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Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism

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Abstract

Pinnipeds, marine carnivores, diverged from terrestrial carnivores ~45 million years ago, before their adaptation to marine environments. This lifestyle change exposed pinnipeds to different microbiota and pathogens, with probable impact on their MHC class I genes. Investigating this question, genomic sequences were determined for 71 MHC class I variants: 27 from harbor seal and 44 from gray seal. These variants form three MHC class I gene lineages, one comprising a pseudogene. The second, a candidate nonclassical MHC class I gene, comprises a nonpolymorphic transcribed gene related to dog DLA-79 and giant panda Aime-1906. The third is the diversity lineage, which includes 62 of the 71 seal MHC class I variants. All are transcribed, and they minimally represent six harbor and 12 gray seal MHC class I genes. Besides species-specific differences in gene number, seal MHC class I haplotypes exhibit gene content variation and allelic polymorphism. Patterns of sequence variation, and of positions for positively selected sites, indicate the diversity lineage genes are the seals’ classical MHC class I genes. Evidence that expansion of diversity lineage genes began before gray and harbor seals diverged is the presence in both species of two distinctive sublineages of diversity lineage genes. Pointing to further expansion following the divergence are the presence of species-specific genes and greater MHC class I diversity in gray seals than harbor seals. The elaboration of a complex variable family of classical MHC class I genes in pinnipeds contrasts with the single, highly polymorphic classical MHC class I gene of dog and giant panda, terrestrial carnivores.

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References

  • Adams EJ, Parham P (2001) Species-specific evolution of MHC class I genes in the higher primates. Immunol Rev 183:41–64

    Article  PubMed  CAS  Google Scholar 

  • Aldridge BM, Bowen L, Smith BR, Antonelis GA, Gulland F, Stott JL (2006) Paucity of class I MHC gene heterogeneity between individuals in the endangered Hawaiian monk seal population. Immunogenetics 58:203–215

    Article  PubMed  CAS  Google Scholar 

  • Arnason A, Gullberg A, Janke A, Kullberg M, Lehman N, Petrov EA, Vainola R (2006) Pinniped phylogeny and a new hypothesis for their origin and dispersal. Mol Phylogenet Evol 46:345–354

    Article  Google Scholar 

  • Ballingall KT, Miltiadou D, Chai ZW, McLean K, Rocchi M, Yaga R, McKeever DJ (2008) Genetic and proteomic analysis of the MHC class I repertoire from four ovine haplotypes. Immunogenetics 60:177–184

    Article  PubMed  CAS  Google Scholar 

  • Bashirova AA, Thomas R, Carrington M (2011) HLA/KIR restraint of HIV: surviving the fittest. Annu Rev Immunol 29:295–317

    Article  PubMed  CAS  Google Scholar 

  • Beck TW, Menninger J, Murphy WJ, Nash WG, O’Brien SJ, Yuhki N (2005) The feline major histocompatibility complex is rearranged by an inversion with a breakpoint in the distal class I region. Immunogenetics 56:702–709

    Article  PubMed  CAS  Google Scholar 

  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329:506–512

    Article  PubMed  CAS  Google Scholar 

  • Bowen L, Aldridge BM, Gulland F, Woo J, Van Bonn W, DeLong R, Stott JL, Johnson ML (2002) Molecular characterization of expressed DQA and DQB genes in the California sea lion (Zalophus californianus). Immunogenetics 54:332–347

    Article  PubMed  CAS  Google Scholar 

  • Bowen L, Aldridge BM, Gulland F, Van Bonn W, DeLong R, Melin S, Lowenstine LJ, Stott JL, Johnson ML (2004) Class II multiformity generated by variable MHC- DRB region configurations in the California sea lion (Zalophus californianus). Immunogenetics 56:12–27

    Article  PubMed  CAS  Google Scholar 

  • Bowen L, Aldridge BM, Delong R, Melin S, Godinez C, Zavala A, Gulland F, Lowenstine L, Stott JL, Johnson ML (2006) MHC gene configuration variation in geographically disparate populations of California sea lions (Zalophus californianus). Mol Ecol 15:529–533

