Stylianos E. Antonarakis, David N. Cooper, in Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics (Seventh Edition), 2019 6.4.17 Variants in Remote Gene Regulatory Elements. Patel VS, Cooper SJ, Deakin JE, Fulton B, Graves T, Warren WC, Wilson RK, Graves JA Bender MA, Mehaffey MG, Telling A, Hug B, Ley TJ, Groudine M, Fiering S The approach is most sensitive for finding CRMs under evolutionary constraint, and although this is true for many CRMs (Pennacchio et al. Frequently, the gene RHBDF1 is adjacent to the MPG gene. Human neuroglobin functions as a redox-regulated nitrite reductase. Spatial organization of gene expression: The active chromatin hub, Protection by neuroglobin and cell-penetrating peptide-mediated delivery in vivo: A decade of research. 1993). 2004. Johnson RM, Buck S, Chiu C, Schneider H, Sampaio I, Gage DA, Shen TL, Schneider MP, Muniz JA, Gumucio DL, et al. Beta thalassemia is an inherited blood disorder that limits your body's ability to make beta-globin. 2010; Soler et al. The multi-subunit hemoglobin binds oxygen cooperatively in the lungs, transports the oxygen through the blood, and releases it in peripheral tissues to support oxidative metabolism. 2001), and the locus can be called MN, the acronym for these two genes (Fig. Hardison R, Slightom JL, Gumucio DL, Goodman M, Stojanovic N, Miller W Bungert J, Dave U, Lim K-C, Kieuw KH, Shavit JA, Liu Q, Engel JD Many of the distal CRMs interact in some manner, as shown by phenotypes of mutations (Bungert et al. Detailed studies over the past three decades have led to the discovery of numerous CRMs in both the -globin gene (HBA) and -globin gene (HBB) clusters (Fig. Grosveld F, van Assendelft GB, Greaves D, Kollias G Understanding -globin gene regulation: Aiming to improve the management of thalassemia. Beta thalassemia is caused by mutations in the beta chain of the hemoglobin molecule. Some of the genes in the larger globin gene cluster in fish are expressed in larvae, and others are expressed in adults (Chan et al. 1990; Satoh et al. Anguita E, Hughes J, Heyworth C, Blobel GA, Wood WG, Higgs DR After the gamma to beta switch, this variety of hemolytic anemia ceases. The resulting excess of -chains bind oxygen poorly, leading to a low concentration of oxygen in tissues (hypoxemia). The conservation of intron position in vertebrate globin genes has been proposed to facilitate the shuffling of exons during protein evolution (Gilbert 1978). 2000b. This showed that some aspects of regulation differ between the two species, and further studies were pursued by engineering a homologous replacement of the mouse Hba gene complex with that of human (Wallace et al. 2006. 2006; Bau et al. . 2008), but no information is available currently on whether the leftmost -globin gene in platypus (in the orientation in Fig. Both proteins must be present for the hemoglobin to pick Evolutionary and developmental aspects of two hemoglobin -chain genes (M and M) of opossum. Hemoglobin Beta Chain. 1). One -globin gene is present on each copy of chromosome 11. [23] HbE has a very unstable - and -globin association. 2010. In marsupials the -globin ortholog is expressed in embryonic erythrocytes, whereas the -globin ortholog is expressed in fetal and adult erythroid cells (Koop and Goodman 1988). Stabilization of the transcription complex through LCRpromoter interactions, perhaps at transcription factories, is one mechanism for gene activation (Wijgerde et al. Johnson RM, Buck S, Chiu CH, Gage DA, Shen TL, Hendrickx AG, Gumucio DL, Goodman M 2003). Active chromatin hub of the mouse -globin locus forms in a transcription factory of clustered housekeeping genes, Cold Spring Harbor Perspectives in Medicine. Oxygen is loaded onto hemoglobin, transported, and unloaded with no chemical (covalent) change to either the oxygen or the heme groups, and the iron in the heme group stays in the reduced state. 1986; Antoniou et al. 2011. 1996, 2000; Satoh et al. Evolutionary strategies for the elucidation of. Proximity among distant regulatory elements at the -globin locus requires GATA-1 and FOG-1. 2004; Grass et al. 2000a; Anguita et al. Hemoglobin is made up of two different protein chains, the alpha and beta chains. 2006), a large fraction is species specific (King et al. 1990; Pondel et al. No globin genes have been mapped to the LA or DS loci in the current assembly of X. tropicalis, but one contig covers a cluster of -like globin genes linked to RHBDF1 (Fig. Specific treatment for beta thalassemia major or Cooley's anemia will be determined by your child's physician based on the following: Treatment for beta thalassemia may include: 3401 Civic Center Blvd. Goh SH, Lee YT, Bhanu NV, Cam MC, Desper R, Martin BM, Moharram R, Gherman RB, Miller JL Expression of -like and -like globin genes must be strictly coordinated. Inclusion in an NLM database does not imply endorsement of, or agreement with, Indeed, this can lead to important insights, such as the impact of differences in expression pattern of a key transcription factor driving a change in developmental timing of expression in humans. Zhou GL, Xin L, Song W, Di LJ, Liu G, Wu XS, Liu DP, Liang CC Hemoglobin is an oxygen-binding protein found in erythrocytes that transports oxygen from the lungs to tissues. 