Distinctive Patterns of Evolution of the δ-Globin Gene (HBD) in Primates

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.

Red Blood Cells Protein Profile Is Modified in Breast Cancer Patients

“…Indeed, embryonic or fetal Hbs have a higher oxygen affinity ( 44 ), which could give them an advantage in oxygen transfer in conditions of hypoxia or anemia, conditions frequently seen in cancer patients ( 45 , 46 ). In this regard, HBD has been involved in the regulation of fetus–adult Hb switch ( 47 ) and was detected in hematopoietic stem cells and hepatocarcinoma cells ( 48 , 49 ). In CTCs, hemoglobin beta has been related to cell survival ( 50 ).…”

Comparative DNA methylation reveals epigenetic adaptation to high altitude in snub-nosed monkeys

“…In this study, we identified that PAN2 was a hypomethylated differentially methylated gene in the Yunnan sub-nosed monkey, implying an enhanced functional activity or expression relative to its counterpart in the golden snub-nosed monkey (Figure 3a). PAN2 acts as a regulator of HIF1A mRNA stability, and the reduction of PAN2 decreases HIF1A mRNA and protein levels (Bett et al, 2013).The similar hypomethylated situation was observed in HBD, which encodes hemoglobin subunit delta -a component of hemoglobin conducting oxygen transport from the lung to the various peripheral tissues (Moleirinho et al, 2015). Studies of plateau pika (Ochotona curzoniae) indicated that hypoxia specifically upregulated the expression of HBD in lung tissues, which was considered to be crucial for surviving in high-altitude environments by aiding in the extraction of oxygen from hypoxic conditions (An et al, 2022).…”

Hydroxyurea attenuates hepatic stellate cell proliferation in vitro and liver fibrogenesis in vivo

“…Hypoxia is considered to be a key factor in promoting the progression of liver fibrosis. 44,45 In humans, hydroxyurea induces the production of fetal hemoglobin (HbF) to approximately 20% of the total hemoglobin pool, 46,47 while normal levels are below 1% soon after birth.…”