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Xenopus in the Amphibian Ancestral Organization of the MHC Revealed

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Xenopus in the Amphibian Ancestral Organization of the MHC Revealed Ancestral Organization of the MHC Revealed in the Amphibian Xenopus Yuko Ohta, Wilfried Goetz, M. Zulfiquer Hossain, Masaru Nonaka and Martin F. Flajnik This information is current as of September 26, 2021. J Immunol 2006; 176:3674-3685; ; doi: 10.4049/jimmunol.176.6.3674 http://www.jimmunol.org/content/176/6/3674 Downloaded from References This article cites 70 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/176/6/3674.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ancestral Organization of the MHC Revealed in the Amphibian Xenopus1 Yuko Ohta,2* Wilfried Goetz,* M. Zulfiquer Hossain,* Masaru Nonaka,† and Martin F. Flajnik* With the advent of the Xenopus tropicalis genome project, we analyzed scaffolds containing MHC genes. On eight scaffolds encompassing 3.65 Mbp, 122 MHC genes were found of which 110 genes were annotated. Expressed sequence tag database screening showed that most of these genes are expressed. In the extended class II and class III regions the genomic organization, excluding several block inversions, is remarkably similar to that of the human MHC. Genes in the human extended class I region are also well conserved in Xenopus, excluding the class I genes themselves. As expected from previous work on the Xenopus MHC, the single classical class I gene is tightly linked to immunoproteasome and transporter genes, defining the true class I region, present in all nonmammalian jawed vertebrates studied to date. Surprisingly, the immunoproteasome gene PSMB10 is found in Downloaded from the class III region rather than in the class I region, likely reflecting the ancestral condition. Xenopus DM␣, DM␤, and C2 genes were identified, which are not present or not clearly identifiable in the genomes of any teleosts. Of great interest are novel V-type Ig superfamily (Igsf) genes in the class III region, some of which have inhibitory motifs (ITIM) in their cytoplasmic domains. Our analysis indicates that the vertebrate MHC experienced a vigorous rearrangement in the bony fish and bird lineages, and a translocation and expansion of the class I genes in the mammalian lineage. Thus, the amphibian MHC is the most evolutionary conserved MHC so far analyzed. The Journal of Immunology, 2006, 176: 3674–3685. http://www.jimmunol.org/ he MHC is the most gene-dense region in the human ge- gesting that this class I region is the primordial organization (5–7). nome and plays an indispensable role in the adaptive im- In some nonmammalian species, there is only a single or few clas- mune system (1). Class I and class II Ag-presenting mol- sical class I genes, perhaps due to a selection for coevolution with T ϩ ecules present small peptides derived from pathogens to CD8 and the Ag-processing genes. Thus, plasticity of class I genes in mam- CD4ϩ T cells, respectively. In the class I system, endogenous pep- malian species is an evolutionarily derived characteristic (5, 7). tides derived from intracellular pathogens are enzymatically Xenopus (especially Xenopus laevis and more recently Xenopus cleaved into small peptides by the immunoproteasome containing tropicalis) has been used historically for developmental studies by guest on September 26, 2021 the specialized ␤-subunits PSMB8, PSMB9, and PSMB10, which (8). Regarding the MHC, this animal is the most comprehensively upon infection replace the constitutive subunits, PSMB5, PSMB6, studied amphibian for characteristics of the adaptive immune sys- and PSMB7, respectively (2). Short peptides of 8–11 aas are trans- tem. Xenopus is a unique model because there are several ported into endoplasmic reticulum by the TAP (TAP1 and TAP2) polyploid species (2n–12n) within the genus that arose by recent and then loaded onto class I molecules associated with tapasin genome-wide duplication (from 2 to 30 million years ago) (9). (TAPBP). The resulting class I-peptide complexes move to the cell Because of its important phylogenetic position, and because it is a surface, where they are recognized by Ag-specific TCRs expressed true diploid (genome size approximately half that of human), X. by CD8ϩ T cells (3). Interestingly, in most mammals, the genes tropicalis has been selected as a model organism for a whole ge- responsible for class I Ag processing are embedded in the class II nome sequencing project (͗www.jgi.doe.gov/xenopus͘). BAC li- region (e.g. PSMB8, PSMB9, TAP1, and TAP2) or in the extended braries have been constructed and available to the public for anal- class II region (e.g., TAPBP, class I transcription regulator, RXRB), ysis and genetic manipulation. In addition, different sources of whereas class I genes themselves are found in another region (4). expressed sequences have been deposited into the expressed se- In contrast, studies of nonmammalian vertebrates have shown that quence tag (EST)3 databases for X. tropicalis and X. laevis, which class I genes are tightly linked to class I-processing genes, sug- facilitates gene annotation. In our previous studies of the Xenopus MHC in which we te- diously cloned the genes orthologous to those of humans one by *University of Maryland, Department of Microbiology and Immunology, 655 West one, it was shown that synteny seemed to be stable between the Baltimore Street, BRB13-009, Baltimore, MD 21201; and †Department of Biological two species separated by 350 million years (6, 10). This is in Sciences, Graduate School of Science, University ofTokyo, Hongo, Bunkyo-ku, To- kyo, Japan contrast to some other nonmammalian vertebrates in which the MHC genes are scattered over the genome, especially for class II Received for publication November 1, 2005. Accepted for publication January 9, 2005. and class III region genes (5, 7, 11–20). In this study, we took The costs of publication of this article were defrayed in part by the payment of page advantage of the genome project and the various EST databases charges. This article must therefore be hereby marked advertisement in accordance and mined them for MHC genes. Our results reveal that the entire with 18 U.S.C. Section 1734 solely to indicate this fact. architecture of the Xenopus MHC is remarkably conserved when 1 This work was supported by National Institutes of Health Grant AI27877 (to Y.O., compared with human, and further show that the teleost and, to a W.G., and M.F.F.) and Grant 15207019 from The Ministry of Education, Culture, Sports, Science, and Technology (to M.N.). 2 Address correspondence and reprint requests to Dr. Yuko Ohta, University of Mary- 3 Abbreviations used in this paper: EST, expressed sequence tag; Igsf, Ig superfamily; land, Department of Microbiology and Immunology, 655 West Baltimore Street, BLAST, Basic local alignment search tool; ORF, open reading frame; TM, trans- BRB13-009, Baltimore, MD 21201. E-mail address: [email protected] membrane; XMIV, Xenopus MHC-linked Ig superfamily. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 3675 lesser extent, bird MHCs are highly derived. In addition, analysis with HindIII or SacI, and fragmented DNA was separated on an agarose gel of the Xenopus MHC has revealed that some major immune genes and blotted onto membranes. The DNA amount was increased proportion- seem to have emerged at the level of amphibians and has uncov- ally to the ploidy level. The gene-specific Ig-domain probe (EST entry CN328971; nt 300–587) was made by using PCR from cDNA library made ered some new Ig superfamily (Igsf) genes that are activating or from X. laevis spleen and intestine, and the sequence was confirmed. Prim- inhibitory receptor candidates, similar to those first discovered on ers used for amplification were as follows: 5Ј-AAA GTG GAA CAG CCT NK cells (21–23). GAG CG-3Ј and 5Ј-CAT CAC ATG CAC AAT GGT TCC-3Ј. Hybrid- ization was performed under low stringency conditions (30% formamide; Materials and Methods 6 ϫ SSC) at 42°C for overnight, and washed in 2 ϫ SSC, 1% SDS at room temperature, followed by 2 ϫ SSC, 0.1% SDS at 55°C (38). The same blot cDNA sequence database searches for MHC genes was later washed under high stringency conditions (0.2 ϫ SSC, 0.1% SDS We obtained accession numbers for genes listed in the human MHC, ex- at 65°C) to eliminate low-homology signals. cluding pseudogenes, from the Wellcome Trust Sanger Institute web site (͗www.sanger.ac.uk͘). Basic local alignment search tool (BLAST)p and Results tBLASTn were performed on the National Center for Bioinformatics In- stitute (NCBI) web site (͗www.ncbi.nlm.nih.gov͘) with either full-length Database mining amino acid sequences or domain-by-domain in the X. laevis, X. tropicalis, The chicken DM␣1 and ␤1-encoding exons (obtained from and/or EST_Others databases using the BLOSUM 45 matrix. Genes with AL023516) were used to search databases for the Xenopus DM E-values of Ͻ0.05 were further confirmed by BLASTp or BLASTx searches in the vertebrate databases using the BLOSUM 45 matrix.
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