An Ancient Mammalian Gene Evidence That Thymus Leukemia
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Hyperconservation of the Putative Antigen Recognition Site of the MHC Class I-b Molecule TL in the Subfamily Murinae: Evidence That Thymus Leukemia Antigen Is This information is current as an Ancient Mammalian Gene of September 24, 2021. Beckley K. Davis, Richard G. Cook, Robert R. Rich and John R. Rodgers J Immunol 2002; 169:6890-6899; ; doi: 10.4049/jimmunol.169.12.6890 Downloaded from http://www.jimmunol.org/content/169/12/6890 References This article cites 57 articles, 20 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/169/12/6890.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Hyperconservation of the Putative Antigen Recognition Site of the MHC Class I-b Molecule TL in the Subfamily Murinae: Evidence That Thymus Leukemia Antigen Is an Ancient Mammalian Gene1 Beckley K. Davis, Richard G. Cook, Robert R. Rich,2 and John R. Rodgers3 “Classical” MHC class I (I-a) genes are extraordinarily polymorphic, but “nonclassical” MHC class I (I-b) genes are monomorphic or oligomorphic. Although diversifying (positive) Darwinian selection is thought to explain the origin and maintenance of MHC class I-a polymorphisms, genetic mechanisms underlying MHC class I-b evolution are uncertain. In one extreme model, MHC class I-b loci are derived by gene duplication from MHC class I-a alleles but rapidly drift into functional obsolescence and are eventually deleted. In this model, extant MHC class I-b genes are relatively young, tend to be dysfunctional or pseudogenic, and orthologies are restricted to close taxa. An alternative model proposed that the mouse MHC class I-b gene thymus leukemia Ag (TL) arose Downloaded from ϳ100 million years ago, near the time of the mammalian radiation. To determine the mode of evolution of TL, we cloned TL from genomic DNA of 11 species of subfamily Murinae. Every sample we tested contained TL, suggesting this molecule has been maintained throughout murine evolution. The sequence similarity of TL orthologs ranged from 85–99% and was inversely pro- portional to taxonomic distance. The sequences showed high conservation throughout the entire extracellular domains with exceptional conservation in the putative Ag recognition site. Our results strengthen the hypotheses that TL has evolved a spe- cialized function and represents an ancient MHC class I-b gene. The Journal of Immunology, 2002, 169: 6890–6899. http://www.jimmunol.org/ he origin and function of MHC-linked class I-b genes Obata et al. (7) studied seven alleles of TL from inbred strains remains unresolved. One view suggests they derive from of Mus musculus and reported it is not closely related to other T “classical” class I-a MHC genes (1), the chief presenters mouse class I genes. They suggested TL originated at or before the of Ag peptides to T cells. Class I-a molecules exhibit extraordinary time of the mammalian radiation (ϳ100 million years ago polymorphism, apparently maintained by positive Darwinian se- (MYA)). Moreover, the ratio of nonsynonymous (dN) to synony- 4 Ͻ lection within the Ag recognition site (ARS) for the ability to mous (dS) substitutions in the putative ARS was 1 and not higher present diverse pathogen peptides (2). In contrast, class I-b genes than for non-ARS residues in TL, consistent with negative or neu- are monomorphic or oligomorphic. Hughes and Nei (1) suggest tral selection (7). The possibility of negative (purifying) selection by guest on September 24, 2021 that many mouse class I-b genes, including thymus leukemia Ags operating on TL, coupled with its apparently ancient origin, sug- (TL), do not have human orthologs but rather were more closely gested that TL may have evolved a specialized and highly con- related to mouse class I-a genes. They proposed that mouse class served function early in mammalian evolution. I-b genes were derived by gene duplication from mouse I-a alleles TLs are encoded by certain MHC class I-b genes within the T but then rapidly drifted into pseudogene status. Indeed, many class subregion (8). They are ϳ45-kDa cell surface glycoproteins non-   I-b genes are poorly expressed in most cell types, either because of covalently associated with 2-microglobulin ( 2m) (3) and are ex- low transcription or protein instability, and some are clearly pseu- pressed