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Cited by 217Hemoglobin structure and functionHemoglobinopathies and Related DisordersChromosomal and Genetic Variations

Evolution of Hemoglobin and Its Genes

Open access
Hardison, R. C.·2012·Cold Spring Harbor Perspectives in Medicine
DOI 10.1101/cshperspect.a011627PMC PMC3543078
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Abstract

Insights into the evolution of hemoglobins and their genes are an abundant source of ideas regarding hemoglobin function and regulation of globin gene expression. 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. Although the genes in and around the α-like globin gene complex are relatively stable, the β-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions. The cis-regulatory modules controlling levels and timing of gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the evolution of vertebrate hemoglobin genes, emphasizing a relatively stable alpha-like globin cluster and more dynamic beta-like clusters shaped by transposition, lineage-specific duplications, losses, and changes in developmental expression. It argues that globin cis-regulatory modules combine deeply conserved core elements with lineage-specific fine-tuning, with implications for understanding globin gene regulation and hemoglobinopathies.

Key findings

  • Humans have five basic globin types encoded on five chromosomes: HBA1/HBA2 at 16p13.3, HBB at 11p15.4, MB at 22q12.3, CYGB at 17q25.1, and NGB at 14q24.3; adult hemoglobin A is an α2β2 heterotetramer, while MB, CYGB, and NGB are single-copy genes and HBB/HBAs are clustered.
  • The alpha-like globin gene cluster at the MN locus is relatively stable across gnathostomes, whereas beta-like globin genes at the DS locus in amniotes likely arose by transposition in the stem amniote and show frequent lineage-specific expansions and deletions; a proposed stem eutherian cluster is 5’-epsilon-gamma-eta-delta-beta-3’.
  • Developmental expression is progressive: zeta-globin is embryonic and alpha-globin fetal/adult; epsilon-globin is embryonic and the most stable beta-like paralog, while gamma-globin is fetal in anthropoid primates but embryonic in prosimians and Glires, and delta/beta are fetal/adult.
  • Regulatory control involves distal CRMs such as the HBA major regulatory element about 60 kb upstream in an NPRL3 intron and the HBB locus control region 50–70 kb upstream; these include conserved and species-specific elements, and BCL11A expression differences contribute to mouse–human gamma-globin timing differences.

Methods

  • Narrative comparative review/chapter synthesizing published molecular, genomic, phylogenetic, and regulatory studies across vertebrates and eutherian mammals; no new experimental data are presented.
  • Uses genome assemblies, gene maps, and flanking diagnostic genes—MPG/NPRL3 for the MN locus, LCMT1/AQP8 for the LA locus, and DCHS1/STIM1 for the DS locus—to infer globin gene cluster evolution.
  • Main analysis is qualitative synthesis of gene duplication, loss, transposition, conversion, and cis-regulatory conservation/divergence.

Limitations

  • The paper states that comparative CRM discovery is most sensitive for CRMs under evolutionary constraint; many CRMs are species-specific, only a small fraction are preserved throughout vertebrate evolution, and human–fish noncoding comparisons have not been a rich resource for globin CRMs. It also notes that critical regulatory aspects can differ even between mouse and human, such as phenotypes of homologous HBA distal MRE deletions.
  • The paper identifies unresolved or unknown points: the linkage of a Xenopus tropicalis beta-like globin cluster to the MN locus is uncertain; no information is available on whether the left-most platypus beta-globin gene is expressed embryonically; Afrotherian gamma-globin developmental timing has not been reported; eta-globin expression in other Laurasiatherians is unknown; and models for the LA locus remain alternative possibilities.
  • Evident from the text: as a review, conclusions depend on cited literature and available genome assemblies, with no primary validation, and some evolutionary models—such as the origin of LA-locus globin genes and the source of beta-like globin genes—remain unresolved.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a011627

Cites

153 of 153 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 101 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The beta-like globin genes in mammals are more similar to each other than they are to the multiple beta-like globin genes in birds.

