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Evolutionary constraints in the ?-globin cluster: the signature of purifying selection at the ?-globin (HBD) locus and its role in developmental gene regulation.

ABSTRACT: Human hemoglobins, the oxygen carriers in the blood, are composed by two ?-like and two ?-like globin monomers. The ?-globin gene cluster located at 11p15.5 comprises one pseudogene and five genes whose expression undergoes two critical switches: the embryonic-to-fetal and fetal-to-adult transition. HBD encodes the ?-globin chain of the minor adult hemoglobin (HbA2), which is assumed to be physiologically irrelevant. Paradoxically, reduced diversity levels have been reported for this gene. In this study, we sought a detailed portrait of the genetic variation within the ?-globin cluster in a large human population panel from different geographic backgrounds. We resequenced the coding and noncoding regions of the two adult ?-globin genes (HBD and HBB) in European and African populations, and analyzed the data from the ?-globin cluster (HBE, HBG2, HBG1, HBBP1, HBD, and HBB) in 1,092 individuals representing 14 populations sequenced as part of the 1000 Genomes Project. Additionally, we assessed the diversity levels in nonhuman primates using chimpanzee sequence data provided by the PanMap Project. Comprehensive analyses, based on classic neutrality tests, empirical and haplotype-based studies, revealed that HBD and its neighbor pseudogene HBBP1 have mainly evolved under purifying selection, suggesting that their roles are essential and nonredundant. Moreover, in the light of recent studies on the chromatin conformation of the ?-globin cluster, we present evidence sustaining that the strong functional constraints underlying the decreased contemporary diversity at these two regions were not driven by protein function but instead are likely due to a regulatory role in ontogenic switches of gene expression.

SUBMITTER: Moleirinho A

PROVIDER: S-EPMC3622298 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evolutionary constraints in the β-globin cluster: the signature of purifying selection at the δ-globin (HBD) locus and its role in developmental gene regulation.

Moleirinho Ana A Seixas Susana S Lopes Alexandra M AM Bento Celeste C Prata Maria J MJ Amorim António A

Genome biology and evolution 20130101 3

Human hemoglobins, the oxygen carriers in the blood, are composed by two α-like and two β-like globin monomers. The β-globin gene cluster located at 11p15.5 comprises one pseudogene and five genes whose expression undergoes two critical switches: the embryonic-to-fetal and fetal-to-adult transition. HBD encodes the δ-globin chain of the minor adult hemoglobin (HbA2), which is assumed to be physiologically irrelevant. Paradoxically, reduced diversity levels have been reported for this gene. In th ...[more]

PMID: 23431002

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Project description: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 ?- and ?-globin family members. In placental mammals, the ?-globin cluster includes three early-expressed genes, ?(HBE)-?(HBG)-??(HBBP1), and the late expressed genes, ? (HBD) and ? (HBB). While HBB encodes the major adult ?-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 ?-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 ?-like globin genes. We further show that not only the mode but also the rate of evolution of the ?-globin gene in higher primates are strictly associated with the fetal/adult ?-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 (?) 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 ? 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 ?-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.

Dataset Information

Evolutionary constraints in the ?-globin cluster: the signature of purifying selection at the ?-globin (HBD) locus and its role in developmental gene regulation.

Publications

Evolutionary constraints in the β-globin cluster: the signature of purifying selection at the δ-globin (HBD) locus and its role in developmental gene regulation.

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