    Article  PubMed  CAS  Google Scholar 

  • Boyington JC, Sun PD (2002) A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol Immunol 38:1007–1021

    Article  PubMed  CAS  Google Scholar 

  • Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD (2000) Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405:537–543

    Article  PubMed  CAS  Google Scholar 

  • Boyson JE, Shufflebotham C, Cadavid LF, Urvater JA, Knapp LA, Hughes AL, Watkins DI (1996) The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. J Immunol 156:4656–4665

    PubMed  CAS  Google Scholar 

  • Breen M, Thomas R, Binns MM, Carter NP, Langford CF (1999) Reciprocal chromosome painting reveals detailed regions of conserved synteny between the karyotypes of the domestic dog (Canis familiaris) and human. Genomics 61:145–155

    Article  PubMed  CAS  Google Scholar 

  • Burnett RC, Geraghty DE (1995) Structure and expression of a divergent canine class I gene. J Immunol 155:4278–4285

    PubMed  CAS  Google Scholar 

  • Burnett RC, DeRose SA, Wagner JL, Storb R (1997) Molecular analysis of six dog leukocyte antigen class I sequences including three complete genes, two truncated genes and one full-length processed gene. Tissue Antigens 49:484–495

    Article  PubMed  CAS  Google Scholar 

  • Cammen K, Hoffman JI, Knapp LA, Harwood J, Amos W (2011) Geographic variation of the major histocompatibility complex in Eastern Atlantic grey seals (Halichoerus grypus). Mol Ecol 20:740–752

    Article  PubMed  CAS  Google Scholar 

  • Cao Y, Fujiwara M, Nikaido M, Okada N, Hasegawa M (2000) Interordinal relationships and timescale of eutherian evolution as inferred from mitochondrial genome data. Gene 259:149–158

    Article  PubMed  CAS  Google Scholar 

  • Carlyle JR, Mesci A, Fine JH, Chen P, Belanger S, Tai LH, Makrigiannis AP (2008) Evolution of the Ly49 and Nkrp1 recognition systems. Semin Immunol 20:321–330

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee HJ, Ho SY, Barnes I, Groves C (2009) Estimating the phylogeny and divergence times of primates using a supermatrix approach. BMC Evol Biol 9:259

    Article  PubMed  Google Scholar 

  • Cheent K, Khakoo SI (2009) Natural killer cells: integrating diversity with function. Immunology 126:449–457

    Article  PubMed  CAS  Google Scholar 

  • Codner GF, Birch J, Hammond JA, Ellis SA (2012) Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I. Immunogenetics 64:435–445

    Article  PubMed  CAS  Google Scholar 

  • Decker DJ, Stewart BS, Lehman N (2002) Major histocompatibility complex class II DOA sequences from three Antarctic seal species verify stabilizing selection on the DO locus. Tissue Antigens 60:534–538

    Article  PubMed  CAS  Google Scholar 

  • Dietz R, Heide-Jørgensen MP, Harkonen T (1989) Mass deaths of harbor seals (Phoca vitulina) in Europe. Ambio 18:258–264

    Google Scholar 

  • Doxiadis GG, de Groot N, Otting N, Blokhuis JH, Bontrop RE (2011) Genomic plasticity of the MHC class I A region in rhesus macaques: extensive haplotype diversity at the population level as revealed by microsatellites. Immunogenetics 63:73–83

    Article  PubMed  Google Scholar 

  • Flajnik MF, Kasahara M (2010) Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11:47–59

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR (2011) Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 39:D913–D919

    Article  PubMed  Google Scholar 

  • Goodman SJ (1998) Patterns of extensive genetic differentiation and variation among European harbor seals (Phoca vitulina vitulina) revealed using microsatellite DNA polymorphisms. Mol Biol Evol 15:104–118

    Article  PubMed  CAS  Google Scholar 

  • Graumann MB, DeRose SA, Ostrander EA, Storb R (1998) Polymorphism analysis of four canine MHC class I genes. Tissue Antigens 51:374–381

    Article  PubMed  CAS  Google Scholar 

  • Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98

    CAS  Google Scholar 

  • Hall AJ, Jepson PD, Goodman SJ, Harkonen T (2006) Phocine distemper virus in the North and European Seas—data and models, nature and nurture. Biol Conserv 131:221–229

