Key Points
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The adaptive immune system as defined in humans — which includes antigen receptors generated by recombination-activating gene (RAG)-mediated rearrangement and diversified by members of the AID-APOBEC family; the major histocompatibility (MHC); extensive chemokine and cytokine networks; and secondary lymphoid tissues — arose early in the evolution of jawed vertebrates (in placoderms).
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The RAG transposon is believed to have invaded an immunoglobulin superfamily exon in early jawed vertebrates. It is thought to have provided a new mechanism for generating antigen receptor diversity and led to the emergence of adaptive immunity.
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Some features of adaptive immunity are evolutionarily conserved across species and other features show great plasticity, the latter driven by pathogens.
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Two rounds of whole-genome duplication produced many paralogues (ohnologues) that are essential for the adaptive immune system of jawed vertebrates.
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Jawless vertebrates have developed an adaptive immune system that employs variable lymphocyte receptors instead of T cell and B cell receptors.
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Two types of variable lymphocyte receptors — VLRA and VLRB — are expressed on T- and B-like lymphoid cells, respectively, which suggests that the origin of cell-mediated and humoral immunity predates the origin of jawed vertebrates.
Abstract
The adaptive immune system (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence system consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS.
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References
Weigert, M. G., Cesari, I. M., Yonkovich, S. J. & Cohn, M. Variability in the λ light chain sequences of mouse antibody. Nature 228, 1045–1047 (1970).
Tonegawa, S. Reiteration frequency of immunoglobulin light chain genes: further evidence for somatic generation of antibody diversity. Proc. Natl Acad. Sci. USA 73, 203–207 (1976).
Davis, M. M., Chien, Y. H., Gascoigne, N. R. & Hedrick, S. M. A murine T cell receptor gene complex: isolation, structure and rearrangement. Immunol. Rev. 81, 235–258 (1984).
Oettinger, M. A., Schatz, D. G., Gorka, C. & Baltimore, D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517–1523 (1990).
Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).
Schluter, S. F., Bernstein, R. M., Bernstein, H. & Marchalonis J. J. 'Big Bang' emergence of the combinatorial immune system. Dev. Comp. Immunol. 23, 107–111 (1999).
Pancer, Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430, 174–180 (2004). This is a seminal paper that described a novel rearranging gene in the lamprey. This work suggested strongly that jawless vertebrates have an alternative form of adaptive immunity that is not dependent on BCRs, TCRs or the MHC.
Rogozin, I. B., Iyer, L. M. et al. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nature Immunol. 8, 647–656 (2007). This paper suggests that the diversity of the VLR gene is generated by a gene conversion-like process that is presumably mediated by cytidine deaminases of the AID-APOBEC family. It also describes the identification of the lamprey VLRA gene.
Hibino, T., Loza-Coll. M. et al. The immune gene repertoire encoded in the purple sea urchin genome. Dev. Biol. 300, 349–365 (2006).
Jones, J. D. & Dangl, J. L. The plant immune system. Nature 444, 323–329 (2006).
Klein, J., Satta, Y., O'hUigin, C. & Takahata, N. The molecular descent of the major histocompatibility complex. Annu. Rev. Immunol. 11, 269–295 (1993).
Flajnik, M. F. Comparative analyses of immunoglobulin genes: surprises and portents. Nature Rev. Immunol. 2, 688–698 (2002).
Kaattari, S., Evans, D. & Klemer, J. Varied redox forms of teleost IgM: an alternative to isotypic diversity? Immunol. Rev. 166, 133–142 (1998).
Dooley, H. & Flajnik, M. F. Shark immunity bites back: affinity maturation and memory response in the nurse shark, Ginglymostoma cirratum. Eur. J. Immunol. 35, 936–945 (2005).
Wilson, M. et al. A novel chimeric Ig heavy chain from a teleost fish shares similarities to IgD. Proc. Natl Acad. Sci. USA 94, 4593–4597 (1997).
Ohta, Y. & Flajnik, M. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc. Natl Acad. Sci. USA 103, 10723–10728 (2006).
Zhao, Y. et al. Identification of IgF, a hinge-region-containing Ig class, and IgD in Xenopus tropicalis. Proc. Natl Acad. Sci. USA 103, 12087–12092 (2006). References 16 and 17 confirm that IgD is much older than previously realized and that it has evolved rapidly over evolutionary time.
