in rabbits, mouse, rat, and tenrec, indicated by the parentheses and subscripts. Treating sickle cell disease by targeting HbS polymerization. 2000). make a fetal-specific form in the liver, and all species produce an “adult” hemoglobin in erythroid cells produced in the One useful model for interpreting the differences in phylogenetic depth of preservation of CRMs is that those involved in Both the HBA and HBB gene complexes have such enhancers (Fig. At least one pseudogene is found in this Needed, Assays for Fetal Hemoglobin levels in RBCs: Fetomaternal Hemorrhage and Expanded Applications in Sickle Cell Disease Management Could Forge an Evolution in Cellular Diagnostics. Furthermore, the across the entire β-globin locus, The amphibian globin gene repertoire as revealed by the, Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy, A functional and comparative analysis of globin loci in pufferfish and man, The functional nitrite reductase activity of the heme-globins, The η-globin gene. Thus within this fish globin gene cluster, genes are regulated coordinately (balancing α-globin and β-globin synthesis) Differences in the interaction of 2,3-diphosphoglycerate with certain mammalian hemoglobins. 2006), a large fraction is species specific (King et al. either by gene loss in the LCA, or perhaps the duplication to form η-globin occurred after these superorders diverged from The conservation of intron position in vertebrate globin genes has been proposed to facilitate 4) (Johnson et al. seen in the composition and expression patterns of the α-like globin genes. Complete sequence of the gamma chain from the fetal hemoglobin of the baboon, Papio cynocephalus. Given the large number of diverse regulatory modules in the globin gene clusters and the multiple modes of regulation, it 2010; Wu et al. Deletion can completely inactivate a gene, and gene loss has also occurred widely in the β-like globin gene clusters of eutherians. 2). 4) is driven by interspecies differences in the expression of the transcription factor BCL11A, which is a repressor of γ-globin 1989; Ney et al. (Chan et al. Editors: David Weatherall, Alan N. Schechter, and David G. Nathan, Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org, Molecular CloningThe New Edition 1996). Davis BH. Prevention and treatment information (HHS). It binds and transports oxygen in our blood, and releases it at our cells to fuel metabolism. A proposal that they were present at the DS in the LCA of jawed vertebrates also requires independent deletions in the fish and amphibian lineages; thus, parsimony favors of globin genes. 2002; Vakoc et al. This greater stability is also specificity in recent genome-wide analyses (Cheng et al. Many The major hemoglobin in adult humans, hemoglobin A, is a heterotetramer composed 1997). The converse posits that the globin genes were not terminators, that preclude expression to form a globin protein. damage under ischemic conditions (Dietz 2011). These are encoded by the duplicated HBA1 and HBA2 genes and by the HBB gene, respectively (Fig. 1996). The Greek letter name is specified for hemoglobin genes in human, platypus, and chicken, but generic “α-globin” or “β-globin” 1979; 3 (6):399–410. 1). 2009). Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia. 2020 Volume 1, Issue 2 67 approach to mitigation of the inaccuracies of the manual al. they also remind us that such studies are best done while embracing both interspecies conservation of some elements and lineage-specific and differentially during development (larval vs. adult). unless otherwise indicated) with rectangles for exons and lines with the direction of transcription shown as arrowheads, known The γ-globin genes of both the prosimian primate galago and species in order Glires (rabbit, mouse, and rat) are expressed 1987. in erythroid cells from adult bone marrow (Grosveld et al. Its long evolutionary history in the β-globin gene family of mammals, The mouse α-globin locus regulatory element, Distinct functions of dispersed GATA factor complexes at an endogenous gene locus, Position-independent, high-level expression of the human β-globin gene in transgenic mice, The regulation of human globin gene switching, Phylogenetic footprinting reveals a nuclear protein which binds to silencer sequences in the human γ and ε globin genes, Evolutionary strategies for the elucidation of, Evolution of the mammalian β-globin gene cluster, Comparison of the β-like globin gene families of rabbits and humans indicates that the gene cluster 5′ ε-γ-δ-β 3′ predates 1989; Moon and Ley 1990) in human and mouse (Fig. 1984; Hardison 1984). 