The mammalian αD-globin gene lineage and a new model for the molecular evolution of α-globin gene clusters at the stem of the mammalian radiation

We have explored the evolution of the α-globin gene family by comparative sequence and phylogenetic analyses of mammalian α-globin genes. Our analyses reveal the existence of a new α-globin gene lineage in mammals that is related to the αD-globin genes of birds, squamates and turtles. The gene is located in the middle of the α-globin gene cluster of a marsupial, Sminthopsis macroura and of humans. It exists in a wide variety of additional mammals, including pigs, cows, cats, and dogs, but is a pseudogene in American marsupials. Evolutionary analyses suggest that the gene has generally evolved under purifying selection, indicative of a functional gene. The presence of mRNA products in humans, pigs, and cows also suggest that the gene is expressed and likely to be functional. The analyses support the hypothesis that the αD-globin gene lineage has an ancient evolutionary origin that predates the divergence of amniotes. The structural similarity of α-globin gene clusters of marsupials and humans suggest that an eight gene cluster (5′-ζ2-ζ1-αD-α3-α2-α1-θ-ω-3′), including seven α-like genes and one β-like globin gene (ω-globin) existed in the common ancestor of all marsupial and eutherian mammals. This basic structure has remained relatively stable in marsupials and in the lineage leading to humans, although ω-globin has been lost from the α-globin gene cluster of humans.