Abstract
Adaptation to various altitudes and oxygen levels is a major aspect of vertebrate evolution. Hemoglobin is an erythrocyte protein belonging to the globin superfamily, and the α-, β-globin genes of jawed vertebrates encode tetrameric ((α2β2) hemoglobin, which contributes to aerobic metabolism by delivering oxygen from the respiratory exchange surfaces into cells. However, there are various gaps in knowledge regarding hemoglobin gene evolution, including patterns in cartilaginous fish and the roles of gene conversion in various taxa. Hence, we evaluated the evolutionary history of the vertebrate hemoglobin gene family by analyses of 97 species representing all classes of vertebrates. By genome-wide analyses, we extracted 879 hemoglobin sequences. Members of the hemoglobin gene family were conserved in birds and reptiles but variable in mammals, amphibians, and teleosts. Gene motifs, structures, and synteny were relatively well-conserved among vertebrates. Our results revealed that purifying selection contributed substantially to the evolution of all vertebrate hemoglobin genes, with mean dN/dS (ω) values ranging from 0.057 in teleosts to 0.359 in reptiles. In general, after the fish-specific genome duplication, the teleost hemoglobin genes showed variation in rates of evolution, and the β-globin genes showed relatively high ω values after a gene transposition event in amniotes. We also observed that the frequency of gene conversion was high in amniotes, with fewer hemoglobin genes and higher rates of evolution. Collectively, our findings provide detail insight into complex evolutionary processes shaping the vertebrate hemoglobin gene family, involving gene duplication, gene loss, purifying selection, and gene conversion.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguileta G, Bielawski JP, Yang Z (2004) Gene conversion and functional divergence in the β-globin gene family. J Mol Evol 59:177–189. https://doi.org/10.1007/s00239-004-2612-0
Aguileta G, Bielawski JP, Yang Z (2006) Proposed standard nomenclature for the α- and β-globin gene families. Genes Genet Syst 81:367–371. https://doi.org/10.1266/ggs.81.367
Akaike H (1974) A new look at the statistical model identification. IEEE Trans Autom Control 19:716–723. https://doi.org/10.1109/tac.1974.1100705
Altekar G, Dwarkadas S, Huelsenbeck JP, Ronquist F (2004) Parallel Metropolis coupled Markov chain Monte Carlo for Bayesian phylogenetic inference. Bioinformatics 20:407–415. https://doi.org/10.1093/bioinformatics/btg427
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410. https://doi.org/10.1016/S0022-2836(05)80360-2
Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, Ren J, Li WW, Noble WS (2009) MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res 37:W202–W208. https://doi.org/10.1093/nar/gkp335
Banville D, Williams JG (1985a) The pattern of expression of the Xenopus laevis tadpole α-globin genes and the amino acid sequence of the three major tadpole α-globin polypeptides. Nucleic Acids Res 13:5407–5421. https://doi.org/10.1093/nar/13.15.5407
Banville D, Williams JG (1985) Developmental changes in the pattern of larval β-globin gene expression in Xenopus laevis: identification of two early larval β-globin mRNA sequences. J Mol Biol 184:611–620. https://doi.org/10.1016/0022-2836(85)90307-9
Bridges C (1936) The bar “gene” a duplication. Science 83:210–211. https://doi.org/10.1126/science.83.2148.210
Cunningham F et al (2019) Ensembl 2019. Nucleic Acids Res 47:D745–D751
Ebner B, Panopoulou G, Vinogradov SN, Kiger L, Marden MC, Burmester T, Hankeln T (2010) The globin gene family of the cephalochordate amphioxus: implications for chordate globin evolution. BMC Evol Biol 10:370. https://doi.org/10.1186/1471-2148-10-370