    Article  Google Scholar 

  • Hammond JA, Pomeroy PP, Hall AJ, Smith VJ (2005) Identification and real-time PCR quantification of Phocine distemper virus from two colonies of Scottish grey seals in 2002. J Gen Virol 86:2563–2567

    Article  PubMed  CAS  Google Scholar 

  • Hammond JA, Guethlein LA, Abi-Rached L, Moesta AK, Parham P (2009) Evolution and survival of marine carnivores did not require a diversity of killer cell Ig-like receptors or Ly49 NK cell receptors. J Immunol 182:3618–3627

    Article  PubMed  CAS  Google Scholar 

  • Harkonen T, Dietz R, Reijnders P, Teilmann J, Harding K, Hall A, Brasseur S, Siebert U, Goodman SJ, Jepson PD, Dau Rasmussen T, Thompson P (2006) The 1988 and 2002 phocine distemper virus epidemics in European harbour seals. Dis Aquat Organ 68:115–130

    Article  PubMed  Google Scholar 

  • Harkonen T, Harding K, Rasmussen TD, Teilmann J, Dietz R (2007) Age- and sex-specific mortality patterns in an emerging wildlife epidemic: the phocine distemper in European harbour seals. PLoS One 2:e887

    Article  PubMed  Google Scholar 

  • Harris CM, Travis JM, Harwood J (2008) Evaluating the influence of epidemiological parameters and host ecology on the spread of phocine distemper virus through populations of harbour seals. PLoS One 3:e2710

    Article  PubMed  Google Scholar 

  • Higdon JW, Bininda-Emonds OR, Beck RM, Ferguson SH (2007) Phylogeny and divergence of the pinnipeds (Carnivora: Mammalia) assessed using a multigene dataset. BMC Evol Biol 7:216

    Article  PubMed  Google Scholar 

  • Hoelzel AR, Stephens JC, O’Brien SJ (1999) Molecular genetic diversity and evolution at the MHC DQB locus in four species of pinnipeds. Mol Biol Evol 16:611–618

    Article  PubMed  CAS  Google Scholar 

  • Hofstetter AR, Sullivan LC, Lukacher AE, Brooks AG (2011) Diverse roles of non-diverse molecules: MHC class Ib molecules in host defense and control of autoimmunity. Curr Opin Immunol 23:104–110

    Article  PubMed  CAS  Google Scholar 

  • Kelley J, Walter L, Trowsdale J (2005) Comparative genomics of major histocompatibility complexes. Immunogenetics 56:683–695

    Article  PubMed  CAS  Google Scholar 

  • Kennedy LJ, Ollier WER, Marti E, Wagner JL, Storb R (2012) Caninine immunogenetics. In: Ostrander EA, Ruvinsky A (eds) The genetics of the dog, 2nd edn. CAB International, Oxon

    Google Scholar 

  • Kulski JK, Anzai T, Shiina T, Inoko H (2004) Rhesus macaque class I duplicon structures, organization, and evolution within the alpha block of the major histocompatibility complex. Mol Biol Evol 21:2079–2091

    Article  PubMed  CAS  Google Scholar 

  • Marrack P, Scott-Browne JP, Dai S, Gapin L, Kappler JW (2008) Evolutionarily conserved amino acids that control TCR–MHC interaction. Annu Rev Immunol 26:171–203

    Article  PubMed  CAS  Google Scholar 

  • Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernandez-Vina M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Muller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J (2010) Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75:291–455

    Article  PubMed  CAS  Google Scholar 

  • Martin DP, Lemey P, Lott M, Moulton V, Posada D, Lefeuvre P (2010) RDP3: a flexible and fast computer program for analyzing recombination. Bioinformatics 26:2462–2463

    Article  PubMed  CAS  Google Scholar 

  • Mellersh CS, Hitte C, Richman M, Vignaux F, Priat C, Jouquand S, Werner P, Andre C, DeRose S, Patterson DF, Ostrander EA, Galibert F (2000) An integrated linkage-radiation hybrid map of the canine genome. Mamm Genome 11:120–130