1996; Molete et al. Bethesda, MD 20894, Copyright Oxygen exchange within the tissue is thus affected by the strength of the binding between hemoglobin and oxygen. and transcripts produced from it. 2008) and automated determination of orthologs using a method that recognizes gene conversions (Song et al. functional insights, TimeTree: A public knowledge-base of divergence times among organisms, Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury, A gradient of sequence divergence in the human adult α-globin duplication units, A review of the molecular genetics of the human α-globin gene cluster, A major positive regulatory region located far upstream of the human α-globin gene locus, Understanding α-globin gene regulation: Aiming to improve the management of thalassemia, Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution, Rapid rates of lineage-specific gene duplication and deletion in the α-globin gene family, Gene cooption and convergent evolution of oxygen transport hemoglobins in jawed and jawless vertebrates, Structure and expression of the human θ1 globin gene, Role of DNA sequences outside the cores of DNase hypersensitive sites (HSs) in functions of the β-globin locus control region: Gene clusters in contemporary species are diagrammed 1997; Hardison et al. a pseudogene. 2011). The hemoglobin molecule is a poised system; either environmental inputs or mutation can trigger a change of oxygen loading or unloading. (2009). 1999; Flint et al. 1993). The 2002; Trent and Hargrove 2002), in sharp contrast to the stringently tissue-specific expression pattern of hemoglobin and myoglobin genes. The δ-globin gene is present in almost all eutherian species examined, but it is frequently a pseudogene (Fig. One globin gene cluster is found in all gnathostomes examined; it is flanked on one side by the genes MPG and NPRL3 (Flint et al. 2000). (Thick gray lines) The major bifurcations 1987). of α-globin and β-globin. Before the divergence of the three major subclasses of mammals (monotremes, marsupials, and placentals), both the ζ-globin MB, CYGB, and NGB are present as single-copy genes, whereas HBB and HBAs are in clusters with multiple related genes. or adaptation. species examined make embryonic-specific hemoglobins in primitive erythroid cells derived from the yolk sac, some species Both monotremes and marsupials have two β-like globin genes. Models for evolution of hemoglobin gene complexes in jawed vertebrates. Fetal hemoglobin binds to oxygen more strongly than adult hemoglobin, enabling the transfer of oxygen from mother to fetus prenatally. genes into the DS locus in the stem amniote (Fig. Epub 2017 Apr 6. ! 2005; Ragoczy et al. 1996; Hardison 2000). Maps of orthologous β-like globin genes and expression timing in mammals. 2006; Bau et al. The concentration of 2,3-DPG varies among groups of mammals. A proposed cluster of five β-like globin genes, in the orientation 5′-ε-γ-η-δ-β-3′, in the stem eutherian is consistent with The MN locus now contains only α-globin genes in eutherians; it retained these and non-globin flanking genes since the gnathostome The “junction” sequence of the rabbit HBA cluster, associated with recombination breakpoints, is assigned to the μ position in this diagram, but it contains only a 1984; Hardison and Margot 1984; Song et al. These three nonglobin genes are in the same arrangement and order in the tetrapods Model for evolution of vertebrate globin genes. the γ-, η-, and δ-globin genes have been gained and lost frequently, sometimes in entire orders of mammals. Myoglobin (encoded by the MB gene) is a related, monomeric heme-bound globin protein found predominantly in skeletal and heart muscle. to erythroid cells. For instance, the major regulatory element (MRE) of the HBA gene complex is located distal to the adult HBA genes (∼60 kb upstream in human), residing in an intron of the large NPRL3 gene (Fig. 1992; Elnitski et al. It shows that the ε-globin genes have been stable over eutherian evolution, whereas Additional heme-containing globins were discovered by mining the wealth of information in the sequence of the human genome 1981; Wright et al. 2008), but it also could be from the LA locus (Hardison 2008). 1980; Karlsson and Nienhuis 1985). is used for frog and fish because the genes are less well characterized. expression changes that have occurred during eutherian evolution. studies has been to use the insights from the evolutionary analyses to better understand mechanisms of gene regulation. signaling from which could regulate mitochondrial respiration and protect tissues (nerves by NGB, heart muscle by MB) from clusters and in their timing of expression (Fig. the shuffling of exons during protein evolution (Gilbert 1978). In contrast, mammals who are experimentally subjected to low oxygen tensions develop decreased oxygen affinity owing to increased red cell 2,3-DPG. (Hardison et al. hemoglobins in primordial life (Hardison 1998, 1999; Tiso et al. Genes in brackets with a question mark could either be present in the LCA and lost in one or more descendant lineages, or The multiple, developmentally regulated genes in the gnathostome α-globin gene clusters are derived from a common ancestral No active γ-globin gene has been identified in Laurasiatherians, with the gene either being absent, (His) of the surrounding globin polypeptide. The θ-globin gene appears to have been generated by a duplication of an α-globin gene after the divergence of Mammals employ one of three different mechanisms for the maintenance of higher oxygen affinity of fetal red cells, compared to maternal red cells. are a fundamental approach to seek novel avenues to therapy. erythroid cells (Fig. Careers. In every case examined in sufficient detail, the δ-globin gene has been involved in a gene conversion, with sequence from The first preserved feature of vertebrate hemoglobin genes is their presence in multi-gene clusters. 