Greenberg, A. S. et al. A novel 'chimeric' antibody class in cartilaginous fish: IgM may not be the primordial immunoglobulin. Eur. J. Immunol. 26, 1123–1129 (1996).
Berstein, R. M., Schluter, S. F., Shen, S. & Marchalonis, J. J. A new high molecular weight immunoglobulin class from the carcharhine shark: implications for the properties of the primordial immunoglobulin. Proc. Natl Acad. Sci. USA 93, 3289–3293 (1996).
Ota, T., Rast, J. P., Litman, G. W. & Amemiya, C. T. Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox. Proc. Natl Acad. Sci. USA 100, 2501–2506 (2003).
Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nature Immunol. 10, 889–898 (2009).
Warr, G. W., Magor, K. E. & Higgins, D. A. IgY: clues to the origins of modern antibodies. Immunol. Today 16, 392–398 (1995).
Mussmann, R., Du Pasquier, L. & Hsu, E. Is Xenopus IgX an analog of IgA? Eur. J. Immunol. 26, 2823–2830 (1996).
Desmyter, A. et al. Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme. Nature Struct. Biol. 3, 803–811 (1996).
Greenberg, A. S. et al. A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 374, 168–173 (1995).
Greenberg, A. S., Steiner, L., Kasahara, M. & Flajnik, M. F. Isolation of a shark immunoglobulin light chain cDNA clone encoding a protein resembling mammalian κ light chains: implications for the evolution of light chains. Proc. Natl Acad. Sci. USA 90, 10603–10607 (1993).
Criscitiello, M. F. & Flajnik, M. F. Four primordial immunoglobulin light chain isotypes, including λ and κ, identified in the most primitive living jawed vertebrates. Eur. J. Immunol. 37, 2683–2694 (2007).
Hohman, V. S., Schuchman, D. B., Schluter, S. F. & Marchalonis, J. J. Genomic clone for sandbar shark λ light chain: generation of diversity in the absence of gene rearrangement. Proc. Natl Acad. Sci. USA 90, 9882–9886 (1993).
Rast, J. P. et al. Immunoglobulin light chain class multiplicity and alternative organizational forms in early vertebrate phylogeny. Immunogenetics 40, 83–99 (1994).
Schwager, J., Burckert, N., Schwager, M. & Wilson, M. Evolution of immunoglobulin light chain genes: analysis of Xenopus IgL isotypes and their contribution to antibody diversity. EMBO J. 10, 505–511 (1991).
Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).
Reynaud, C. A., Anquez, V., Grimal, H. & Weill, J. C. A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 48, 379–388 (1987).
Knight, K. L. & Becker, R. S. Molecular basis of the allelic inheritance of rabbit immunoglobulin VH allotypes: implications for the generation of antibody diversity. Cell 60, 963–970 (1990).
Hinds, K. R. & Litman, G. W. Major reorganization of immunoglobulin VH segmental elements during vertebrate evolution. Nature 320, 546–549 (1986).
Hinds-Frey, K. R., Nishikata, H., Litman, R. T. & Litman, G. W. Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity. J. Exp. Med. 178, 815–824 (1993).
Diaz, M., Greenberg, A. S. & Flajnik, M. F. Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: possible role in antigen-driven reactions in the absence of germinal centers. Proc. Natl Acad. Sci. USA 95, 14343–14348 (1998).
Lee, S. S., Tranchina, D., Ohta, Y., Flajnik, M. F. & Hsu, E. Hypermutation in shark immunoglobulin light chain genes results in contiguous substitutions. Immunity 16, 571–582 (2002).
Daggfeldt, A., Bengten, E. & Pilstrom, L. A cluster type organization of the loci of the immunoglobulin light chain in Atlantic cod (Gadus morhua L.) and rainbow trout (Oncorhynchus mykiss Walbaum) indicated by nucleotide sequences of cDNAs and hybridization analysis. Immunogenetics 38, 199–209 (1993).
Hsu, E. & Criscitiello, M. F. Diverse immunoglobulin light chain organizations in fish retain potential to revise B cell receptor specificities. J. Immunol. 177, 2452–2462 (2006).
Lange, M. D., Waldbieser, G. C. & Lobb, C. J. Patterns of receptor revision in the immunoglobulin heavy chains of a teleost fish. J. Immunol. 182, 5605–5622 (2009).
