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The Evolution of Multiple Isotypic IgM Heavy Chain Genes in the Shark¹

Victor Lee^*, Jing Li Huang^*, Ming Fai Lui^*, Karolina Malecek^*, Yuko Ohta, Arne Mooers and Ellen Hsu^2,*

^* Department of Physiology and Pharmacology, State University of New York Health Science Center, Brooklyn, NY 11203; Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; and Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

The IgM H chain gene organization of cartilaginous fishes consists of 15–200 miniloci, each with a few gene segments (V_H-D1-D2-J_H) and one C gene. This is a gene arrangement ancestral to the complex IgH locus that exists in all other vertebrate classes. To understand the molecular evolution of this system, we studied the nurse shark, which has relatively fewer loci, and characterized the IgH isotypes for organization, functionality, and the somatic diversification mechanisms that act upon them. Gene numbers differ slightly between individuals (15), but five active IgM subclasses are always present. Each gene undergoes rearrangement that is strictly confined within the minilocus; in B cells there is no interaction between adjacent loci located 120 kb apart. Without combinatorial events, the shark IgM H chain repertoire is based on junctional diversity and, subsequently, somatic hypermutation. We suggest that the significant contribution by junctional diversification reflects the selected novelty introduced by RAG in the early vertebrate ancestor, whereas combinatorial diversity coevolved with the complex translocon organization. Moreover, unlike other cartilaginous fishes, there are no germline-joined VDJ at any nurse shark µ locus, and we suggest that such genes, when functional, are species-specific and may have specialized roles. With an entire complement of IgM genes available for the first time, phylogenetic analyses were performed to examine how the multiple Ig loci evolved. We found that all domains changed at comparable rates, but V_H appears to be under strong positive selection for increased amino acid sequence diversity, and surprisingly, so does Cµ2.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Institutes of Health (GM068095) and Natural Sciences and Engineering Research Council Canada. A.M. and E.H. were fellows of the Wissenschaftskolleg zu Berlin, 2006-2007.

² Address correspondence and reprint requests to Dr. Ellen Hsu, State University of New York, 450 Clarkson Avenue, Box 31, Brooklyn, NY 11203. E-mail address: hsue{at}hscbklyn.edu

³ Abbreviation used in this paper: BAC, bacterial artificial chromosome.

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