1984. Absence of beta chain causes beta-zero-thalassemia. [5], HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans. The MN locus now contains only -globin genes in eutherians; it retained these and non-globin flanking genes since the gnathostome LCA, while losing -globin genes in many vertebrate lineages. 1987; Talbot et al. The mouse -globin locus regulatory element. The medaka draft genome and insights into vertebrate genome evolution. Can the product of the gene be a real globin? Maniatis T, Goodbourn S, Fischer JA The gene clusters are triplicated in goats and duplicated in cows, indicated by the parentheses and subscripts. The LA locus has undergone dramatic losses or gains of globin genes. 4) is driven by interspecies differences in the expression of the transcription factor BCL11A, which is a repressor of -globin gene expression (Sankaran et al. Gumucio D, Shelton D, Zhu W, Millinoff D, Gray T, Bock J, Slightom J, Goodman M 1991). 2005; Ragoczy et al. 2008) or a gene duplication independent of the one that established therian -globin and -globin genes (Opazo et al. 2005. They are bound by key transcription factors active in erythroid cells, such as GATA1 and TAL1 (Johnson et al. It is related to invertebrate nerve globins, indicating that an ancestral gene was present before the divergence of vertebrates and invertebrates more than 800 million years ago (Fig. [21] This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic. 2003. Thalassemia includes a number of different forms of anemia. Organization, structure, and evolution of the nonadult rat -globin gene cluster, Structure and organization of the bovine -globin genes. Hemoglobin subunit beta (beta globin, -globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the HBB gene, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA). In contrast to placental mammals and chickens, which have only -like globin genes at the MN locus, the orthologous loci in the monotreme platypus and in marsupials have a set of -like globin genes plus a globin gene related to -globin, the -globin gene (Wheeler et al. The change in developmental timing of expression of -globin orthologs between mouse and human (Fig. Jeffreys AJ, Wilson V, Wood D, Simons JP, Kay RM, Williams JG Hemoglobins were originally discovered as abundant proteins in red blood cells of mammals and other jawed vertebrates (gnathostomes) that bind and release oxygen reversibly. [7][25] It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival. hemoglobin electrophoresis with A2 quantitation - a lab procedure that differentiates the types of hemoglobin present, Your child's age, overall health, and medical history, Your child's tolerance for specific medications, procedures, or therapies, Expectations for the course of the disease, Medications (to decrease amount of iron in the body, called chelation therapy), Possible surgical removal of the gallbladder, 2022 The Childrens Hospital of Philadelphia. 1996. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. 2002. 2008). 1989; Higgs et al. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF . However, intron positions differ considerably in globin genes outside vertebrates, suggesting that the conservation of intron position could simply reflect an ancestral state that has not changed over vertebrate evolution (Hardison 1998). 2) (Higgs et al. 2). [12], Beta thalassemia is an inherited genetic mutation in one (Beta thalassemia minor) or both (Beta thalassemia major) of the Beta globin alleles on chromosome 11. Strategies being pursued to reactivate -globin gene expression in adult erythroid cells, either pharmacologically or by gene therapy, in a sense are attempts to modulate expression patterns in humans that recapitulate expression changes that have occurred during eutherian evolution. The locus control region is required for association of the murine -globin locus with engaged transcription factories during erythroid maturation. The symbols and backgrounds are similar to those in Figure 3. 1980. Whitelaw E, Tsai SF, Hogben P, Orkin SH 2009; Yu et al. Complete nucleotide sequence of the human -globin gene. Ragoczy T, Bender MA, Telling A, Byron R, Groudine M Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W, et al. 1992. 2002). Its mRNA is abundant in brain tissue but also is present in many other tissues. 4). 5). Origin and ascendancy of a chimeric fusion gene: The /-globin gene of paenungulate mammals. Revealing mammalian evolutionary relationships by comparative analysis of gene clusters. Primary sequence and epigenetic determinants of in vivo occupancy of genomic DNA by GATA1. A few themes have emerged. Hemoglobins are produced only in erythroid cells, where they are the major protein. 1997b. Yu M, Riva L, Xie H, Schindler Y, Moran TB, Cheng Y, Yu D, Hardison R, Weiss MJ, Orkin SH, et al. [16], More than a thousand naturally occurring HBB variants have been discovered. 