Fago A, Giangiacomo L, D’Avino R, Carratore V, Romano M, Boffi A, Chiancone E (2001) Hagfish hemoglobins: structure, function, and oxygen-linked association. J Biol Chem 276:27415–23. https://doi.org/10.1074/jbc.M100759200
Flint J, Tufarelli C, Peden J, Clark K, Daniels RJ, Hardison R, Miller W, Philipsen S, Tan-Un KC, McMorrow T, Frampton J, Alter BP, Frischauf AM, Higgs DR (2001) Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster. Hum Mol Genet 10:371–82. https://doi.org/10.1093/hmg/10.4.371
Fuchs C, Burmester T, Hankeln T (2006) The amphibian globin gene repertoire as revealed by the Xenopus genome. Cytogenet Genome Res 112:296–306. https://doi.org/10.1159/000089884
Gaudry MJ, Storz JF, Butts GT, Campbell KL, Hoffmann FG (2014) Repeated evolution of chimeric fusion genes in the β-globin gene family of laurasiatherian mammals. Genome Biol Evol 6:1219–34. https://doi.org/10.1093/gbe/evu097
Giardina B, Mosca D, De Rosa MC (2004) The Bohr effect of haemoglobin in vertebrates: an example of molecular adaptation to different physiological requirements. Acta Physiol Scand 182:229–44. https://doi.org/10.1111/j.1365-201X.2004.01360.x
Glasauer SM, Neuhauss SC (2014) Whole-genome duplication in teleost fishes and its evolutionary consequences. Mol Genet Genomics 289:1045–60. https://doi.org/10.1007/s00438-014-0889-2
Goldman N, Yang ZH (1994) Codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol. 11:725–736. https://doi.org/10.1093/oxfordjournals.molbev.a040153
Goodman M, Czelusniak J, Koop BF, Tagle DA, Slightom JL (1987) Globins: a case study in molecular phylogeny. Cold Spring Harb Symp Quant Biol 52:875–90. https://doi.org/10.1101/sqb.1987.052.01.096
Hardison RC (2012) Evolution of hemoglobin and its genes. Cold Spring Harb Perspect Med 2:a011627. https://doi.org/10.1101/cshperspect.a011627
Hoffmann FG, Opazo JC, Storz JF (2010a) Gene cooption and convergent evolution of oxygen transport hemoglobins in jawed and jawless vertebrates. Proc Natl Acad Sci USA 107:14274–9. https://doi.org/10.1073/pnas.1006756107
Hoffmann FG, Storz JF, Gorr TA, Opazo JC (2010b) Lineage-specific patterns of functional diversification in the alpha- and beta-globin gene families of tetrapod vertebrates. Mol Biol Evol 27:1126–1138. https://doi.org/10.1093/molbev/msp325
Hoffmann FG, Opazo JC, Storz JF (2011) Differential loss and retention of cytoglobin, myoglobin, and globin-E during the radiation of vertebrates. Genome Biol Evol 3:588–600. https://doi.org/10.1093/gbe/evr055
Hoffmann FG, Opazo JC, Hoogewijs D, Hankeln T, Ebner B, Vinogradov SN, Bailly X, Storz JF (2012) Evolution of the globin gene family in deuterostomes: lineage-specific patterns of diversification and attrition. Mol Biol Evol 29:1735–45. https://doi.org/10.1093/molbev/mss018
Hoffmann FG, Opazo JC, Storz JF (2012b) Whole-genome duplications spurred the functional diversification of the globin gene superfamily in vertebrates. Mol Biol Evol 29:303–312. https://doi.org/10.1093/molbev/msr207
Hoffmann FG, Vandewege MW, Storz JF, Opazo JC (2018) Gene turnover and diversification of the α- and β-Globin gene families in sauropsid vertebrates. Genome Biol Evol 10:344–358. https://doi.org/10.1093/gbe/evy001
Honzatko RB, Hendrickson WA (1986) Molecular models for the putative dimer of sea lamprey hemoglobin. Proc Natl Acad Sci USA 83:8487–8491. https://doi.org/10.1073/pnas.83.22.8487
Hosbach HA, Wyler T, Weber R (1983) The Xenopus laevis globin gene family: chromosomal arrangement and gene structure. Cell 32:45–53. https://doi.org/10.1016/0092-8674(83)90495-6
Hu B, Jin J, Guo AY, Zhang H, Luo J, Gao G (2015) GSDS 2.0: an upgraded gene feature visualization server. Bioinformatics 31:1296–1297. https://doi.org/10.1093/bioinformatics/btu817
