Abstract
In most vertebrates, hemoglobin (Hb) is a heterotetramer composed of two dissimilar globin chains, which change during development according to the patterns of expression of α- and β-globin family members. In placental mammals, the β-globin cluster includes three early-expressed genes, ε(HBE)-γ(HBG)-ψβ(HBBP1), and the late expressed genes, δ (HBD) and β (HBB). While HBB encodes the major adult β-globin chain, HBD is weakly expressed or totally silent. Paradoxically, in human populations HBD shows high levels of conservation typical of genes under strong evolutionary constraints, possibly due to a regulatory role in the fetal-to-adult switch unique of Anthropoid primates. In this study, we have performed a comprehensive phylogenetic and comparative analysis of the two adult β-like globin genes in a set of diverse mammalian taxa, focusing on the evolution and functional divergence of HBD in primates. Our analysis revealed that anthropoids are an exception to a general pattern of concerted evolution in placental mammals, showing a high level of sequence conservation at HBD, less frequent and shorter gene conversion events. Moreover, this lineage is unique in the retention of a functional GATA-1 motif, known to be involved in the control of the developmental expression of the β-like globin genes. We further show that not only the mode but also the rate of evolution of the δ-globin gene in higher primates are strictly associated with the fetal/adult β-cluster developmental switch. To gain further insight into the possible functional constraints that have been shaping the evolutionary history of HBD in primates, we calculated dN/dS (ω) ratios under alternative models of gene evolution. Although our results indicate that HBD might have experienced different selective pressures throughout primate evolution, as shown by different ω values between apes and Old World Monkeys + New World Monkeys (0.06 versus 0.43, respectively), these estimates corroborated a constrained evolution for HBD in Anthropoid lineages, which is unlikely to be related to protein function. Collectively, these findings suggest that sequence change at the δ-globin gene has been under strong selective constraints over 65 Myr of primate evolution, likely due to a regulatory role in ontogenic switches of gene expression.
Highlights
Hemoglobin (Hb), found in the circulating red blood cells of all vertebrates, is the major oxygen-transporting molecule, playing a key role in the cellular aerobic metabolism [27]
We conducted a phylogenetic analysis of the adult β-like globin genes, HBD and HBB, in a diverse dataset, including monotremes, marsupials and placental mammals, and one avian species, which was used as outgroup
The phylogenies obtained with Maximum Likelihood (ML), Bayesian Inference (BI) and the codon model approach were similar when either the complete gene sequence or the coding sequence (CDS) were used (Fig 1A– 1D and S4 Fig)
Summary
Hemoglobin (Hb), found in the circulating red blood cells of all vertebrates, is the major oxygen-transporting molecule, playing a key role in the cellular aerobic metabolism [27]. Hb is a heterotetramer composed of two α-like and two β-like globin chains that are differentially expressed during development, such that functionally distinct Hb isoforms are synthesized in embryonic and adult erythroid cells [27,28,29] These globin chains are encoded by members of the α- and β-globin gene families, which arose via tandem duplication of an ancestral, single-copy globin gene approximately 450–500 Mya, in the common ancestor of jawed vertebrates [14,23,25,35,78]. The fine tuning of the level and timing of expression of each of these genes relies on interactions with the locus control region (LCR), located from approximately 6 to 18 kb upstream of HBE [4,11,84]
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