    Article  PubMed  CAS  Google Scholar 

  • Moffett A, Loke C (2006) Immunology of placentation in eutherian mammals. Nat Rev Immunol 6:584–594

    Article  PubMed  CAS  Google Scholar 

  • Neefjes J, Jongsma ML, Paul P, Bakke O (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11:823–836

    PubMed  CAS  Google Scholar 

  • Nery MF, Gonzalez DJ, Hoffmann FG, Opazo JC (2012) Resolution of the laurasiatherian phylogeny: evidence from genomic data. Mol Phylogenet Evol 64:685–689

    Article  PubMed  Google Scholar 

  • Orange JS, Ballas ZK (2006) Natural killer cells in human health and disease. Clin Immunol 118:1–10

    Article  PubMed  CAS  Google Scholar 

  • Pan H-J, Wan Q-H, Fang S-G (2008) Molecular characterization of major histocompatibility complex class I genes from the giant panda (Ailuropoda melanoleuca). Immunogenetics 60:185–193

    Article  PubMed  CAS  Google Scholar 

  • Parham P, Ohta T (1996) Population biology of antigen presentation by MHC class I molecules. Science 272:67–74

    Article  PubMed  CAS  Google Scholar 

  • Parham P, Abi-Rached L, Matevosyan L, Moesta AK, Norman PJ, Older Aguilar AM, Guethlein LA (2010) Primate-specific regulation of natural killer cells. J Med Primatol 39:194–212

    Article  PubMed  CAS  Google Scholar 

  • Rada C, Lorenzi R, Powis SJ, van den Bogaerde J, Parham P, Howard JC (1990) Concerted evolution of class I genes in the major histocompatibility complex of murine rodents. Proc Natl Acad Sci U S A 87:2167–2171

    Article  PubMed  CAS  Google Scholar 

  • Rajalingam R (2012) Overview of the killer cell immunoglobulin-like receptor system. Methods Mol Biol 882:391–414

    Article  PubMed  Google Scholar 

  • Robinson J, Mistry K, McWilliam H, Lopez R, Marsh SG (2010) IPD—the Immuno Polymorphism Database. Nucleic Acids Res 38:D863–D869

    Article  PubMed  CAS  Google Scholar 

  • Robinson J, Mistry K, McWilliam H, Lopez R, Parham P, Marsh SG (2011) The IMGT/HLA database. Nucleic Acids Res 39:D1171–D1176

    Article  PubMed  Google Scholar 

  • Rodgers JR, Cook RG (2005) MHC class Ib molecules bridge innate and acquired immunity. Nat Rev Immunol 5:459–471

    Article  PubMed  CAS  Google Scholar 

  • Ross P, Buntzman AS, Vincent BG, Grover EN, Gojanovich GS, Collins EJ, Frelinger JA, Hess PR (2012) Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited. Tissue Antigens 80(2):175–183

    Article  PubMed  CAS  Google Scholar 

  • Saito Y, Naruse TK, Akari H, Matano T, Kimura A (2012) Diversity of MHC class I haplotypes in cynomolgus macaques. Immunogenetics 64:131–141

    Article  PubMed  CAS  Google Scholar 

  • Saper MA, Bjorkman PJ, Wiley DC (1991) Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol 219:277–319

    Article  PubMed  CAS  Google Scholar 

  • Slade RW (1992) Limited MHC polymorphism in the southern elephant seal: implications for MHC evolution and marine mammal population biology. Proc Biol Sci 249:163–171

    Article  PubMed  CAS  Google Scholar 

  • Staden R, Beal KF, Bonfield JK (2000) The Staden package, 1998. Methods Mol Biol 132:115–130

    PubMed  CAS  Google Scholar 

  • Tallmadge RL, Campbell JA, Miller DC, Antczak DF (2010) Analysis of MHC class I genes across horse MHC haplotypes. Immunogenetics 62:159–172

    Article  PubMed  CAS  Google Scholar 

  • Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599

    Article  PubMed  CAS  Google Scholar 

  • Tanaka-Matsuda M, Ando A, Rogel-Gaillard C, Chardon P, Uenishi H (2009) Difference in number of loci of swine leukocyte antigen classical class I genes among haplotypes. Genomics 93:261–273

