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The evolution of the immunoglobulin heavy chain variable region (IgV H ) in Leporids: an unusual case of transspecies polymorphism

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Abstract

In domestic rabbit (Oryctolagus cuniculus), three serological types have been distinguished at the variable domain of the antibody H chain, the so-called V H a allotypes a1, a2, and a3. They correspond to highly divergent allelic lineages of the V H 1 gene, which is the gene rabbit utilizes in more than 80% of VDJ rearrangements. The sharing of serological V H a markers between rabbit and snowshoe hare (Lepus americanus) has suggested that the large genetic distances between rabbit V H 1 alleles (9–14% nucleotide differences) can be explained by unusually long lineage persistence times (transspecies polymorphism). Because this interpretation of the serological data is uncertain, we have determined the nucleotide sequences of V H genes expressed in specimens of Lepus species. Two sequence groups were distinguished, one of which occurred only in hare specimen displaying serological motifs of the rabbit V H a-a2 allotype. Sequences of this group are part of a monophyletic cluster containing the V H 1 sequences of the rabbit a2 allotype. The fact that this “transspecies a2 cluster” did not include genes of other rabbit V H a allotypes (a1, a3, and a4) is incompatible with the existence of a common V H a ancestor gene within the species, and suggests that the divergence of the V H a lineages preceded the Lepus vs Oryctolagus split. The sequence data are furthermore compatible with the hypothesis that the V H a polymorphism can be two times older than the divergence time between the Lepus and Oryctolagus lineages, which was estimated at 16–24 million years.

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Reference

  • Callou C (1995) Modifications de l'aire de répartition du Lapin (Oryctolagus cuniculus) en France et en Espagne, du Pléistocène à l'époque actuelle. État de la question. Anthropozoologica 21:95–114

    Google Scholar 

  • Cazenave PA, Bennamar A, Sogn JA, Kindt TJ (1987) Immunoglobulin genes in the feral rabbit. In: Dubiski S (ed) The rabbit in contemporary immunological research. Longman, New York, pp 148–160

    Google Scholar 

  • Cooper MD, Perey DY, Gabrielsen AE, Sutherland DE, McKneally MF, Good RA (1968) Production of an antibody deficiency syndrome in rabbits by neonatal removal of organized intestinal lymphoid tissues. Int Arch Allergy Appl Immunol 33:65–88

    PubMed  CAS  Google Scholar 

  • Dray SG, Young O, Nisonoff A (1963) Distribution of allotypic specificities among rabbit immunoglobulin γ-globulin molecules genetically defined at two loci. Nature 199:52

    Article  PubMed  CAS  Google Scholar 

  • Esteves PJ, Lanning D, Zhai SK, Ferrand N, Knight KL, van der Loo W (2004) Allelic variation at the VHa locus in natural populations of rabbit (Oryctolagus cuniculus, L.). J Immunol 172:1044–1053

    PubMed  CAS  Google Scholar 

  • Fan WM, Kasahara M, Gutknecht J, Klein D, Mayer WE, Jonker M, Klein J (1989) Shared class II MHC polymorphisms between humans and chimpanzees. Hum Immunol 26:107–121

    Article  PubMed  CAS  Google Scholar 

  • Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791

    Article  Google Scholar 

  • Friedman ML, Tunyaplin C, Zhai SK, Knight KL (1994) Neonatal V H , D, and JH gene usage in rabbit B lineage cells. J Immunol 152:632–641

    PubMed  CAS  Google Scholar 

  • Glazko GV, Nei M (2003) Estimation of divergence times for major lineages of primate species. Mol Biol Evol 20:424–434

    Article  PubMed  CAS  Google Scholar 

  • Halanych KM, Robinson TJ (1999) Multiple substitutions affect the phylogenetic utility of cytochrome b and 12S rDNA data: examining a rapid radiation in leporid (Lagomorpha) evolution. J Mol Evol 48:369–379

    Article  PubMed  CAS  Google Scholar 

  • Herd ZL, Edmonds JW (1977) Population genetics of Aa and Ab immunoglobulin allotypes in wild rabbits of south-eastern Australia. I. Allotype frequencies. J Immunogenet 4:315–323

    Article  PubMed  CAS  Google Scholar 

  • Horng WJ, Papagiannes E, Dray S, Rodkey LS (1980) Expression of cross-reacting determinants of the immunoglobulin heavy chain variable region a3 allotype in Oryctolagus and Lepus. Mol Immunol 17:111–117

    Article  PubMed  CAS  Google Scholar 

  • Kabat EA, Wu TT, Perry HM, Gottsman KS, Foeller C (1991) Sequences of proteins of immunologic interest, 5th edn. US Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD

    Google Scholar 

  • Kim BS, Dray S (1973) Expression of the a, x, and y variable region genes of heavy chains among IgG, IgM, and IgA molecules of normal and a locus allotype-suppressed rabbits. J Immunol 111:750–760

    PubMed  CAS  Google Scholar 

  • Klein J, Satta Y, Takahata N, O'hUigin C (1993) Trans-specific Mhc polymorphism and the origin of species in primates. J Med Primatol 22:57–64

    PubMed  CAS  Google Scholar 

  • Knight KL, Becker RS (1990) Molecular basis of the allelic inheritance of rabbit immunoglobulin V H allotypes: implications for the generation of antibody diversity. Cell 60:963–970

    Article  PubMed  CAS  Google Scholar 

  • Krug MS, Berger SL (1987) First strand cDNA synthesis primed with oligo (dT). Methods Enzymol 152:316

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Tamura K, Nei M (2004) MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform 5:150–163

    Article  PubMed  CAS  Google Scholar 

  • Lanning D, Sethupathi P, Rhee KJ, Zhai SK, Knight KL (2000a) Intestinal microflora and diversification of the rabbit antibody repertoire. J Immunol 165:2012–2019

    PubMed  CAS  Google Scholar 

  • Lanning D, Zhu X, Zhai SK, Knight KL (2000b) Development of the antibody repertoire in rabbit: gut-associated lymphoid tissue, microbes, and selection. Immunol Rev 175:214–228

    Article  PubMed  CAS  Google Scholar 

  • Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P (1988) HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 335:268–271

    Article  PubMed  CAS  Google Scholar 

  • Lefranc MP, Giudicelli V, Kaas Q, Duprat E, Jabado-Michaloud J, Scaviner D, Ginestoux C, Clement O, Chaume D, Lefranc G (2005) IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res 33(Database Issue):D593–D597

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Martinez N (1989) Revision sistematica y biostratigrafica de los lagomorphos (Mammalia) del Terciario y Cuaternario de España. Memorias del Museo Paleontologico de la Universidad de Zaragoza, n°3. Diputacion General de Aragon

  • Mage RG, Bernstein KE, McCartney-Francis N, Alexander CB, Young-Cooper GO, Padlan EA, Cohen GH (1984) The structural and genetic basis for expression of normal and latent V H a allotypes of the rabbit. Mol Immunol 21:1067–1081

    Article  PubMed  CAS  Google Scholar 

  • Mayer WE, O'hUigin C, Zaleska-Rutczynska Z, Klein J (1992) Trans-species origin of Mhc-DRB polymorphism in the chimpanzee. Immunogenetics 37:12–23

    Article  PubMed  CAS  Google Scholar 

  • Nei M, Kumar S (2000) Molecular evolution and phylogenetics. Oxford University Press, New York

    Google Scholar 

  • Nei M, Gu X, Sitnikova T (1997) Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc Natl Acad Sci U S A 94:7799–7806

    Article  PubMed  CAS  Google Scholar 

  • Ota T, Nei M (1994) Divergent evolution and evolution by the birth-and-death process in the immunoglobulin V H gene family. Mol Biol Evol 11:469–482

    PubMed  CAS  Google Scholar 

  • Oudin J (1960) Allotype of rabbit serum proteins. I. Immunochemical analysis leading to the individualization of seven main allotypes. J Exp Med 112:107–124

    Article  PubMed  CAS  Google Scholar 

  • Ros F, Puels J, Reichenberger N, van Schoten W, Buelow R, Platzer J (2004) Sequence analysis of 0.5 Mb of the rabbit germline immunoglobulin heavy chain locus. Gene 330:49–59

    Article  PubMed  CAS  Google Scholar 

  • Roux KH (1981) A fourth heavy chain variable region subgroup, w, with 2 variants defined by an induced auto-antiserum in the rabbit. J Immunol 127:626–632

    PubMed  CAS  Google Scholar 

  • Rzhetsky A, Nei M (1992) Statistical properties of the ordinary least-squares, generalized least-squares, and minimum-evolution methods of phylogenetic inference. J Mol Evol 35:367–675

    Article  PubMed  CAS  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    PubMed  CAS  Google Scholar 

  • Sehgal D, Obiakor H, Mage RG (2002) Distinct clonal Ig diversification patterns in young appendix compared to antigen-specific splenic clones. J Immunol 168:5424–5433