Jeffreys AJ, Wilson V, Wood D, Simons JP, Kay RM, Williams JG (1980) Linkage of adult alpha- and beta-globin genes in X. laevis and gene duplication by tetraploidization. Cell 21:555–564. https://doi.org/10.1016/0092-8674(80)90493-6
Jetz W, Fine PV (2012) Global gradients in vertebrate diversity predicted by historical area-productivity dynamics and contemporary environment. PLoS Biol 10:e1001292. https://doi.org/10.1371/journal.pbio.1001292
Johnson RM, Buck S, Chiu C, Schneider H, Sampaio I, Gage DA, Shen TL, Schneider MP, Muniz JA, Gumucio DL, Goodman M (1996) Fetal globin expression in New World monkeys. J Biol Chem 271:14684–14691. https://doi.org/10.1074/jbc.271.25.14684
Kaessmann H (2010) Origins, evolution, and phenotypic impact of new genes. Genome Res 20:1313–1326. https://doi.org/10.1101/gr.101386.109
Kakar S, Hoffman FG, Storz JF, Fabian M, Hargrove MS (2010) Structure and reactivity of hexacoordinate hemoglobins. Biophys Chem 152:1–14. https://doi.org/10.1016/j.bpc.2010.08.008
Katoh K, Standley DM (2013) MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30:772–780. https://doi.org/10.1093/molbev/mst010
Lanfear R, Frandsen PB, Wright AM, Senfeld T, Calcott B (2017) PartitionFinder 2: new methods for selecting partitioned models of evolution for molecular and morphological phylogenetic analyses. Mol Biol Evol 34(3):772–773. https://doi.org/10.1093/molbev/msw260
Lanfranchi G, Pallavicini A, Laveder P, Valle G (1994) Ancestral hemoglobin switching in lampreys. Dev Biol 164:402–408. https://doi.org/10.1006/dbio.1994.1210
Letunic I, Bork P (2019) Interactive Tree Of Life (iTOL) v4: recent updates and new developments. Nucleic Acids Res 47:W256–W259. https://doi.org/10.1093/nar/gkz239
Meyer A (1998) Hox gene variation and evolution. Nature 391:225, 227–228. https://doi.org/10.1038/34530
Meyer A, Van de Peer Y (2005) From 2R to 3R: evidence for a fish-specific genome duplication (FSGD). Bioessays 27(9):937–945. https://doi.org/10.1002/bies.20293
Mito M, Chong KT, Miyazaki G, Adachi S, Park SY, Tame JR, Morimoto H (2002) Crystal structures of deoxy- and carbonmonoxyhemoglobin F1 from the hagfish Eptatretus burgeri. J Biol Chem 277:21898–21905. https://doi.org/10.1074/jbc.M111492200
Miyata M, Gillemans N, Hockman D et al (2020) An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells. Blood 136(3):269–278. https://doi.org/10.1182/blood.2020004826
Nguyen LT, Schmidt HA, von Haeseler A, Minh BQ (2015) IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol 32:268–274. https://doi.org/10.1093/molbev/msu300
Opazo JC, Hoffmann FG, Storz JF (2008) Differential loss of embryonic globin genes during the radiation of placental mammals. Proc Natl Acad Sci USA 105:12950–12955. https://doi.org/10.1073/pnas.0804392105
Opazo JC, Sloan AM, Campbell KL, Storz JF (2009) Origin and ascendancy of a chimeric fusion gene: the beta/delta-globin gene of paenungulate mammals. Mol Biol Evol 26:1469–1478. https://doi.org/10.1093/molbev/msp064
Opazo JC, Butts GT, Nery MF, Storz JF, Hoffmann FG (2013) Whole-genome duplication and the functional diversification of teleost fish hemoglobins. Mol Biol Evol 30:140–153. https://doi.org/10.1093/molbev/mss212
Opazo JC, Hoffmann FG, Natarajan C, Witt CC, Berenbrink M, Storz JF (2015) Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression. Mol Biol Evol 32:871–887. https://doi.org/10.1093/molbev/msu341
Opazo JC, Lee AP, Hoffmann FG, Toloza-Villalobos J, Burmester T, Venkatesh B, Storz JF (2015) Ancient duplications and expression divergence in the globin gene superfamily of vertebrates: insights from the Elephant Shark Genome and transcriptome. Mol Biol Evol 32:1684–1694. https://doi.org/10.1093/molbev/msv054