on activated T cells (9), developing thymocytes and small dogenes (3). Moreover, some mouse class I-b genes such as Qa-2 intestinal epithelium, and intraepithelial lymphocytes (10, 11) and (4) and H2-B1 (5) still appear to be more closely related to mouse certain leukemias (12). Cell surface expression of TL is TAP-in- class I-a genes than to any rat MHC gene. This process is consis- dependent (13–15). The observations that TL is expressed at a site tent with Ohno’s (6) model of gene duplication, in which one enriched for ␥␦ T cells and is oligomorphic led to the hypothesis duplicated copy is released from selection pressure and usually that TL presents conserved Ags to ␥␦ T cells in the gut (10, 16, degenerates into a pseudogene. 17). However, no peptides or motifs have been characterized (13, 18), leaving open the possibility that TL does not present peptide. Unlike H2-M3 and Qa-1 (19–21), TL orthologs have not been reported in other species (22, 23). Obata et al. (7) suggested TL is Department of Immunology, Baylor College of Medicine, Houston, TX 77030 not closely related to other mouse H2 genes but their phylogenetic Received for publication August 26, 2002. Accepted for publication October 15, 2002. analysis could not rule out the possibility that TL arose relatively The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance recently from another mouse MHC class I gene. The “young TL ” with 18 U.S.C. Section 1734 solely to indicate this fact. model is consistent with the model of Hughes and Nei (1) that 1 This work was supported by the National Institutes of Health Grants RO1 AI30036 monomorphic MHC class I-b genes arise by duplication from and AI18882 (to R.R.R.) and RO1 AI17897 (to R.G.C. and J.R.R.). MHC class I-a alleles. However, to achieve the degree of diver- 2 Emory University School of Medicine, Atlanta, GA 30322. gence noted by Obata (7), the young TL models require that a 3 Address correspondence and reprint requests to Dr. John R. Rodgers, Department of proto-TL gene would undergo rapid diversifying evolution (posi- Immunology, Baylor College of Medicine, One Baylor Plaza Room M929, Houston, tive selection) for some new function, rather than degenerate under TX 77030. E-mail address: [email protected] neutral evolution. In contrast, the “old TL ” model posits that TL is 4 Abbreviations used in this paper: ARS, Ag recognition site; TL, thymus leukemia as old as it appears, that is, that it has evolved like a molecular Ag; MYA, million years ago; dN, rate of nonsynonymous substitution; dS, rate of   synonymous substitution; 2m, 2-microglobulin; cytb, cytochrome b. clock. This model leaves unspecified the origin of the proto-TL Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 6891 gene itself, for example, whether it arose from an early mammalian Table I. Revision of nomenclature of TL genes MHC class I-a allele. These two models differ chiefly in the time of divergence from non-TL MHC genes, and thus the rapidity with Old Nomenclature Relative which TL must have diverged from a putative MHC class I-a or- (phenotype) Locus/Strain New Nomenclature Expression igin. To distinguish between these models and obtain direct evi- TLa a1 (TLA) A/J MumuTL0101 High dence for the time of divergence, we collected TL sequences from TLa a2 (TLA) A/J MumuTL0102 High the murine genera Mus and Rattus. TLa a3 (TLA) A/J MumuTL0103 High a4 A The Old World subfamily Murinae within family Muridae in- TLa (TL ) A/J MumuTL0104 High TLa b (TLB) T3b/C3H MumuTL0201 Low cludes several lineages whose relationships are unclear. One lin- TLa c (TLC) T3d/BALB/cJ MumuTL0202 Low eage includes Rattus and its close allies, Tokudaia and Diplothrix TLa d (TLC) T18/BALB/cJ MumuTL0301 Intermediate (24). A second lineage includes Mus and, probably, Hybomys and TLa e (TLE) P/J MumuTL0401 High TLa f (TLF) 129/Boy MumuTL0501 Intermediate Mastomys. These two lineages diverged between 14 and 40 MYA. g G w1 (25, 26). The genus Mus consists of four subgenera, Mus, Nanno- TLa (TL ) TLa /molossinus MumuTL0302 Unknown mys (African pygmy mice), Pyromys (spiny mice), and Coelymys (shrew mice). These subgenera diverged ϳ9 MYA (27). We characterized the extracellular domains of 27 different TL total of 200 ng of genomic DNA was amplified using platinum Pfx (In- sequences from 10 species of Mus, including 2 subspecies from M.