1997b; Flint et al. 2004). 2005), but it has some limitations. Domain opening and synergism between HS2 and HS3, Linkage of adult α- and β-globin genes in, Fetal globin expression in New World monkeys, Humans and Old World monkeys have similar patterns of fetal globin expression, Cooperative activities of hematopoietic regulators recruit RNA polymerase II to a tissue-specific chromatin domain, Developmental regulation of human globin genes, The medaka draft genome and insights into vertebrate genome evolution, Genome-wide identification of TAL1’s functional targets: Insights into its mechanisms of action in primary erythroid cells, Evaluation of regulatory potential and conservation scores for detecting, ENCODE Groups for Transcriptional Regulation and Multispecies Sequence Analysis, Evolutionary and developmental aspects of two hemoglobin β-chain genes (εM and βM) of opossum, Initial sequencing and analysis of the human genome, Absence of special fetal hemoglobin in beagle dogs, Transcriptional and translational analysis of the human θ globin gene, The molecular genetics of human hemoglobins, Regulation of inducible and tissue-specific gene expression, Identification of DNA sequences required for transcription of the human α1-globin gene in a new SV40 host-vector system, Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription, Sequences flanking hypersensitive sites of the β-globin locus control region are required for synergistic enhancement, Conservation of the primary structure, organization, and function of the human and mouse β-globin locus-activating regions, An encyclopedia of mouse DNA elements (Mouse ENCODE), Fine structure genetic analysis of a β-globin promoter, Tandem AP-1-binding sites within the human β-globin dominant control region function as an inducible enhancer in erythroid Spatial organization of gene expression: The active chromatin hub, Protection by neuroglobin and cell-penetrating peptide-mediated delivery in vivo: A decade of research. 1968 Oct;23(11):1030-9. provide potential therapy (Tang et al. 1996), perhaps representing a transitional state intermediate between the fetal onset seen in most eutherians and the prenatal 1983). chromosomes. embraces both conservation and lineage-specific innovation (Hardison and Taylor 2012). but rather different losses and inactivations have occurred in the lineages to each species. the paralogous β-globin gene copied into the δ-globin gene locus (Spritz et al. indicating that an ancestral gene was present before the divergence of vertebrates and invertebrates more than 800 million are combinations of conserved and acquired features. cis-regulatory modules (CRMs), and signals for occupancy of TAL1, GATA1, and CTCF based on genome-wide ChIP-seq and the signal 5A,B). of an embryonic ε-globin gene, Long human–mouse sequence alignments reveal novel regulatory elements: A reason to sequence the mouse genome, Locus control regions of mammalian β-globin gene clusters: Combining phylogenetic analyses and experimental results to gain The number to the left All (D) The mouse β-globin gene (Hbb) cluster, showing chr7:110,932,001–111,067,000. globin for oxygen transport, but surprisingly, it is more closely related to CYGB than to the gnathostome hemoglobins (Fig. Genes are lost and gained in specific lineages (Hoffmann et al. suggests that the η-globin gene was lost in the LCA for Glires (Opazo et al. Physiologically, the nitrite reductase activity could provide a means to produce nitric oxide under hypoxic conditions, 8600 Rockville Pike 2). The factor occupancy and DNase sensitivity tracks show data from the human (ENCODE Project Consortium et al. related to β-globin, the ω-globin gene (Wheeler et al. The gene clusters are triplicated Pseudogenes are DNA segments β-globin locus, The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation, Revealing mammalian evolutionary relationships by comparative analysis of gene clusters, Complete nucleotide sequence of the human δ-globin gene, A comparison of adult and foetal horse haemoglobins, Embryonic ε and γ globin genes of a prosimian primate (, Concerted evolution led to high expression of a prosimian primate δ globin gene locus, A dominant control region from the human β-globin locus conferring integration site-independent gene expression, Restoration of the CCAAT box and insertion of the CACCC motif activate δ-globin gene expression, Human neuroglobin functions as a redox-regulated nitrite reductase, Looping and interaction between hypersensitive sites in the active β-globin locus, Triplication of a four-gene set during evolution of the goat β-globin locus produced three genes now expressed differentially PBDE, human peripheral blood-derived erythroblasts; Hemoglobin function in the vertebrates: an evolutionary model. Hemoglobin subunit beta, (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the HBB gene, which along with alpha globin (), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA). 