title: 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.
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal.
authors: Ana
authors: A
authors: Moleirinho
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors: Alexandra M
authors: AM
authors: Lopes
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors: Susana
authors: S
authors: Seixas
authors: Genetics and Genomics Group, The Pirbright Institute, Compton Laboratory, Compton, Berkshire, United Kingdom.
authors: Ramiro
authors: R
authors: Morales-Hojas
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal.
authors: Maria J
authors: MJ
authors: Prata
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal.
authors: António
authors: A
authors: Amorim
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005785:Gene Conversion; D006801:Humans; D008957:Models, Genetic; D010802:Phylogeny; D011323:Primates; D017422:Sequence Analysis, DNA; D055546:delta-Globins / Q000235:genetics*
chemical_list: D055546:delta-Globins