    “However, the beta-like globin genes in mammals are more similar to each other than they are to the multiple beta-like globin genes in birds (Hardison and Miller 1993; Reitman et al. 1993).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hardison and Miller 1993

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    • cites Reitman et al. 1993

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  • Findingown data

    Some 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.

    “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. 5)”
    Quote in the paperNot a substantial claim
  • Premisecitation

    In all jawed vertebrates, erythrocytes produced at distinct developmental stages contain different forms of hemoglobin.

    “In all jawed vertebrates, erythrocytes produced at distinct developmental stages contain different forms of hemoglobin.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Maniatis et al. 1980

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    • cites Karlsson and Nienhuis 1985

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  • Premisecitation

    In cyclostomes, the heme-containing globin used for oxygen transport is more closely related to cytoglobin than to gnathostome hemoglobins.

    “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 (Hoffmann et al. 2010) (Fig. 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hoffmann et al. 2010

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  • Premisenone given

    In contrast to the pentacoordinate heme complex in hemoglobins and myoglobin, heme forms a hexacoordinate complex with both neuroglobin and cytoglobin, having two His residues coordinated with the Fe.

    “In contrast to the pentacoordinate heme complex in hemoglobins and MB, heme forms a hexacoordinate complex with both NGB and CYGB, having two His residues, termed proximal and distal, coordinated with the Fe.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 55
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingnone given

    No globin genes have been mapped to the LA or DS loci in the current assembly of Xenopus tropicalis, but one contig covers a cluster of beta-like globin genes linked to RHBDF1.

    “No globin genes have been mapped to the LA or DS loci in the current assembly of Xenopus tropicalis, but one contig covers a cluster of beta-like globin genes linked to RHBDF1 (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The two beta-globin genes in platypus are more similar to each other than to other beta-like globin genes, consistent with either a gene conversion event or a gene duplication independent of the one that established therian epsilon-globin and beta-globin genes.

    “The two beta-globin genes in platypus are more similar to each other than to other beta-like globin genes, consistent with either a gene conversion event (Patel et al. 2008) or a gene duplication independent of the one that established therian epsilon-globin and beta-globin genes (Opazo et al. 2008b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Patel et al. 2008

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    • cites Opazo et al. 2008b

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  • May combine two claims.

    Findingnone given

    The full set of five beta-like globin genes is not utilized in any extant mammal examined; at least one pseudogene is found in this gene cluster for almost every eutherian species.

    “The full set of five beta-like globin genes is not utilized in any extant mammal examined. At least one pseudogene is found in this gene cluster for almost every eutherian species (Fig. 4), and any exceptions to this could reflect a lack of detailed characterization of the genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Both the HBA and HBB gene complexes have strong distal enhancers.

    “Both the HBA and HBB gene complexes have such enhancers (Fig. 5)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The genes in and around the alpha-like globin gene complex are relatively stable, whereas the beta-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions.

    “While the genes in and around the alpha-like globin gene complex are relatively stable, the beta-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The five types of globin genes are located on five different chromosomes: HBA1 and HBA2 at 16p13.3, HBB at 11p15.4, MB at 22q12.3, CYGB at 17q25.1, and NGB at 14q24.3.

    “The five types of globin genes listed in Fig. 1 are located on five different chromosomes: HBA1 and HBA2 at chromosomal position 16p13.3, HBB at 11p15.4, MB at 22q12.3, CYGB at 17q25.1, and NGB at 14q24.3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    All species examined make embryonic-specific hemoglobins in primitive erythroid cells derived from the yolk sac, some species make a fetal-specific form in the liver, and all species produce an adult hemoglobin in erythroid cells produced in the bone marrow.