5). Fetal hemoglobin: A special hemoglobin synthesized by the developing baby that has a higher affinity for oxygen which allows it to withdraw O 2 from the mother’s hemoglobin. In all jawed vertebrates, erythrocytes produced at distinct developmental stages contain different forms of hemoglobin. Results: We identified three hemoglobin switches in the life cycle of the sea lamprey. during development, A ubiquitously expressed human hexacoordinate hemoglobin, An erythroid-specific, developmental-stage-independent enhancer far upstream of the human “β-like globin” genes, Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1, Chromosome looping at the human α-globin locus is mediated via the major upstream regulatory element (HS-40), The human β-globin gene 3′ enhancer contains multiple binding sites for an erythroid-specific protein, Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence, Genome analysis of the platypus reveals unique signatures of evolution, Linkage of the β-like ω-globin gene to α-like globin genes in an Australian marsupial supports the chromosome duplication with sequences homologous to those of actively expressed globin genes, but they harbor mutations, such as frameshifts or chain Many of the distal CRMs interact in some manner, as shown by phenotypes of mutations (Bungert et al. (C) The human β-globin gene (HBB) cluster, showing chr11:5,218,001–5,353,000. The timing of expression is indicated by distinctive background shading as indicated in the legend. clusters suggest that cross-species evolutionary comparisons of genomic DNA could be effective for finding regulatory regions 1) (Hoffmann et al. The known CRMs are from King et al. Further work is needed to ascertain whether this cluster is linked to the MN locus (Fuchs et al. 2012). 2008a). the mammalian radiation, Hemoglobins from bacteria to man: Evolution of different patterns of gene expression, The evolution of hemoglobin: Studies of a very ancient protein suggest that changes in gene regulation are an important part the hemoglobins, revealing a rich history of gene duplications and losses as well as translocations. a homologous replacement of the mouse Hba gene complex with that of human (Wallace et al. or other respiratory organs to peripheral tissues that need the oxygen for efficient metabolism. 2003). 2001; Hughes et al. The timing of expression is based on multiple reports in the literature (Stockell et al. 2002) of assembled genomes of human (Lander et al. 2008) and automated determination of orthologs using a method that recognizes gene conversions (Song et al. in embryonic erythroid cells (Rohrbaugh and Hardison 1983; Whitelaw et al. 5A). Sizes of and spacing between genes are not to scale. The gene maps are not complete, nor are they to scale; the genes shown here were deletions, inactivations, and reactivations. A wide range of animals, vertebrate and invertebrate, use hemoglobins to transport oxygen, carrying it from lungs, gills, Major duplication events in globin gene evolution are noted along the tree, and time of origin of some major animal groups 1980; Rohrbaugh and Hardison 1983; Shapiro et al. 2003), and these globin genes were retained in fish but lost in tetrapods. clusters, either an ancestral developmental regulatory mechanism was enforced on the newly duplicated genes or the mechanism Privacy, Help (2005). Evolution of new physiologies, such as acclimation to high altitudes and fetal hemoglobin, is only a step or two away. for DNase hypersensitive sites (DHSs) based on genome-wide DNase-seq. of the evolutionary story, Conserved noncoding sequences are reliable guides to regulatory elements, Assignment of orthologous relationships among mammalian α-globin genes by examining flanking regions reveals a rapid rate stages is widespread in vertebrates and beyond, and studies of hemoglobin switching are pursued in several non-human species 2007), and comparisons of noncoding genomic DNA between human and fish have not been a rich resource for discovery of CRMs in 2003). 1984; Hardies et al. The genes are represented by boxes, with those above the line transcribed from left to right and those below the line in The α-like globins are paralogous, meaning that they are homologous genes generated by gene duplication. are expressed in fetal and adult erythroid cells (Fig. In marsupials the ε-globin ortholog is expressed in embryonic 1995). The Fetal Hemoglobin (HbF) Test is based on a monoclonal antibody directed to fetal hemoglobin (hemoglobin F). times of these duplications relative to speciation events, refer to figures in the primary references (Burmester et al. Science. 2004; Patel et al. (Koop and Goodman 1988; Opazo et al.