Patel VS, Ezaz T, Deakin JE, Graves JA (2010) Globin gene structure in a reptile supports the transpositional model for amniote α- and β-globin gene evolution. Chromosome Res 18:897–907. https://doi.org/10.1007/s10577-010-9164-5
Philipsen S, Hardison RC (2018) Evolution of hemoglobin loci and their regulatory elements. Blood Cells Mol Dis 70:2–12. https://doi.org/10.1016/j.bcmd.2017.08.001
Reitman M, Grasso JA, Blumenthal R, Lewit P (1993) Primary sequence, evolution, and repetitive elements of the Gallus gallus (chicken) beta-globin cluster. Genomics 18:616–626. https://doi.org/10.1016/s0888-7543(05)80364-7
Ronquist F, Teslenko M, van der Mark P, Ayres DL, Darling A, Höhna S, Larget B, Liu L, Suchard MA, Huelsenbeck JP (2012) MrBayes 3.2: efficient Bayesian phylogenetic inference and model choice across a large model space. Syst Biol 61:539–542. https://doi.org/10.1093/sysbio/sys029
Salamov AA, Solovyev VV (2000) Ab initio gene finding in Drosophila genomic DNA. Genome Res 10:516–522. https://doi.org/10.1101/gr.10.4.516
Schwarze K, Burmester T (2013) Conservation of globin genes in the “living fossil” Latimeria chalumnae and reconstruction of the evolution of the vertebrate globin family. Biochim Biophys Acta 1834:1801–1812. https://doi.org/10.1016/j.bbapap.2013.01.019
Schwarze K, Campbell KL, Hankeln T, Storz JF, Hoffmann FG, Burmester T (2014) The globin gene repertoire of lampreys: convergent evolution of hemoglobin and myoglobin in jawed and jawless vertebrates. Mol Biol Evol 31:2708–2721. https://doi.org/10.1093/molbev/msu216
Schwarze K, Singh A, Burmester T (2015) The full globin repertoire of turtles provides insights into vertebrate globin evolution and function. Genome Biol Evol 7:1896–1913. https://doi.org/10.1093/gbe/evv114
Song G, Hsu CH, Riemer C, Zhang Y, Kim HL, Hoffmann F, Zhang L, Hardison RC, NISC Comparative Sequencing Program, Green ED, Miller W (2011) Conversion events in gene clusters. BMC Evol Biol 11:226. https://doi.org/10.1186/1471-2148-11-226
Song G, Riemer C, Dickins B, Kim HL, Zhang L, Zhang Y, Hsu CH, Hardison RC, Nisc Comparative Sequencing Program, Green ED, Miller W (2012) Revealing mammalian evolutionary relationships by comparative analysis of gene clusters. Genome Biol Evol 4:586–601. https://doi.org/10.1093/gbe/evs032
Storz JF (2016) Gene duplication and evolutionary innovations in hemoglobin-oxygen transport. Physiology (bethesda) 31:223–232. https://doi.org/10.1152/physiol.00060.2015
Storz JF, Opazo JC, Hoffmann FG (2011) Phylogenetic diversification of the globin gene superfamily in chordates. IUBMB Life 63:313–322. https://doi.org/10.1002/iub.482
Storz JF, Opazo JC, Hoffmann FG (2013) Gene duplication, genome duplication, and the functional diversification of vertebrate globins. Mol Phylogenet Evol 66:469–478. https://doi.org/10.1016/j.ympev.2012.07.013
Storz JF, Natarajan C, Moriyama H, Hoffmann FG, Wang T, Fago A, Malte H, Overgaard J, Weber RE (2015) Oxygenation properties and isoform diversity of snake hemoglobins. Am J Physiol Regul Integr Comp Physiol 309:R1178–R1191. https://doi.org/10.1152/ajpregu.00327.2015
Talavera G, Castresana J (2007) Improvement of phylogenies after removing divergent and ambiguously aligned blocks from protein sequence alignments. Syst Biol 56:564–577. https://doi.org/10.1080/10635150701472164
Tatusova TA, Madden TL (1999) BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett 174:247–250. https://doi.org/10.1111/j.1574-6968.1999.tb13575.x
Tempel S (2012) Using and understanding RepeatMasker. Methods Mol Biol (clifton, N.J.) 859:29–51. https://doi.org/10.1007/978-1-61779-603-6_2
Van de Peer Y, Maere S, Meyer A (2009) The evolutionary significance of ancient genome duplications. Nat Rev Genet 10:725–732. https://doi.org/10.1038/nrg2600