    “All species examined make embryonic-specific hemoglobins in primitive erythroid cells derived from the yolk sac, some species make a fetal-specific form in the liver, and all species produce an “adult” hemoglobin in erythroid cells produced in the bone marrow (Maniatis et al. 1980; Karlsson and Nienhuis 1985).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Maniatis et al. 1980

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    • cites Karlsson and Nienhuis 1985

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  • May combine two claims.

    Premisecitation

    In humans, epsilon-globin is made in embryonic erythrocytes, gamma-globins are produced in fetal liver erythroid cells, and delta- and beta-globins are made in erythroid cells from adult bone marrow.

    “In humans, epsilon-globin is made in embryonic erythrocytes, gamma-globins are produced in fetal liver erythroid cells, and the delta- and beta-globins are made in erythroid cells from adult bone marrow (Grosveld et al. 1993).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grosveld et al. 1993

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  • May combine two claims.

    Premisecitation

    Neuroglobin, encoded by NGB, is the most distantly related globin found in the human genome; its mRNA is abundant in brain tissue but also present in many other tissues.

    “The most distantly related globin found in the human genome is neuroglobin, encoded by NGB (Burmester et al. 2000). Its mRNA is abundant in brain tissue but also is present in many other tissues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Burmester et al. 2000

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Myoglobin is a monomeric heme-bound globin protein found predominantly in skeletal and heart muscle, encoded by MB, and it facilitates diffusion of oxygen to mitochondria.

    “Myoglobin (encoded by the MB gene) is a related, monomeric heme-bound globin protein found predominantly in skeletal and heart muscle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wittenberg and Wittenberg 1987

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  • May combine two claims.

    Interpretationcitation

    Neuroglobin is related to invertebrate nerve globins, indicating that an ancestral gene was present prior to the divergence of vertebrates and invertebrates over 800 million years ago.

    “It is related to invertebrate nerve globins, indicating that an ancestral gene was present prior to the divergence of vertebrates and invertebrates over 800 million years ago (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Burmester et al. 2000

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Intron positions differ considerably in globin genes outside vertebrates, suggesting that the conservation of intron position in vertebrate globin genes could simply reflect an ancestral state that has not changed over vertebrate evolution.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hardison 1998

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  • May combine two claims.

    Premisenone given

    All globin genes consist of at least three exons separated by two introns; introns differ dramatically in size but are in homologous locations, and CYGB and NGB each have an additional exon.

    “All the genes consist of at least three exons separated by two introns. While the introns differ dramatically in size, they are in homologous locations. The CYGB and NGB genes each have an additional exon.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    MB, CYGB and NGB are present as single-copy genes whereas HBB and HBAs are in clusters with multiple related genes.

    “MB, CYGB and NGB are present as single-copy genes whereas HBB and HBAs are in clusters with multiple related genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both hexacoordinate heme globins have been implicated in nitric oxide metabolism, with cytoglobin showing nitric oxide dioxygenase activity converting nitric oxide to nitrate, and neuroglobin showing nitrite reductase activity to form nitric oxide.

    “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. 2011), and NGB showing nitrite reductase activity to form nitric oxide (Tiso et al. 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Oleksiewicz et al. 2011

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    • cites Tiso et al. 2011

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  • May combine two claims.

    Premisecitation

    Cytoglobin, encoded by CYGB, is found in many tissues, in contrast to the stringently tissue-specific expression pattern of hemoglobin and myoglobin genes.

    “Cytoglobin, encoded by the CYGB gene (Fig. 1), is found in many tissues (Burmester et al. 2002; Trent and Hargrove 2002), in sharp contrast to the stringently tissue-specific expression pattern of hemoglobin and myoglobin genes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Burmester et al. 2002

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    • cites Trent and Hargrove 2002

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  • May combine two claims.

    Interpretationnone given

    The hemoglobins produced at distinct developmental stages have different affinities for oxygen and are subject to complex regulation by cofactors, favoring an overall movement of oxygen from the maternal bloodstream to that of the fetus or embryo.