Zimmerman, A. M., Yeo, G., Howe, K., Maddox, B. J. & Steiner, L. A. Immunoglobulin light chain (IgL) genes in zebrafish: genomic configurations and inversional rearrangements between (VL-JL-CL) gene clusters. Dev. Comp. Immunol. 32, 421–434 (2008).
Danilova, N., Bussmann, J., Jekosch, K. & Steiner, L. A. The immunoglobulin heavy-chain locus in zebrafish: identification and expression of a previously unknown isotype, immunoglobulin Z. Nature Immunol. 6, 295–302 (2005).
Hansen, J. D., Landis, E. D. & Phillips, R. B. Discovery of a unique Ig heavy-chain isotype (IgT) in rainbow trout: implications for a distinctive B cell developmental pathway in teleost fish. Proc. Natl Acad. Sci. USA 102, 6919–6924 (2005).
Zinkernagel, R. M. & Doherty, P. C. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251, 547–548 (1974).
Charlemagne, J., Fellah, J. S., De Guerra, A., Kerfourn, F. & Partula, S. T-cell receptors in ectothermic vertebrates. Immunol. Rev. 166, 87–102 (1998).
Guo, J. et al. Regulation of the TCRα repertoire by the survival window of CD4+CD8+ thymocytes. Nature Immunol. 3, 469–476 (2002).
Havran, W. L. et al. Limited diversity of T-cell receptor γ-chain expression of murine Thy-1+ dendritic epidermal cells revealed by V γ 3-specific monoclonal antibody. Proc. Natl Acad. Sci. USA 86, 4185–4189 (1989).
Morita, C. T. et al. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3, 495–507 (1995).
Thedrez, A. et al. Self/non-self discrimination by human γδ T cells: simple solutions for a complex issue? Immunol. Rev. 215, 123–135 (2007).
Rock, E. P., Sibbald, P. R., Davis, M. M. & Chien, Y. H. CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328 (1994).
Criscitiello, M. F., Saltis, M. & Flajnik, M. F. An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks. Proc. Natl Acad. Sci. USA 103, 5036–5041 (2006).
Parra, Z. E. et al. A unique T cell receptor discovered in marsupials. Proc. Natl Acad. Sci. USA 104, 9776–9781 (2007).
Sciammas, R. & Bluestone, J. A. TCRγδ cells and viruses. Microbes Infect. 1, 203–212 (1999).
Chen, H. et al. Characterization of arrangement and expression of the T cell receptor γ locus in the sandbar shark. Proc. Natl Acad. Sci. USA 106, 8591–8596 (2009).
Flajnik, M. F. & Kasahara, M. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15, 351–362 (2001).
Kaufman, J. Co-evolving genes in MHC haplotypes: the 'rule' for nonmammalian vertebrates? Immunogenetics 50, 228–236 (1999).
Trowsdale, J. Genetic and functional relationships between MHC and NK receptor genes. Immunity 15, 363–374 (2001).
Rogers, S. L., Viertlboeck, B. C., Gobel, T. W. & Kaufman, J. Avian NK activities, cells and receptors. Semin. Immunol. 20, 353–360 (2008).
Nyholm, S. V. et al. fester, a candidate allorecognition receptor from a primitive chordate. Immunity 25, 163–173 (2006).
Sakano, H., Huppi, K., Heinrich, G. & Tonegawa, S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280, 288–294 (1979).
Du Pasquier, L., Zucchetti, I. & De Santis, R. Immunoglobulin superfamily receptors in protochordates: before RAG time. Immunol. Rev. 198, 233–248 (2004).
Hernández Prada, J. A. et al. Ancient evolutionary origin of diversified variable regions demonstrated by crystal structures of an immune-type receptor in amphioxus. Nature Immunol. 7, 875–882 (2006).
Yu, C. et al. Genes 'waiting' for recruitment by the adaptive immune system: the insights from amphioxus. J. Immunol. 174, 3493–3500 (2005).
Suzuki, T., Shin, I., Fujiyama, A., Kohara, Y. & Kasahara, M. Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors. J. Immunol. 174, 2885–2891 (2005).
Pancer, Z., Mayer, W. E., Klein, J. & Cooper, M. D. Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc. Natl Acad. Sci. USA 101, 13273–13278 (2004).
Thompson, C. B. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531–539 (1995).
Fugmann, S. D., Messier, C., Novack, L. A., Cameron, R. A. & Rast, J. P. An ancient evolutionary origin of the Rag1/2 gene locus. Proc. Natl Acad. Sci. USA 103, 3728–3733 (2006). This paper demonstrates that RAG1 and RAG2 were present in echinoderms (sea urchins) approximately 100 million years before the emergence of the AIS.
