gene of the third set, beta F, is expressed during fetal development. Because the beta C, beta A and beta F genes have arisen quite recently during evolution, they have very similar nucleotide sequences. It is reasonable to assume that the few differences which are seen are important in developmental control. As one approach to defining regions involved in the regulation of the beta A, beta C and beta F genes their chromatin structure at different times of development has been characterized. Both DNase I sensitivity and accessibility to restriction endonucleases have been employed. While the entire beta globin locus is more sensitive to DNase in erythroid than non-erythroid cells, specific regions such as the 5' end of the genes are more accessible in cells expressing that particular gene.