1990). Within the three major subclasses of mammals, the -like globin genes at the DS locus have been duplicated and lost in specific lineages (Fig. The unfolding story regarding how this arose during vertebrate evolution is dynamic and complex. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with fetal hemoglobin (HbF) makes up the remaining 3% of adult hemoglobin. Hemoglobin is made from two similar proteins that "stick together". Most contemporary mammals retain at least two copies of these genes (in some cases, they are pseudogenes). Exploration of these genes in many different species continues to illuminate some and challenge other evolutionary models. 2008. 2001), platypus (Warren et al. The number to the left of each cluster specifies the chromosome on which it is located; for the frog gene clusters, the scaffold identifier is given. 2011. 1990; Johnson et al. 2). 2005. Grass JA, Jing H, Kim SI, Martowicz ML, Pal S, Blobel GA, Bresnick EH Fish species show an interesting contrast, in that the gene cluster orthologous (homologous genes generated by a speciation event) to that of the mammalian -globin gene cluster contains both -like and -like globin genes (Fig. Before [17] The homozygous allele has become one of the deadliest genetic factors,[18] whereas people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia. -globin is made in embryonic red cells, and -globin is produced in fetal and adult red cells (Fig. 1987. This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position (6GluVal). Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of -thalassemia. Without medical treatment death often occurs before age 12. Hemoglobin Hasharon is due to an Asp47His mutation in the alpha globin gene (HBA1) and results in unstable binding with the gamma chain in the production of HbF. The human -globin gene contains multiple regulatory regions: Identification of one promoter and two downstream enhancers. This gene has the most consistent features across species of any of the paralogous -like globin genes. Beta thalassemia can cause you to experience anemia symptoms. All species examined within the therians (marsupial and placental mammals) have an ortholog of the -globin gene. Currently, this is the only example of an active -globin gene, but studies of expression in other Laurasiatherians would reveal whether it is active in other species, and if the timing of expression is embryonic. 2006. An official website of the United States government. Hemoglobin is a tetrameric molecule composed of two pairs of polypeptide subunits. 1). 1996). Species in an early diverging branch of vertebrates, the cyclostomes (represented by hagfish and lampreys), also use a heme-containing globin for oxygen transport, but surprisingly, it is more closely related to CYGB than to the gnathostome hemoglobins (Fig. 5A). Stockell A, Perutz MF, Muirhead H, Glauser SC Because differential regulation during development is a consistent property of these independently derived gene clusters, either an ancestral developmental regulatory mechanism was enforced on the newly duplicated genes or the mechanism evolved by convergence. The three-dimensional folding of the -globin gene domain reveals formation of chromatin globules. Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence. 1996, 2000). [20] HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (6GluLys). A vertebrate globin expressed in the brain. 2008a). Higgs DR, Garrick D, Anguita E, De Gobbi M, Hughes J, Muers M, Vernimmen D, Lower K, Law M, Argentaro A, et al. Thalassemia is a hemoglobinopathy that is among the most common inherited disorders of hemoglobin production. 2001). During the first 1 to 2 years of life, the child with thalassemia can be pale, fussy, have a poor appetite, and many infections. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin. [5] It is 147 amino acids long and has a molecular weight of 15,867 Da. Within each complex, the genes are all in the same 5'-3' orientation and are arranged in the order in which they are expressed during development. The presence of -like globin genes in the DS locus in amniotes but absence in both fish and amphibians is most easily explained by transposition of the -like globin genes into the DS locus in the stem amniote (Fig. Philadelphia, PA 19104, Know My Rights About Surprise Medical Bills. 2005. Looping and interaction between hypersensitive sites in the active -globin locus. This exquisite regulation is exerted, at least in part, by the binding of specific transcription factors to DNA sequences that serve as cis-regulatory modules (CRMs), such as promoters and enhancers (Maniatis et al. Some are located proximal to and within the genes, such as promoters and internal enhancers (Mellon et al. 4). Zhang Y, Wu W, Cheng Y, King DC, Harris RS, Taylor J, Chiaromonte F, Hardison RC Tang DC, Ebb D, Hardison RC, Rodgers GP 4). Hemoglobins are produced only in erythroid cells, where they are the major protein. Normal adult blood also contains 2.5% Hb A2 (composed of alpha and delta chains) and < 1.4% hemoglobin F (fetal hemoglobin), which . Identification of DNA sequences required for transcription of the human 1-globin gene in a new SV40 host-vector system. 