    “The hemoglobins produced at distinct developmental stages have different affinities for oxygen and are subject to complex regulation by cofactors, favoring an overall movement of oxygen from the maternal bloodstream to that of the fetus or embryo.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The cis-regulatory modules controlling levels and timing of globin gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals.

    “The cis-regulatory modules controlling levels and timing of gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In fish, the gene cluster orthologous to the mammalian alpha-globin gene cluster contains both alpha-like and beta-like globin genes, and some genes are expressed in larvae and others in adults.

    “Fish species show an interesting contrast, in that the gene cluster orthologous (homologous genes generated by a speciation event) to that of the mammalian alpha-globin gene cluster contains both alpha-like and beta-like globin genes (Fig. 2). 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. 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chan et al. 1997

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  • May combine two claims.

    Premisenone given

    The three non-globin genes LCMT1, AQP8, and ARHGAP17 are in the same arrangement and order in tetrapods (human, platypus, chicken and frog), but the LA locus is devoid of globin genes in these species.

    “These three non-globin 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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Within the fish globin gene cluster, genes are regulated coordinately (balancing alpha-globin and beta-globin synthesis) and differentially during development (larval vs. adult).

    “Thus within this fish globin gene cluster, genes are regulated coordinately (balancing alpha-globin and beta-globin synthesis) and differentially during development (larval vs. adult).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A second locus contains alpha- and beta-globin genes in the pufferfish Fugu rubripes, and examination of genome assemblies of zebrafish and Medaka shows a similar arrangement; the globin genes are flanked by LCMT1 and AQP8, and the locus can be called LA.

    “A second locus contains alpha- and beta-globin genes in the pufferfish Fugu rubripes (Gillemans et al. 2003), and examination of the genome assemblies of zebrafish and Medaka shows a similar arrangement (Fig. 2). The globin genes in this locus are flanked by the genes LCMT1 and AQP8, and the locus can be called “LA”.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gillemans et al. 2003

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  • May combine two claims.

    Premisecitation

    Expression of alpha-like and beta-like globin genes must be strictly coordinated; balanced production of alpha-globin and beta-globin in erythroid cells is required for efficient formation of hemoglobin, and an imbalance leads to thalassemias.

    “Expression of alpha-like and beta-like globin genes must be strictly coordinated. A balanced production of alpha-globin and beta-globin in erythroid cells is required for the efficient formation of hemoglobin, and an imbalance leads to the pathological phenotypes of inherited anemias called thalassemias (Weatherall and Clegg 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Weatherall and Clegg 2001

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  • May combine two claims.

    Premisecitation

    One globin gene cluster is found in all gnathostomes examined; it is flanked on one side by MPG and NPRL3, and the locus can be called MN.

    “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. 2001), and the locus can be called “MN”, the acronym for these two genes (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Flint et al. 2001

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  • May combine two claims.

    Premisenone given

    Differential expression of paralogous globin genes within a cluster and coordinated regulation between gene clusters on different chromosomes are consistent properties in amniotes.

    “As just discussed, differential expression of paralogous globin genes within a cluster and coordinated regulation between gene clusters on different chromosomes are consistent properties in amniotes (birds and mammals).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A third locus contains only beta-like globin genes in amniotes; the beta-like globin genes in amniotes are flanked by olfactory receptor genes, and in placental mammals hundreds of OR genes are in this locus along with additional multigene families such as TRIM genes.

    “A third locus contains only beta-like globin genes in amniotes. The beta-like globin genes in amniotes are flanked by olfactory receptor (OR) genes (Bulger et al. 1999; Patel et al. 2008). In placental mammals, hundreds of OR genes are in this locus, along with additional multigene families such as TRIM genes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bulger et al. 1999

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    • cites Patel et al. 2008

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  • May combine two claims.

    Interpretationreasoning

    Since differential regulation during development is a consistent property of independently derived beta-like globin gene clusters, either an ancestral developmental regulatory mechanism was enforced on the newly duplicated genes or the mechanism evolved by convergence.