Kapitonov, V. V. & Jurka, J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol. 3, e181 (2005). This work shows that a transposable element, transib, contains the RAG1 core element and is found in many animal species, including invertebrates.
Dreyfus, D. H. Paleo-immunology: evidence consistent with insertion of a primordial herpes virus-like element in the origins of acquired immunity. PLoS ONE 4, e5778 (2009).
Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R. & Desiderio, S. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen–receptor–gene rearrangement. Immunity 27, 561–571 (2007).
Klein, J. & Nikolaidis, N. The descent of the antibody-based immune system by gradual evolution. Proc. Natl Acad. Sci. USA 102, 169–174 (2005).
Flajnik, M. F. & Du Pasquier, L. Evolution of innate and adaptive immunity: can we draw a line? Trends Immunol. 25, 640–644 (2004).
Ohno, S. Evolution by Gene Duplication (Springer, 1970).
Furlong, R. F. & Holland, P. W. Were vertebrates octoploid? Phil. Trans. R. Soc. Lond. B 357, 531–544 (2002).
Panopoulou, G. & Poustka, A. J. Timing and mechanism of ancient vertebrate genome duplications — the adventure of a hypothesis. Trends Genet. 21, 559–567 (2005).
Kasahara, M. The 2R hypothesis: an update. Curr. Opin. Immunol. 19, 547–552 (2007).
Van de Peer, Y., Maere, S. & Meyer, A. The evolutionary significance of ancient genome duplications. Nature Rev. Genet. 10, 725–732 (2009).
Kasahara, M., Nakaya, J., Satta, Y. & Takahata, N. Chromosomal duplication and the emergence of the adaptive immune system. Trends Genet. 13, 90–92 (1997).
Kasahara, M., Suzuki, T. & Du Pasquier, L. On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates. Trends Immunol. 25, 105–111 (2004).
Okada, K. & Asai, K. Expansion of signaling genes for adaptive immune system evolution in early vertebrates. BMC Genomics 9, 218 (2008). This paper provides a comprehensive analysis of ohnologues that are involved in the AIS of jawed vertebrates.
Kasahara, M. What do the paralogous regions in the genome tell us about the origin of the adaptive immune system? Immunol. Rev. 166, 159–175 (1998).
Kasahara, M. et al. Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex. Proc. Natl Acad. Sci. USA 93, 9096–9101 (1996).
Katsanis, N., Fitzgibbon, J. & Fisher, E. M. Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci. Genomics 35, 101–108 (1996).
Vienne, A. et al. Evolution of the proto-MHC ancestral region: more evidence for the plesiomorphic organisation of human chromosome 9q34 region. Immunogenetics 55, 429–436 (2003).
Olinski, R. P., Lundin, L. G. & Hallbook, F. Conserved synteny between the Ciona genome and human paralogons identifies large duplication events in the molecular evolution of the insulin-relaxin gene family. Mol. Biol. Evol. 23, 10–22 (2006). Based on the comparative analysis of the insulin-relaxin family in humans and C. intestinalis , this paper proposes that the MHC paralogy group and the neurotrophin paralogy group were derived from a single contiguous region on an invertebrate proto-chromosome.
Abi-Rached, L., Gilles, A., Shiina, T., Pontarotti, P. & Inoko, H. Evidence of en bloc duplication in vertebrate genomes. Nature Genet. 31, 100–105 (2002).
Azumi, K. et al. Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: 'waiting for Godot'. Immunogenetics 55, 570–581 (2003).
Holland, L. Z. et al. The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res. 18, 1100–1111 (2008). This paper provides a comprehensive analysis of the genes that encode the major biological systems in amphioxi. Among the genes analysed are those involved in host defence.
Hallbook, F., Wilson, K., Thorndyke, M. & Olinski, R. P. Formation and evolution of the chordate neurotrophin and Trk receptor genes. Brain Behav. Evol. 68, 133–144 (2006).
Belov, K. et al. Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex. PLoS Biol. 4, e46 (2006).
Kasahara, M. Genome dynamics of the major histocompatibility complex: insights from genome paralogy. Immunogenetics 50, 134–145 (1999).