2004), frog Xenopus tropicalis (Hellsten et al. One common interpretation is that the embryonic expression pattern was ancestral, and the recruitment to fetal expression was an adaptation in the anthropoids, coinciding with a duplication of the -globin gene (Johnson et al. Depending on the specific mutation present, the amount of beta globin produced may be reduced ( +) or absent ( 0 ). In vivo enhancer analysis of human conserved non-coding sequences, The LCR-like -globin positive regulatory element functions as an enhancer in transiently transfected cells during erythroid differentiation. The -globin genes of both the prosimian primate galago and species in order Glires (rabbit, mouse, and rat) are expressed in embryonic erythroid cells (Rohrbaugh and Hardison 1983; Whitelaw et al. Further work is needed to ascertain whether this cluster is linked to the MN locus (Fuchs et al. The -like globin gene cluster does show some dynamic features. Center for Comparative Genomics and Bioinformatics, Huck Institute of Genome Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802. Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W Maps of the gene clusters were derived from a combination of viewing annotations in the UCSC Genome Browser (Kent et al. Thalassemias are a heterogeneous grouping of genetic disorders that result from a decreased synthesis of alpha or beta chains of hemoglobin (Hb). Hemoglobin is the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. Two alpha chains plus two delta chains constitute HbA2, which with HbF comprises the remaining 3% of adult hemoglobin. 1980; Rohrbaugh and Hardison 1983; Shapiro et al. Concomitantly with the recruitment of -globin genes to fetal expression in anthropoid primates, the onset of expression of the -globin gene was delayed to shortly before birth in catarrhine primates (Old World monkeys, apes, and humans) (Johnson et al. 2012. 2010). Molecular mechanisms and physiological significance. 2008b; Patel et al. 2002. The regulation of human globin gene switching. The beta globin ( HBB) gene maps in the short arm of chromosome 11, in a region containing also the delta globin gene, the embryonic epsilon gene, the fetal A-gamma and G-gamma genes, and a. Both monotremes and marsupials have two -like globin genes. These three nonglobin genes are in the same arrangement and order in the tetrapods (human, platypus, chicken, and frog), but the LA locus is devoid of globin genes in these species. (Thick gray lines) The major bifurcations during evolution of the lineages exemplified by species at the top. One useful model for interpreting the differences in phylogenetic depth of preservation of CRMs is that those involved in core regulatory functions may be conserved across a wide group of species and show evidence of evolutionary constraint. 2009; Kassouf et al. Genome-wide identification of TAL1s functional targets: Insights into its mechanisms of action in primary erythroid cells. The severity and type of anemia depends upon the number of genes that are affected. 2008; Hardison and Taylor 2012). 1984; Myers et al. This article presents the multiple genes and gene families encoding human globins, summarizes major events in the evolution of the hemoglobin gene clusters, and discusses how these studies provide insights into regulation of globin genes. This work is supported by National Institutes of Health grants from NIDDK (R01 DK65806) and NHGRI (RC2 HG005573). The G-PCK-1 mRNA, which contains the entire 3-UTR of the PEPCK mRNA, was degraded with a half-life of 1.2 hours. Bender MA, Roach JN, Halow J, Close J, Alami R, Bouhassira EE, Groudine M, Fiering SN 1996; Molete et al. 2000). [6][7] At least 50 disease-causing mutations in this gene have been discovered. The gene maps are not complete, nor are they to scale; the genes shown here were chosen to illustrate logic for the proposed ancestral arrangements and transpositions in two clades. 2001. Beta thalassemia major occurs when a person inherits two abnormal alleles. These strong enhancers could be a key component of the distal regulatory structure, perhaps an active chromatin hub. Sickle cell disease (SCD) is a structural and monogenetic genetic disorder due to a mutation that occurs in the globin -chain, resulting in the formation of hemoglobin S (Hb S), a protein composed of two normal, and two -type mutant chains. Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, Steinhoff HJ, Goedecke A, Schrader J, Gladwin MT, et al. Thalassemia is an inherited disorder that affects the production of normal hemoglobin (a type of protein in red blood cells that carries oxygen to the tissues of the body). In adults, hemoglobin consists of four protein subunits: usually two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA. [13] Beta thalassemia major can be treated by lifelong blood transfusions or bone marrow transplantation. Furthermore, the timing of expression can change dramatically between clades, notably the delay in -globin (fetal) and -globin (adult) gene expression in anthropoid primates. 