    Article  PubMed  CAS  Google Scholar 

  • Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882

    Article  PubMed  CAS  Google Scholar 

  • Trowsdale J (2011) The MHC, disease and selection. Immunol Lett 137:1–8

    Article  PubMed  CAS  Google Scholar 

  • Vivian JP, Duncan RC, Berry R, O’Connor GM, Reid HH, Beddoe T, Gras S, Saunders PM, Olshina MA, Widjaja JM, Harpur CM, Lin J, Maloveste SM, Price DA, Lafont BA, McVicar DW, Clements CS, Brooks AG, Rossjohn J (2011) Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B. Nature 479:401–405

    Article  PubMed  CAS  Google Scholar 

  • Wagner JL (2003) Molecular organization of the canine major histocompatibility complex. J Hered 94:23–26

    Article  PubMed  CAS  Google Scholar 

  • Wagner JL, Palti Y, DiDario D, Faraco J (2005) Sequence of the canine major histocompatibility complex region containing non-classical class I genes. Tissue Antigens 65:549–555

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Whitman MC, Natarajan K, Tormo J, Mariuzza RA, Margulies DH (2002) Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. J Biol Chem 277:1433–1442

    Article  PubMed  CAS  Google Scholar 

  • Weber DS, Stewart BS, Schienman J, Lehman N (2004) Major histocompatibility complex variation at three class II loci in the northern elephant seal. Mol Ecol 13:711–718

    Article  PubMed  CAS  Google Scholar 

  • Welch AY, Kasahara M, Spain LM (2003) Identification of the mouse killer immunoglobulin-like receptor (Kir1) gene family mapping to chromosome X. Immunogenetics 54:782–790

    PubMed  CAS  Google Scholar 

  • Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556

    PubMed  CAS  Google Scholar 

  • Yang Z, Wong WS, Nielsen R (2005) Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118

    Article  PubMed  CAS  Google Scholar 

  • Yuhki N, O’Brien SJ (1988) Molecular characterization and genetic mapping of class I and class II MHC genes of the domestic cat. Immunogenetics 27:414–425

    Article  PubMed  CAS  Google Scholar 

  • Yuhki N, O’Brien SJ (1994) Exchanges of short polymorphic DNA segments predating speciation in feline major histocompatibility complex class I genes. J Mol Evol 39:22–33

    Article  PubMed  Google Scholar 

  • Yuhki N, Heidecker GF, O’Brien SJ (1989) Characterization of MHC cDNA clones in the domestic cat. Diversity and evolution of class I genes. J Immunol 142:3676–3682

    PubMed  CAS  Google Scholar 

  • Yuhki N, Beck T, Stephens R, Neelam B, O’Brien SJ (2007) Comparative genomic structure of human, dog, and cat MHC: HLA, DLA, and FLA. J Hered 98:390–399

    Article  PubMed  CAS  Google Scholar 

  • Yuhki N, Mullikin JC, Beck T, Stephens R, O’Brien SJ (2008) Sequences, annotation and single nucleotide polymorphism of the major histocompatibility complex in the domestic cat. PLoS One 3:e2674

    Article  PubMed  Google Scholar 

  • Zhong JF, Harvey JT, Boothby JT (1998) Characterization of a harbor seal class I major histocompatability complex cDNA clone. Immunogenetics 48:422–424

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the Sea Mammal Research Unit at the Scottish Oceans Institute for their generous help in collecting the samples. This work was supported by NIH grant AI24258 to P.P. We thank three anonymous reviewers of this paper for their constructive and insightful advice.

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  1. John A. Hammond

    Present address: Livestock Viral Diseases Program, Institute for Animal Health, Compton, RG20 7NN, UK

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  1. Department of Structural Biology, Stanford University School of Medicine, Fairchild D-159 299 Campus Drive West, Stanford, CA, 94305, USA

    John A. Hammond, Lisbeth A. Guethlein, Paul J. Norman & Peter Parham

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Hammond, J.A., Guethlein, L.A., Norman, P.J. et al. Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism. Immunogenetics 64, 915–933 (2012). https://doi.org/10.1007/s00251-012-0651-z

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