Marchalonis, J. J. & Edelman, G. M. Phylogenetic origins of antibody structure. III. Antibodies in the primary immune response of the sea lamprey, Petromyzon marinus. J. Exp. Med. 127, 891–914 (1968).
Finstad, J. & Good, R. A. The evolution of the immune response. III. Immunologic responses in the lamprey. J. Exp. Med. 120, 1151–1168 (1964).
Litman, G. W., Finstad, F. J., Howell, J., Pollara, B. W. & Good, R. A. The evolution of the immune response. III. Structural studies of the lamprey immunoglobulin. J. Immunol. 105, 1278–1285 (1970).
Linthicum, D. S. & Hildemann, W. H. Immunologic responses of Pacific hagfish. III. Serum antibodies to cellular antigens. J. Immunol. 105, 912–918 (1970).
Mayer, W. E. et al. Isolation and characterization of lymphocyte-like cells from a lamprey. Proc. Natl Acad. Sci. USA 99, 14350–14355 (2002).
Uinuk-Ool, T. et al. Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc. Natl Acad. Sci. USA 99, 14356–14361 (2002).
Suzuki, T., Shin, I., Kohara, Y. & Kasahara, M. Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes. Dev. Comp. Immunol. 28, 993–1003 (2004).
Pancer, Z. & Cooper, M. D. The evolution of adaptive immunity. Annu. Rev. Immunol. 24, 497–518 (2006).
Nagawa, F. et al. Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nature Immunol. 8, 206–213 (2007). This paper is the first to analyse the genetic mechanisms involved in VLR gene assembly. It proposes that LRR modules are tethered by a copy-choice mechanism.
Alder, M. N. et al. Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310, 1970–1973 (2005).
Kim, H. M. et al. Structural diversity of the hagfish variable lymphocyte receptors. J. Biol. Chem. 282, 6726–6732 (2007).
Herrin, B. R. et al. Structure and specificity of lamprey monoclonal antibodies. Proc. Natl Acad. Sci. USA 105, 2040–2045 (2008).
Han, B. W., Herrin, B. R., Cooper, M. D. & Wilson, I. A. Antigen recognition by variable lymphocyte receptors. Science 321, 1834–1837 (2008).
Velikovsky, C. A. et al. Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen. Nature Struct. Mol. Biol. 16, 725–730 (2009).
Alder, M. N. et al. Antibody responses of variable lymphocyte receptors in the lamprey. Nature Immunol. 9, 319–327 (2008).
Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009). This paper indicates that lampreys have two lineages of lymphoid cells that resemble T and B cells of jawed vertebrates.
Pancer, Z. et al. Variable lymphocyte receptors in hagfish. Proc. Natl Acad. Sci. USA 102, 9224–9229 (2005).
Kasamatsu, J., Suzuki, T., Ishijima, J., Matsuda, Y. & Kasahara, M. Two variable lymphocyte receptor genes of the inshore hagfish are located far apart on the same chromosome. Immunogenetics 59, 329–331 (2007).
Haruta, C., Suzuki, T. & Kasahara, M. Variable domains in hagfish: NICIR is a polymorphic multigene family expressed preferentially in leukocytes and is related to lamprey TCR-like. Immunogenetics 58, 216–225 (2006).
Yokoyama, W. M. & Plougastel, B. F. Immune functions encoded by the natural killer gene complex. Nature Rev. Immunol. 3, 304–316 (2003).
Takahashi, T. et al. Natural killer cell receptors in the horse: evidence for the existence of multiple transcribed LY49 genes. Eur. J. Immunol. 34, 773–784 (2004).
Bell, J. J. & Bhandoola, A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452, 764–767 (2008).
Boehm, T. One problem, two solutions. Nature Immunol. 10, 811–813 (2009).
Wada, H. et al. Adult T-cell progenitors retain myeloid potential. Nature 452, 768–772 (2008).
Litman, G. W., Cannon, J. P. & Dishaw, L. J. Reconstructing immune phylogeny: new perspectives. Nature Rev. Immunol. 5, 866–879 (2005).
Beutler, B. et al. Genetic analysis of resistance to viral infection. Nature Rev. Immunol. 7, 753–766 (2007).
Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).
Solem, S. T. & Stenvik, J. Antibody repertoire development in teleosts — a review with emphasis on salmonids and Gadus morhua L. Dev. Comp. Immunol. 30, 57–76 (2006).
Matsunaga, T. & Rahman, A. What brought the adaptive immune system to vertebrates? — The jaw hypothesis and the seahorse. Immunol. Rev. 166, 177–186 (1998).