1999; Patel et al. As a curiosity, the same mutation was also associated to a decrease in serum LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes. 1995; Jackson et al. If the body does not manufac Fetal hemoglobin (HbF) is the dominant form of hemoglobin present in the fetus during gestation. 1983. 2005). Ney P, Sorrentino B, McDonagh K, Nienhuis A 2010; Wilson et al. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition. 4). (HbA), contains two alpha and two beta subunits. Oleksiewicz U, Liloglou T, Field JK, Xinarianos G In summary, the history of the gene clusters encoding hemoglobins is dynamic and complex. The orientation of the gene clusters is the reverse of the genome assembly in panels C and D, so that globin genes in all panels are arranged with transcription from left to right. The -thalassemias are more important in terms of patient suffering and expense than the -thalassemias. Several additional CRMs are present around the MRE (Anguita et al. 2006; Vernimmen et al. 1980. Hemoglobin gene expression is restricted to erythroid cells. The protein CTCF is bound at specific sites in the gene clusters, some of which serve as insulators that localize the effects of distal enhancers on target genes (Bulger et al. A cluster of CRMs called the locus control region (LCR) is found 5070 kb upstream of the HBB gene (Grosveld et al. 1988; Leung et al. 1961) and dog (LeCrone 1970), and based on the absence of evidence for a fetal-specific hemoglobin, the -globin homologs are predicted to be expressed embryonically in Figure 4. Activation of globin genes and other erythroid genes occurs with relocation of the chromatin domain to transcriptionally active regions of the nucleus (Schubeler et al. The most common is HbS, which causes sickle cell disease. For other uses, see, positive regulation of nitric oxide biosynthetic process, GRCh38: Ensembl release 89: ENSG00000244734, GRCm38: Ensembl release 89: ENSMUSG00000073940, "Natural selection: uncovering mechanisms of evolutionary adaptation to infectious disease", "How malaria has affected the human genome and what human genetics can teach us about malaria", "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases", "The human beta-globin locus control region", "Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers", "Hemoglobin variants: biochemical properties and clinical correlates", "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010", "The distribution of haemoglobin C and its prevalence in newborns in Africa", "Hb E/beta-thalassaemia: a common & clinically diverse disorder", "Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe, 10.1182/blood.V100.4.1172.h81602001172_1172_1176, "A review of the molecular genetics of the human alpha-globin gene cluster", "A 65 bp duplication/insertion in exon II of the beta globin gene causing beta0-thalassemia", https://en.wikipedia.org/w/index.php?title=Hemoglobin_subunit_beta&oldid=1119685291, Overview of all the structural information available in the, This page was last edited on 2 November 2022, at 21:52. 1981; Wright et al. In contrast, some of the other distal CRMs are present only in mouse, such as the one in the first intron of Nrpl3 and the most distal CRM in the Hbb LCR (Fig. 1987; Talbot et al. Tandem AP-1-binding sites within the human -globin dominant control region function as an inducible enhancer in erythroid cells. Human -globin locus control region: Analysis of the 5 DNaseI hypersensitive site HS2 in transgenic mice. Maps of orthologous -like globin genes and expression timing in amniotes. Beta thalassemia minor results in a mild microcytic anemia that is often asymptomatic or may cause fatigue and or pale skin. The diversity of hemoglobins, their critical functions, their exquisite regulation, and the pathological consequences of some mutations make this a fascinating family of proteins and genes. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. 1988. [10][11] The interaction is two-fold. Beta thalassemia is caused by mutations in the beta chain of the hemoglobin molecule. 1993. Hb beta chain-related hemoglobinopathies are a group of inherited blood disorders that affect hemoglobin, a major component of red blood cells that are responsible for carrying oxygen throughout the body. Gene clusters in contemporary species are diagrammed at the top of the figure, and inferred gene arrangements in the last common ancestor to jawed vertebrates are diagrammed at the bottom. 1997). 1989; Whitelaw et al. : TAT-mediated delivery of neuroglobin protects against focal cerebral ischemia in mice. 2008). Each gene is shown as a rectangle, colored by the orthology relationship to the human genes, labeled by the Greek letters at the top. It has long been described as an oxygen storage protein, and it facilitates diffusion of oxygen to the mitochondria (Wittenberg and Wittenberg 1987). Structure and expression of the human 1 globin gene. The human alpha globin gene cluster is located on chromosome 16 and spans about 30 kb, including seven alpha like globin genes and . 