Wang K, Shen Y, Yang Y, Gan X, Liu G, Hu K, Li Y, Gao Z, Zhu L, Yan G, He L, Shan X, Yang L, Lu S, Zeng H, Pan X, Liu C, Yuan Y, Feng C, Xu W, Zhu C, Xiao W, Dong Y, Wang W, Qiu Q, He S (2019) Morphology and genome of a snailfish from the Mariana Trench provide insights into deep-sea adaptation. Nat Ecol Evol 3:823–833. https://doi.org/10.1038/s41559-019-0864-8
Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 24:1586–1591. https://doi.org/10.1093/molbev/msm088
Yang J, Chen X, Bai J, Fang D, Qiu Y, Jiang W, Yuan H, Bian C, Lu J, He S, Pan X, Zhang Y, Wang X, You X, Wang Y, Sun Y, Mao D, Liu Y, Fan G, Zhang H, Chen X, Zhang X, Zheng L, Wang J, Cheng L, Chen J, Ruan Z, Li J, Yu H, Peng C, Ma X, Xu J, He Y, Xu Z, Xu P, Wang J, Yang H, Wang J, Whitten T, Xu X, Shi Q (2016) The Sinocyclocheilus cavefish genome provides insights into cave adaptation. BMC Biol 14:1. https://doi.org/10.1186/s12915-015-0223-4
You X, Bian C, Zan Q, Xu X, Liu X, Chen J, Wang J, Qiu Y, Li W, Zhang X, Sun Y, Chen S, Hong W, Li Y, Cheng S, Fan G, Shi C, Liang J, Tom Tang Y, Yang C, Ruan Z, Bai J, Peng C, Mu Q, Lu J, Fan M, Yang S, Huang Z, Jiang X, Fang X, Zhang G, Zhang Y, Polgar G, Yu H, Li J, Liu Z, Zhang G, Ravi V, Coon SL, Wang J, Yang H, Venkatesh B, Wang J, Shi Q (2014) Mudskipper genomes provide insights into the terrestrial adaptation of amphibious fishes. Nat Commun 5:5594. https://doi.org/10.1038/ncomms6594
Zhang Y, Song G, Vinar T, Green ED, Siepel A, Miller W (2009) Evolutionary history reconstruction for Mammalian complex gene clusters. J Comput Biol 16:1051–1070. https://doi.org/10.1089/cmb.2009.0040
Zhang G, Li C, Li Q, Li B, Larkin DM, Lee C, Storz JF, Antunes A, Greenwold MJ, Meredith RW, Ödeen A, Cui J, Zhou Q, Xu L, Pan H, Wang Z, Jin L, Zhang P, Hu H, Yang W, Hu J, Xiao J, Yang Z, Liu Y, Xie Q, Yu H, Lian J, Wen P, Zhang F, Li H, Zeng Y, Xiong Z, Liu S, Zhou L, Huang Z, An N, Wang J, Zheng Q, Xiong Y, Wang G, Wang B, Wang J, Fan Y, da Fonseca RR, Alfaro-Núñez A, Schubert M, Orlando L, Mourier T, Howard JT, Ganapathy G, Pfenning A, Whitney O, Rivas MV, Hara E, Smith J, Farré M, Narayan J, Slavov G, Romanov MN, Borges R, Machado JP, Khan I, Springer MS, Gatesy J, Hoffmann FG, Opazo JC, Håstad O, Sawyer RH, Kim H, Kim KW, Kim HJ, Cho S, Li N, Huang Y, Bruford MW, Zhan X, Dixon A, Bertelsen MF, Derryberry E, Warren W, Wilson RK, Li S, Ray DA, Green RE, O’Brien SJ, Griffin D, Johnson WE, Haussler D, Ryder OA, Willerslev E, Graves GR, Alström P, Fjeldså J, Mindell DP, Edwards SV, Braun EL, Rahbek C, Burt DW, Houde P, Zhang Y, Yang H, Wang J, Avian Genome Consortium, Jarvis ED, Gilbert MT, Wang J (2014) Comparative genomics reveals insights into avian genome evolution and adaptation. Science 346:1311–1320. https://doi.org/10.1126/science.1251385
Acknowledgements
We thank members from Peng’s lab for constructive discussion. This work was funded by the grant from the National Natural Science Foundation of China (No. 31872204).
Funding
This work was funded by the grant from the National Natural Science Foundation of China (No. 31872204).
Author information
Authors and Affiliations
Contributions
ZP contributed to the study conception and design. YM, TP, ZQ and FS contributed to material preparation, data collection and analysis. YM, and TP prepared the first draft of the manuscript and all authors commented on the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mao, Y., Peng, T., Shao, F. et al. Molecular evolution of the hemoglobin gene family across vertebrates. Genetica 151, 201–213 (2023). https://doi.org/10.1007/s10709-023-00187-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10709-023-00187-9