Kaufman, J., Volk, H. & Wallny, H. J. A 'minimal essential Mhc' and an 'unrecognized Mhc': two extremes in selection for polymorphism. Immunol. Rev. 143, 63–88 (1995).
Flajnik, M. F. Churchill and the immune system of ectothermic vertebrates. Immunol. Rev. 166, 5–14 (1998).
Tasumi, S. et al. High-affinity lamprey VLRA and VLRB monoclonal antibodies. Proc. Natl Acad. Sci. USA 106, 12891–12896 (2009).
Travis, J. Origins. On the origin of the immune system. Science 324, 580–582 (2009).
Fall-Ngai, M. Adaptive immunity: care for the community. Nature 445, 153 (2007).
Long, J. A., Trinajstic, K. & Johanson, Z. Devonian arthrodire embryos and the origin of internal fertilization in vertebrates. Nature 457, 1124–1127 (2009).
Friedman, R. & Hughes, A. L. Pattern and timing of gene duplication in animal genomes. Genome Res. 11, 1842–1847 (2001).
Hughes, A. L. & Friedman, R. 2R or not 2R: testing hypotheses of genome duplication in early vertebrates. J. Struct. Funct. Genomics 3, 85–93 (2003).
Gibson, T. J. & Spring, J. Evidence in favour of ancient octaploidy in the vertebrate genome. Biochem. Soc. Trans. 28, 259–264 (2000).
Lundin, L. G., Larhammar, D. & Hallbook, F. Numerous groups of chromosomal regional paralogies strongly indicate two genome doublings at the root of the vertebrates. J. Struct. Funct. Genomics 3, 53–63 (2003).
Putnam, N. H. et al. The amphioxus genome and the evolution of the chordate karyotype. Nature 453, 1064–1071 (2008). This paper, written by core members of the amphioxus genome project, describes the salient features of the amphioxus genome, with emphasis on genome evolution. It provides strong evidence to support the 2R hypothesis.
Kuraku, S., Meyer, A. & Kuratani, S. Timing of genome duplications relative to the origin of the vertebrates: did cyclostomes diverge before or after? Mol. Biol. Evol. 26, 47–59 (2009). This paper proposes that, contrary to the commonly held view, both the first and second rounds of WGD occurred after the emergence of a common ancestor of vertebrates and before the divergence of jawed and jawless vertebrates.
Karre, K. NK cells, MHC class I molecules and the missing self. Scand. J. Immunol. 55, 221–228 (2002).
Jaillon, O. et al. Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype. Nature 431, 946–957 (2004).
Vandepoele, K., De Vos, W., Taylor, J. S., Meyer, A. & Van de Peer, Y. Major events in the genome evolution of vertebrates: paranome age and size differ considerably between ray-finned fishes and land vertebrates. Proc. Natl Acad. Sci. USA 101, 1638–1643 (2004).
Blair, J. E. & Hedges, S. B. Molecular phylogeny and divergence times of deuterostome animals. Mol. Biol. Evol. 22, 2275–2284 (2005).
Kasahara, M. The chromosomal duplication model of the major histocompatibility complex. Immunol. Rev. 167, 7–32 (1999).
Horton, R. et al. Gene map of the extended human MHC. Nature Rev. Genet. 5, 889–899 (2004).
Acknowledgements
M.F.F. has been funded by the US National Institutes of Health grants AI027877 and RR006603. M.K. has been funded by a KAKENHI grant for the priority area 'Comparative Genomics' from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Supplementary information
Supplementary Figure 1
The HOX paralogy group. (PDF 269 kb)
Supplementary Table 1
Representative Ohnologs mapping to the MHC/neurotrophin- and HOX-paralogons (PDF 207 kb)
Related links
Glossary
- Somatic hypermutation
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Mutation of the variable gene after mature B cells are stimulated. It results in affinity maturation of the antibody response. Like the class switch, it requires activation-induced cytidine deaminase.
- Variable–diversity–joining rearrangement
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(VDJ rearrangement.) The recombination-activating gene (RAG)-mediated ligation of T cell receptor or B cell receptor variable (V), diversity (D) and joining (J) gene segments during lymphocyte ontogeny, which generates the antigen receptor repertoire.