2002; Trent and Hargrove 2002), in sharp contrast to the stringently tissue-specific expression pattern of hemoglobin and myoglobin genes. Chan F, Robinson J, Brownlie A, Shivdasani R, Donovan A, Brugnara C, Kim J, Lau B, Witkowska H, Zon L 1996), perhaps representing a transitional state intermediate between the fetal onset seen in most eutherians and the prenatal onset observed in humans. Evaluation of regulatory potential and conservation scores for detecting. Embryonic and globin genes of a prosimian primate (. ENCODE Project Consortium, Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, Gingeras TR, Kent WJ, Birney E, et al. Linkage of adult - and -globin genes in. 1993). Slide 6: 2008a,b; Hoffmann et al. 2007). 1988. -like globin genes were acquired at the DS locus in the stem amniote, and subsequently they duplicated and acquired differential developmental expression independently in the avian and mammalian lineages. Among its related pathways are Innate Immune System and Erythrocytes take up carbon dioxide and release oxygen . 1), is found in many tissues (Burmester et al. Given the presence of globin genes at this locus in all gnathostomes examined, one can infer with considerable confidence that the MN locus contained globin genes in the last common ancestor (LCA) of vertebrates (Fig. In human, the HBB gene is located on chromosome 11 at position p15.5. The molecular genetics of human hemoglobins. Forrester WC, Thompson C, Elder JT, Groudine M The major hemoglobin in adult humans, hemoglobin A, is a heterotetramer composed of two -globin and two -globin polypeptides, each with an associated heme group. 2006. Extensive phylogenetic comparisons indicate that this gene cluster in the LCA of tetrapods contained orthologs to -globin, -globin (also called D), and -globin (or A) genes (Hoffmann and Storz 2007; Hoffmann et al. [22], Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (26GluLys), leads to the formation of haemoglobin E (HbE). These could contribute to functional differences between the species, perhaps by modifying the distal regulatory structure. Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, et al. 2001; Hughes et al. Regulation of inducible and tissue-specific gene expression. Many people are given iron replacement under the mistaken belief that their anemia is the iron-deficient type. Thalassemia major patients require lifelong blood transfusions, require close monitoring for complications, and treatment or iron overload (from chronic blood transfusions). Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudine M, Bender MA, et al. 2000b, 2001). Schoenfelder S, Sexton T, Chakalova L, Cope NF, Horton A, Andrews S, Kurukuti S, Mitchell JA, Umlauf D, Dimitrova DS, et al. Gillemans N, McMorrow T, Tewari R, Wai AW, Burgtorf C, Drabek D, Ventress N, Langeveld A, Higgs D, Tan-Un K, et al. In all species examined, including birds, the active orthologs to the -globin gene are expressed in embryonic erythroid cells, and the orthologs of the -globin gene are expressed in fetal and adult erythroid cells (Fig. 1989; Moon and Ley 1990) in human and mouse (Fig. Gene ID: 3043, updated on 20-Feb-2023 Summary The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. 1991; Milot et al. 2009. 2003). 5), and interspecies DNA alignments show that both are preserved across mammals and have been under strong constraint (Elnitski et al. 1995. The beta-like gene cluster is located on the short arm of chromosome 11, and contains five functional genes (, , G, A, and ) and one pseudogene. 2002; Tolhuis et al. Cytoglobin, encoded by the CYGB gene (Fig. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria. The known CRMs are from Hughes et al. 1990; Bender et al. 2001). Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the globin cluster. Beta-globin is an important protein needed to make hemoglobin and red blood cells. Genes in the - and -globin lineage are located to the right in the gene clusters and, if active, are expressed in fetal and/or adult erythroid cells. The timing of expression is based on multiple reports in the literature (Stockell et al. 2004. The converse posits that the globin genes were not present at the LA locus of the LCA, but moved into it during the lineage to fish. 2010). 2009; Fujiwara et al. The .gov means its official. 1984; Hardison and Margot 1984; Song et al. Bethesda, MD 20894, Web Policies This suggests that the oxygen transport function of heme-containing globins arose by independent, convergent evolution in the two major branches of vertebrates. (A) The human -globin gene (HBA) cluster, showing chr16:125,001250,000. official website and that any information you provide is encrypted It shows that the -globin genes have been stable over eutherian evolution, whereas the -, -, and -globin genes have been gained and lost frequently, sometimes in entire orders of mammals. Sickle cell disease is a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. Model for evolution of vertebrate globin genes. 