Phylogenetic comparisons suggest that distance from the locus control region guides developmental expression of primate β-type globin genes

Phylogenetic inferences drawn from comparative data on mammalian β-globin gene clusters indicate that the ancestral primate cluster contained a locus control region (LCR) and five paralogously related β-type globin loci (5′-LCR-ε-γ-ψη-δ-β-3′), with ε and γ expressed solely during embryonic life. A γ locus tandem duplication (5′-γ¹-γ²-3′) triggered γ's evolution toward fetal expression but by a different trajectory in platyrrhines (New World monkeys) than in catarrhines (Old World monkeys and apes, including humans). In platyrrhine (e.g., Cebus) fetuses, γ¹ at the ancestral distance from ε is down-regulated, whereas γ² at increased distance is up-regulated. Catarrhine γ¹ and γ² acquired longer distances from ε (14 and 19 kb, respectively), and both are upregulated throughout fetal life with γ¹'s expression predominating over γ²'s. On enlarging the platyrrhine expression data, we find Aotus γ is embryonic, Alouatta γ is inactive at term, and in Callithrix, γ¹ is down-regulated fetally, whereas γ² is up-regulated. Of eight mammalian taxa now represented per taxon by embryonic, fetal, and postnatal β-type globin gene expression data, four taxa are primates, and data for three of these primates are from this laboratory. Our results support a model in which a short distance (<10 kb) between ε and the adjacent γ is a plesiomorphic character that allows the LCR to drive embryonic expression of both genes, whereas a longer distance (>10 kb) impedes embryonic activation of the downstream gene.