    “Since 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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Extensive phylogenetic comparisons indicate that the alpha-like globin gene cluster in the LCA of tetrapods contained orthologs to zeta-globin, mu-globin (also called alphaD) and alpha-globin (or alphaA) genes, and this arrangement is still seen in chickens.

    “Extensive phylogenetic comparisons indicate that this gene cluster in the LCA of tetrapods contained orthologs to zeta-globin, mu-globin (also called alphaD) and alpha-globin (or alphaA) genes (Hoffmann and Storz 2007; Hoffmann et al. 2008), and this arrangement is still seen in chickens (Fig. 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hoffmann and Storz 2007

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    • cites Hoffmann et al. 2008

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  • May combine two claims.

    Interpretationreasoning

    A proposal that beta-like globin genes were present at DS in the LCA of jawed vertebrates requires independent deletions in the fish and amphibian lineages, so parsimony favors the transposition model.

    “A proposal that they were present at DS in the LCA of jawed vertebrates also requires independent deletions in the fish and amphibian lineages, so parsimony favors the transposition model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The MN locus now contains only alpha-globin genes in eutherians; it retained these and non-globin flanking genes since the gnathostome LCA while losing beta-globin genes in many vertebrate lineages.

    “The MN locus now contains only alpha-globin genes in eutherians; it retained these and non-globin flanking genes since the gnathostome LCA while losing beta-globin genes in many vertebrate lineages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The alpha-like globin gene cluster shows dynamic features: genes are lost and gained in specific lineages, and some genes have undergone multiple conversion events during mammalian evolution.

    “The alpha-like globin gene cluster does show some dynamic features. Genes are lost and gained in specific lineages (Hoffmann et al. 2008), and some of the genes have undergone multiple conversion events during mammalian evolution (Hess et al. 1984; Song et al. 2011; Song et al. 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hoffmann et al. 2008

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    • cites Hess et al. 1984

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    • cites Song et al. 2011

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  • May combine two claims.

    Interpretationreasoning

    Beta-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.

    “Beta-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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The genomic context (MN locus) has been a constant across gnathostome evolution, and the expression patterns of the zeta- and alpha-globin genes are strikingly consistent in amniotes.

    “However, the genomic context, i.e. the MN locus, has been a constant across gnathostome evolution, and the expression patterns of the zeta- and alpha-globin genes are strikingly consistent in amniotes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both monotremes and marsupials have two beta-like globin genes; in marsupials the epsilon-globin ortholog is expressed in embryonic erythrocytes whereas the beta-globin ortholog is expressed in fetal and adult erythroid cells.

    “Both monotremes and marsupials have two beta-like globin genes. In marsupials the epsilon-globin ortholog is expressed in embryonic erythrocytes whereas the beta-globin ortholog is expressed in fetal and adult erythroid cells (Koop and Goodman 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Koop and Goodman 1988

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  • May combine two claims.

    Premisecitation

    The mu-globin and theta-globin genes each are present in only a single copy, and while they are transcribed, no evidence has been found for polypeptide products of either in mammals.

    “The mu-globin and theta-globin genes each are present in only a single copy, and while they are transcribed, no evidence has been found for polypeptide products of either in mammals (Clegg 1987; Hsu et al. 1988; Leung et al. 1989; Goh et al. 2005; Cooper et al. 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Clegg 1987

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    • cites Hsu et al. 1988

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    • cites Leung et al. 1989

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  • May combine two claims.

    Premisecitation

    In all species examined, including birds, the active orthologs to the zeta-globin gene are expressed in embryonic erythroid cells and the orthologs of the alpha-globin gene are expressed in fetal and adult erythroid cells.

    “In all species examined, including birds, the active orthologs to the zeta-globin gene are expressed in embryonic erythroid cells and the orthologs of the alpha-globin gene are expressed in fetal and adult erythroid cells (Higgs et al. 1989; Whitelaw et al. 1990) (Fig. 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Higgs et al. 1989

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    • cites Whitelaw et al. 1990

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  • May combine two claims.