    PubMed  CAS  Google Scholar 

  • Short JA, Sethupathi P, Zhai SK, Knight KL (1991) VDJ genes in VHa2 allotype-suppressed rabbits. Limited germline VH gene usage and accumulation of somatic mutations in D regions. J Immunol 147:4014–4018

    PubMed  CAS  Google Scholar 

  • Sitnikova T (1996) Bootstrap method of interior-branch test for phylogenetic trees. Mol Biol Evol 13:605–611

    PubMed  CAS  Google Scholar 

  • Sitnikova T, Su C (1998) Coevolution of immunoglobulin heavy- and light-chain variable-region gene families. Mol Biol Evol 15:617–625

    PubMed  CAS  Google Scholar 

  • Su C, Nei M (1999) Fifty-million-year-old polymorphism at an immunoglobulin variable region gene locus in the rabbit evolutionary lineage. Proc Natl Acad Sci U S A 96:9710–9715

    Article  PubMed  CAS  Google Scholar 

  • Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    Article  PubMed  CAS  Google Scholar 

  • van der Loo W (1987) Studies on the adaptive significance of the immunoglobulin alleles (ig allotypes) in wild rabbit. In: Dubiski S (ed) The rabbit in contemporary immunological research. Longman, New York, pp 164–190

    Google Scholar 

  • van der Loo W (1993) Variance analysis of immunoglobulin alleles in natural populations of rabbit (Oryctolagus cuniculus): the extensive interallelic divergence at the b locus could be the outcome of overdominance-type selection. Genetics 135:171–187

    PubMed  CAS  Google Scholar 

  • van der Loo W, De Baetselier P, Hamers-Casterman C, Hamers R (1977) Evidence for quasi-silent germline genes coding for phylogenetically ancient determinants of the rabbit a locus allotypes. Eur J Immunol 7:15–22

    Article  PubMed  Google Scholar 

  • van der Loo W, Mougel F, Sanchez MS, Bouton C, Castien E, Fonseca A, Ferrand N, Soriguer R, Monnerot M (1999) Cytonuclear disequilibria in wild populations of rabbit (Oryctolagus cuniculus L.) suggest unequal allele turnover rates at the b locus (IGKC1). Immunogenetics 49:629–643

    Article  PubMed  Google Scholar 

  • Xia X, Xie Z (2001) DAMBE: software package for data analysis in molecular biology and evolution. J Heredity 92:371–373

    Article  CAS  Google Scholar 

  • Yamada F, Takaki M, Suzuki H (2002) Molecular phylogeny of Japanese Leporidae, the Amami rabbit Pentalagus furnessi, the Japanese hare Lepus brachyurus, and the mountain hare Lepus timidus, inferred from mitochondrial DNA sequences. Genes Genet Syst 77:107–116

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Boonthum A, Zhai SK, Knight KL (1999) B lymphocyte selection and age-related changes in VH gene usage in mutant Alicia rabbits. J Immunol 163:3313–3320

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Paulo Celio Alves for all the help in collecting tissue samples of Oryctolagus and Lg, and Franz Suchentrunk for providing us with tissue samples of Le. This work was partially supported by Direcção Geral de Florestas, by a grant of the Foundation for Science and Technology-Portugal (Praxis XXI/BPD/14551/2003) to P.E., by the National Institutes of Health grants AI50260 and AI49458 to K.L.K. and D.L., and by a grant of the Belgian Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Krediet 1.5579.98-FWOKN35) to W.vdL.

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Authors and Affiliations

  1. Centro de Investigação em Biodiversidade e Recursos Genéticos (CIBIO), ICETA-UP, Campus Agrário de Vairão Rua Padre Armando Quintas, Vairão, 4485-661, Portugal

    P. J. Esteves, N. Ferrand & W. van der Loo

  2. Departamento de Zoologia e Antropologia, Faculdade de Ciências da Universidade do Porto, Porto, Portugal

    P. J. Esteves, N. Ferrand & W. van der Loo

  3. Institute of Molecular Biology and Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium

    P. J. Esteves & W. van der Loo

  4. Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, 60153, USA

    D. Lanning, K. L. Knight & S. K. Zhai

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  1. P. J. Esteves
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  2. D. Lanning
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  3. N. Ferrand
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  4. K. L. Knight
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  5. S. K. Zhai
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  6. W. van der Loo
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Correspondence to W. van der Loo.

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Esteves, P.J., Lanning, D., Ferrand, N. et al. The evolution of the immunoglobulin heavy chain variable region (IgV H ) in Leporids: an unusual case of transspecies polymorphism. Immunogenetics 57, 874–882 (2005). https://doi.org/10.1007/s00251-005-0022-0

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