2006) or if they are on different chromosomes. Conservation of sequence and structure flanking the mouse and human -globin loci: The -globin genes are embedded within an array of odorant receptor genes. In the -globin gene cluster, a regulatory region 10 kb upstream of the -globin (HBE) gene has been identified that is capable of directing a high level of position-independent -globin gene . These are encoded by the duplicated HBA1 and HBA2 genes and by the HBB gene, respectively (Fig. Genes in the -, -, and -globin gene lineage are toward the left in the gene clusters and are expressed in embryonic erythroid cells, except for the -globin genes in anthropoid primates, which were coopted for fetal-specific expression. Initial sequencing and analysis of the human genome, Absence of special fetal hemoglobin in beagle dogs, Transcriptional and translational analysis of the human globin gene. . 2008). 2007), and from recent publications (Fuchs et al. Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury, A gradient of sequence divergence in the human adult -globin duplication units. Bulger M, Schubeler D, Bender MA, Hamilton J, Farrell CM, Hardison RC, Groudine M [9] The normal allelic variant is 1600 base pairs (bp) long and contains three exons. Beta thalassemia major is a severe medical condition. 1984; Hardies et al. 4) (Johnson et al. Allosteric regulation and temperature dependence of oxygen binding in human neuroglobin and cytoglobin. Strong enhancers (MRE in the HBA clusters and HS2 in the HBB clusters) and adult globin gene promoters are in gold, and groups of distal CRMs (such as the LCR) are in tan. [24], Malaria due to Plasmodium falciparum is a major selective factor in human evolution. Kassouf MT, Hughes JR, Taylor S, McGowan SJ, Soneji S, Green AL, Vyas P, Porcher C How these genes are altered determines the specific type of beta thalassemia in a child: Persons with thalassemia minor have a 50/50 chance of passing the gene to their offspring, who would also have thal minor. Beta thalassemia major - both (two) beta chain genes have deletions, causing the most severe type of beta thalassemia. The sixth coordination site is bound reversibly by oxygen. Hemoglobinis a protein that is carried by red cells. Talbot D, Collis P, Antoniou M, Vidal M, Grosveld F, Greaves DR FOIA Combinatorial transcriptional control in blood stem/progenitor cells: Genome-wide analysis of ten major transcriptional regulators, Myoglobin-mediated oxygen delivery to mitochondria of isolated cardiac myocytes. Maniatis T, Fritsch EF, Lauer J, Lawn RM A wide range of animals, vertebrate and invertebrate, use hemoglobins to transport oxygen, carrying it from lungs, gills, or other respiratory organs to peripheral tissues that need the oxygen for efficient metabolism. Times of major separations used in creation of the figure are taken from TimeTree (Hedges et al. Targeted deletion of 5HS1 and 5HS4 of the -globin locus control region reveals additive activity of the DNaseI hypersensitive sites. The timing of expression is indicated by distinctive background shading as indicated in the legend. The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. 1996). Hsu S, Marks J, Shaw J, Tam M, Higgs D, Shen C, Shen C 1995. Thalassemias are a common cause of hypochromic microcytic anemia which arises from the reduced or absent synthesis of the globin chain of hemoglobin. 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 the transposition model. -globin genes are also present in Afrotherians, but the developmental timing of their expression has not been reported. In most eutherian species, the -globin gene is expressed in fetal and adult erythroid cells (Fig. Nuclear localization and histone acetylation: A pathway for chromatin opening and transcriptional activation of the human -globin locus. Wallace HA, Marques-Kranc F, Richardson M, Luna-Crespo F, Sharpe JA, Hughes J, Wood WG, Higgs DR, Smith AJ As previously mentioned, in sickle-cell anemia, the gene for beta globin is mutated. 1997b; Flint et al. Accessibility 2004) both in human and mouse (Fig. Position-independent, high-level expression of the human -globin gene in transgenic mice. The Greek letter name is specified for hemoglobin genes in human, platypus, and chicken, but generic -globin or -globin is used for frog and fish because the genes are less well characterized. Genes diagnostic for a particular genomic region can be found flanking hemoglobin gene clusters (Bulger et al. Maps of orthologous -like globin genes and expression timing in mammals. 2005; Cooper et al. 2004). Platypus globin genes and flanking loci suggest a new insertional model for -globin evolution in birds and mammals. Mutant beta globin causes sickle cell anemia. -thalassemia is a hereditary hematological disease caused by over 350 mutations in the -globin gene (HBB). The separation of -like and -like globin gene clusters in amniotes requires coordination of expression between different chromosomes. sharing sensitive information, make sure youre on a federal 2). Song G, Riemer C, Dickins B, Kim HL, Zhang L, Zhang Y, Hsu CH, Hardison RC, NISC Comparative Sequencing Program, Green ED, et al. Vyas P, Vickers MA, Simmons DL, Ayyub H, Craddock CF, Higgs DR This implies that the -like globin gene clusters were generated by independent gene duplications in the bird and mammal lineages. 