    Premisenone given

    Before the divergence of the three major subclasses of mammals (monotremes, marsupials and placentals), both the zeta-globin and alpha-globin genes duplicated; most contemporary mammals retain at least two copies of these genes (in some cases pseudogenes).

    “Before the divergence of the three major subclasses of mammals (monotremes, marsupials and placentals), both the zeta-globin alpha-globin genes duplicated. Most contemporary mammals retain at least two copies of these genes (in some cases they are pseudogenes).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Fetal and adult hemoglobins were found to be identical for horse and dog, and based on the absence of evidence for a fetal-specific hemoglobin, the eta-globin homologs are predicted to be expressed embryonically.

    “Fetal and adult hemoglobins were found to be identical for horse (Stockell et al. 1961) and dog (LeCrone 1970), and based on the absence of evidence for a fetal-specific hemoglobin, the eta-globin homologs are predicted to expressed embryonically in Fig. 4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Stockell et al. 1961

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    • cites LeCrone 1970

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  • May combine two claims.

    Premisenone given

    Deletion can completely inactivate a gene, and gene loss has occurred widely in the beta-like globin gene clusters of eutherians.

    “Deletion can completely inactivate a gene, and gene loss has also occurred widely in the beta-like globin gene clusters of eutherians.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    No ortholog for the eta-globin gene is found in the species sampled from the orders Glires, but it is present in the sister clades Primates and Laurasiatherians; this strongly suggests that the eta-globin gene was lost in the LCA for Glires.

    “No ortholog for the eta-globin gene is found in the species sampled from the orders Glires (rodents and lagomorphs), but it is present in the sister clades Primates and Laurasiatherians (represented by dog, horse, bat, goat and cow). This strongly suggests that the eta-globin gene was lost in the LCA for Glires (Opazo et al. 2008a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Opazo et al. 2008a

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  • May combine two claims.

    Premisecitation

    The eta-globin gene homolog in goats is expressed embryonically; currently this is the only example of an active eta-globin gene.

    “The eta-globin gene homolog in goats is expressed embryonically (Shapiro et al. 1983). Currently, this is the only example of an active eta-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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shapiro et al. 1983

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The eta-globin gene is a pseudogene in all primates.

    “The eta-globin gene is a pseudogene in all primates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The delta-globin gene is present in almost all eutherian species examined, but it is frequently a pseudogene.

    “The delta-globin gene is present in almost all eutherian species examined, but it is frequently a pseudogene (Fig. 4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    One common interpretation is that embryonic expression pattern was ancestral, and the recruitment to fetal expression was an adaptation in the anthropoids, coinciding with a duplication of the gamma-globin gene.

    “One common interpretation is that embryonic expression pattern was ancestral, and the recruitment to fetal expression was an adaptation in the anthropoids, coinciding with a duplication of the gamma-globin gene (Johnson et al. 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Johnson et al. 1996

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both beta-globin genes in platypus are expressed in adults, but no information is available currently on whether the left-most beta-globin gene in platypus is also expressed in embryonic erythroid cells.

    “Both the beta-globin genes in platypus are expressed in adults (Patel et al. 2008), but no information is available currently on whether the left-most beta-globin gene in platypus (in the orientation in Fig. 4) is also expressed in embryonic erythroid cells, as is expected based on its position.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Patel et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The eta-globin gene is absent from sampled members of the superorders Xenarthra or Afrotheria, which can be explained either by gene loss in the LCA or perhaps the duplication to form eta-globin occurred after these superorders diverged from the other eutherians.

    “The eta-globin gene is also absent from sampled members of the superorders Xenarthra or Afrotheria, which can be explained either by gene loss in the LCA or perhaps the duplication to form eta-globin occurred after these superorders diverged from the other eutherians.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    No active gamma-globin gene has been identified in Laurasiatherians, with the gene either being absent, partially deleted or harboring inactivating mutations; the loss of the gamma-globin gene was not in the stem Laurasiatherian, but rather different losses and inactivations have occurred in the lineages to each species.