- Immunoglobulins
-
Also known as antibodies or B cell receptors, they are composed of two identical heavy (H) and light (L) chains that are covalently linked by disulphide bonds. Monomeric immunoglobulins are bivalent, and the binding site is made up of the amino-terminal variable domains of one H and one L chain. The class or isotype of an immunoglobulin is defined by its H chain.
- Jawless fish
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Primordial vertebrates without jaws, of which the only two extant forms are lampreys and hagfish.
- Major histocompatibility complex
-
A large complex of tightly linked genes, many of which are involved in immunity. It encodes the polymorphic class I and class II molecules, which present antigens in the form of peptides to cytotoxic and helper T cells, respectively.
- Jawed vertebrates
-
Vertebrates from cartilaginous fish to mammals. The first class of vertebrates with jaws, the placoderms, all became extinct.
- Mucosal immunity
-
Immune responses made across epithelial surfaces, such as the gut and lung.
- Immunoglobulin new antigen receptor
-
(IgNAR.) A specialized antibody in sharks that is composed of disulphide-linked heavy chains and no associated light chains.
- Translocon organization
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An organization of immunoglobulin genes in which there are multiple variable (V), diversity (D) and joining (J) segments upstream of a single constant gene.
- Cluster organization
-
An organization of immunoglobulin genes in which there are single variable (V), diversity (D), joining (J) and constant gene segments, although sometimes two or three diversity segments occur together. Also known as minilocus organization.
- Receptor editing
-
The re-rearrangement of antigen receptor genes to avoid self reactivity in the case of B cells or to express new receptors that can be positively selected in the case of T cells.
- Class switch
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The rearrangement of an existing variable–diversity–joining (VDJ) exon from the 5′ end of the immunoglobulin M gene to downstream constant (C) genes. Like somatic hypermutation, it requires activation-induced cytidine deaminase.
- Major histocompatibility complex restriction
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T cell receptors recognize antigens in the form of small peptides ranging from 9–22 amino acids that are bound to major histocompatibility complex (MHC) class I or class II molecules. The T cell receptor recognizes both the MHC protein and the peptide antigen — this is known as 'MHC restriction'.
- Complementarity-determining region 3
-
A loop in the variable (V) region of the B cell receptor and T cell receptor chains that is encoded by the variable–diversity–joining (VDJ) intersection that is generated by recombination-activating gene (RAG)-mediated somatic rearrangement. It is the part of the antigen-binding site that is most diverse in amino acid sequence and length.
- Transporter associated with antigen processing
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(TAP). A transporter of the ATP-binding cassette superfamily that is involved in the transport of peptides from the cytosol into the lumen of the endoplasmic reticulum. It is a heterodimer composed of TAP1 and TAP2 subunits and has a crucial role in the transport of major histocompatibility complex class I-binding peptides.
- Tapasin
-
A protein that facilitates the binding of peptides to major histocompatibility complex (MHC) class I molecules by forming a bridge between MHC class I molecules and transporter associated with antigen processing (TAP).
- Recombination signal sequences
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Conserved nucleotide sequences flanking variable (V), diversity (D) and joining (J) segments that are recognized by the recombination-activating gene (RAG) proteins to induce rearrangement.
- Immunoglobulin superfamily
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Domains of 90–100 amino acids composed of 7–9 β strands forming two sheets, generally stabilized by a disulphide bond. Found in B cell receptor, T cell receptor and major histocompatibility complex molecules.
- Ohnologues
-
Paralogues, named after Susumu Ohno, that are thought to have emerged close to the origin of vertebrates by whole-genome duplication.
- Paralogy group
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A set of paralogons that are derived from a single ancestral region.
- Paralogues
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(Also known as paralogous genes.) Genes within a single species that belong to the same gene family. In contrast to 'paralogues', 'orthologues' refers to genes that diverged by speciation events.
- Paralogons
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Chromosomal segments that contain closely linked sets of paralogues. Also known as paralogous regions.
- Agglutinin
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Any substance that can clump particles together.
- AID-APOBEC
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A family of cytidine deaminases that are involved in the hypermutation of variable–diversity–joining (VDJ) segments, in the immunoglobulin class switch and in defence against viruses. Two members of the family are implicated in generating diversity in variable lymphocyte receptors.
- Allelic exclusion
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The expression of a single receptor in cells with the potential to express more than two receptors.
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Flajnik, M., Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11, 47–59 (2010). https://doi.org/10.1038/nrg2703
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DOI: https://doi.org/10.1038/nrg2703
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