2005), but it has some limitations. Goodman M, Koop BF, Czelusniak J, Weiss ML HbC provides near full protection against Plasmodium falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals. 2). Both the -globin genes in platypus are expressed in adults (Patel et al. There is one beta chain gene on each #11 chromosome, for a total of two. 1999; Patel et al. 3) (Higgs et al. Carter D, Chakalova L, Osborne CS, Dai YF, Fraser P Both these hexacoordinate heme globins have been implicated in nitric oxide metabolism, with CYGB showing nitric oxide dioxygenase activity, converting nitric oxide to nitrate (Oleksiewicz et al. 1996. GeneCards Summary for HBB Gene. A dominant control region from the human -globin locus conferring integration site-independent gene expression. Jackson JD, Petrykowska H, Philipsen S, Miller W, Hardison R Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the -globin genotype provides some prediction of disease severity for -thalassemia. 2002; Anguita et al. 2). [26] People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Each hemoglobin molecule is a tetramer made of four polypeptide globin chains. Kasahara M, Naruse K, Sasaki S, Nakatani Y, Qu W, Ahsan B, Yamada T, Nagayasu Y, Doi K, Kasai Y, et al. Bourque G, Leong B, Vega VB, Chen X, Lee YL, Srinivasan KG, Chew JL, Ruan Y, Wei CL, Ng HH, et al. 2006). 2007. 1986. The assignments of orthologous relationships are based on grouping within phylogenetic comparisons of coding sequences (Koop and Goodman 1988; Opazo et al. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al. Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M 2007. Grosveld F, Antoniou M, Berry M, de Boer E, Dillon N, Ellis J, Fraser P, Hanscombe O, Hurst J, Imam A, et al. 2001. Genome analysis of the platypus reveals unique signatures of evolution. 2002; Opazo et al. Comparative analyses continue to be a rich source of insights, but they must be performed in a context that embraces both conservation and lineage-specific innovation (Hardison and Taylor 2012). Comment on Cai et al. 1990). 1996. Models for evolution of hemoglobin gene complexes in jawed vertebrates. Hence this locus can be called DS (Fig. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains. Editors: David Weatherall, Alan N. Schechter, and David G. Nathan, Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org, National Library of Medicine In people with beta thalassemia, low levels of hemoglobin reduce oxygen levels in the body. Signs and symptoms of sickle cell disease . Bender MA, Bulger M, Close J, Groudine M 1984. Heme synthesis occurs in both the cytosol and the . Thal minor is further divided into thalassemia minima (a person has little to no symptoms) and thalassemia intermedia (a person has moderate to severe anemia). government site. Before the divergence of the three major subclasses of mammals (monotremes, marsupials, and placentals), both the -globin and -globin genes duplicated. Fortunately, the treatment for thalassemia has improved greatly and outcomes are improved. Locus control regions of mammalian -globin gene clusters: Combining phylogenetic analyses and experimental results to gain functional insights, TimeTree: A public knowledge-base of divergence times among organisms. The multiple, developmentally regulated genes in the gnathostome -globin gene clusters are derived from a common ancestral gene cluster (Flint et al. in the lungs and delivers it to the peripheral tissues to maintain the viability of cells. 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. As a library, NLM provides access to scientific literature. The CRMs found in one or a limited range of species could be involved in fine-tuning those core regulatory processes, perhaps helping that species adapt to a unique niche. The evolutionary comparisons summarized here illustrate the power of this approach, but they also remind us that such studies are best done while embracing both interspecies conservation of some elements and lineage-specific changes for others. Stylianos E. Antonarakis, David N. Cooper, in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013. 1988; Wall et al. 2002; Vakoc et al. Opazo JC, Sloan AM, Campbell KL, Storz JF Tagle D, Slightom J, Jones R, Goodman M 2002. The relative similarities among orthologous genes indicate that this gene cluster was formed by a series of duplications, first to make the ancestor to - and -globin genes and the ancestor to -, -, and -globin genes, followed by duplications to generate the proposed five-gene cluster (Hardison and Miller 1993). Myoglobin (encoded by the MB gene) is a related, monomeric heme-bound globin protein found predominantly in skeletal and heart muscle. 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