    “No active gamma-globin gene has been identified in Laurasiatherians, with the gene either being absent, partially deleted or harboring inactivating mutations. Note that the loss of the gamma-globin gene was not in the stem Laurasiatherian, but rather different losses and inactivations have occurred in the lineages to each species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The gamma-globin genes of both the prosimian primate galago and species in order Glires are expressed in embryonic erythroid cells, whereas the gamma-globin genes of anthropoid primates are expressed only in fetal erythroid cells.

    “The gamma-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. 1990; Satoh et al. 1999), whereas the gamma-globin genes of anthropoid primates (monkeys, apes and humans) are expressed only in fetal erythroid cells (Johnson et al. 1996; Johnson et al. 2000) (”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rohrbaugh and Hardison 1983

      Not checked in the free run.

    • cites Whitelaw et al. 1990

      Not checked in the free run.

    • cites Satoh et al. 1999

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    All species examined within the therians have an ortholog of the epsilon-globin gene; it is always present at the left end of the gene cluster, it is almost always a single gene, and in all species examined, it is expressed only in embryonic erythroid cells.

    “All species examined within the therians (marsupial and placental mammals) have an ortholog of the epsilon-globin gene. This gene has the most consistent features across species of any of the paralogous beta-like globin genes. It is always present at the left end of the gene cluster, it is almost always a single gene, and in all species examined, it is expressed only in embryonic erythroid cells (”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The epsilon-globin genes have been stable over eutherian evolution, whereas the gamma-, eta-, and delta-globin genes have been gained and lost frequently, sometimes in entire orders of mammals.

    “It shows that the epsilon-globin genes have been stable over eutherian evolution, whereas the gamma-, and eta-, and delta-globin genes have been gained and lost frequently, sometimes in entire orders of mammals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    The approach of cross-species evolutionary comparisons has been successful in many studies, but it has limitations.

    “This approach has been successful in many studies (e.g., Gumucio et al. 1992; Elnitski et al. 1997; Hardison et al. 1997b; Flint et al. 2001; Hughes et al. 2005), but it has some limitations.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gumucio et al. 1992

      Not checked in the free run.

    • cites Elnitski et al. 1997

      Not checked in the free run.

    • cites Hardison et al. 1997b

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Hemoglobin gene expression is restricted to erythroid cells; the genes are expressed at extremely high levels late in erythroid differentiation, with balanced production of alpha-globin and beta-globin; paralogous globin genes are expressed at progressive developmental stages.

    “Hemoglobin gene expression is restricted to erythroid cells. The genes are expressed at extremely high levels late in erythroid differentiation, with balanced production of alpha-globin and beta-globin. Paralogous globin genes are expressed at progressive developmental stages.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Strategies being pursued to reactivate gamma-globin gene expression in adult erythroid cells, either pharmacologically or by gene therapy, are attempts to modulate expression patterns in humans that recapitulate expression changes that have occurred during eutherian evolution.

    “Strategies being pursued to reactive gamma-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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Differences in expression pattern of a key transcription factor drive a change in developmental timing of expression in humans.

    “the impact of differences in expression pattern of a key transcription factor driving a change in developmental timing of expression in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Interspecies DNA alignments show that both the HBA and HBB strong enhancers are preserved across mammals and have been under strong constraint.

    “interspecies DNA alignments show that both are preserved across mammals and have been under strong constraint (Elnitski et al. 1997; Flint et al. 2001)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Elnitski et al. 1997

      Not checked in the free run.

    • cites Flint et al. 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The approach is most sensitive for finding CRMs under evolutionary constraint, and while this is true for many CRMs, a large fraction is species-specific.

    “The approach is most sensitive for finding CRMs under evolutionary constraint, and while this is true for many CRMs (Pennacchio et al. 2006), a large fraction is species-specific (King et al. 2007; Bourque et al. 2008; Hardison and Taylor 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pennacchio et al. 2006

      Not checked in the free run.

    • cites King et al. 2007

      Not checked in the free run.

    • cites Bourque et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Critical aspects of the expression patterns or mechanisms can differ, even between mouse and human; phenotypes differ between mouse and human for deletions of the homologous distal MREs of the HBA gene complexes.

    “Furthermore, critical aspects of the expression patterns or mechanisms can differ, even between mouse and human. For example, the phenotypes differ between mouse and human for deletions of the homologous distal MREs of the HBA gene complexes (Anguita et al. 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Anguita et al. 2002

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These mouse-only distal CRMs could contribute to functional differences between the species, perhaps by modifying the distal regulatory structure.

    “These could contribute to functional differences between the species, perhaps by modifying the distal regulatory structure.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These strong enhancers could be a key component of the distal regulatory structure, perhaps an active chromatin hub.

    “These strong enhancers could be a key component of the distal regulatory structure, perhaps an active chromatin hub.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A strong distal enhancer is required for high level expression of globin genes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    CRMs found in one or a limited range of species could be involved in fine-tuning core regulatory processes, perhaps helping that species adapt to a unique niche.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    CRMs involved in core regulatory functions may be conserved across a wide group of species and show evidence of evolutionary constraint.

    “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.”
    Quote in the paperSubstantial claim
61 of 61

  • The paper relies on this without support.

    Comparative evolutionary analyses of globin genes can provide insights into mechanisms of gene regulation.

    “One motivation for comparative studies has been to utilize the insights from the evolutionary analyses to better understand mechanisms of gene regulation.”

  • The paper relies on this without support.

    Many human hemoglobinopathies result from inadequate expression of globin genes, and attempts to modulate globin gene expression are a fundamental approach to seek novel avenues to therapy.

    “Many human hemoglobinopathies result from inadequate expression of globin genes, and attempts to modulate globin gene expression are a fundamental approach to seek novel avenues to therapy.”

  • The paper relies on this without support.

    A strong distal enhancer is required for high level expression of globin genes.

    “For example, a strong distal enhancer is required for high level expression of globin genes.”
3 of 3

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Cites

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Research works printed but not linked: 1

  1. Weatherall DJ Clegg JB Thalassemia Syndromes 2001 Oxford Blackwell Science Ltd

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Related

Authors
Hardison, R. C.
Affiliations
Pennsylvania State University (US)
Corresponding author
Hardison, R. C.
ORCID
Hardison, R. C.
Venue
Cold Spring Harbor Perspectives in Medicine
Publisher
Cold Spring Harbor Laboratory
Published
2012-12-01
Volume
2
Issue
12
Pages
a011627-a011627
ISSN
2157-1422 (ISSN-L)
DOI
10.1101/cshperspect.a011627
PMC
PMC3543078
OpenAlex
W2155337754
Semantic Scholar
73b13bfe4c1c0fbdf2c864e8792e16a09a8f000d
Cited by
217
References
153
Citations by year
2026: 16 · 2025: 21 · 2024: 32 · 2023: 23 · 2022: 19 · 2021: 17 · 2020: 20 · 2019: 16 · 2018: 13 · 2017: 18 · 2016: 9 · 2015: 4 · 2014: 3 · 2013: 5 · 2012: 1
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Human Genome Research Institute (HG005573, RC2HG005573)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065806, DK65806, R01 DK65806)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
hemoglobin evolution, globin genes, globin gene cluster, beta-globin gene cluster, globin gene regulation, cis-regulatory modules, gene transposition
MeSH terms
Animals, Multigene Family, Heme, Hemoglobins, Humans, Genetic Linkage, Mammals, Models, Genetic, Gene Expression, Evolution, Molecular, Gene Regulatory Networks

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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