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Somatic Hypermutation and Junctional Diversification at Ig Heavy Chain Loci in the Nurse Shark¹

Karolina Malecek^*, Julie Brandman^*, Jennie E. Brodsky^*, Yuko Ohta, Martin F. Flajnik and Ellen Hsu^2,*

^* Department of Physiology and Pharmacology, State University of New York Health Science Center, Brooklyn, NY 11203; and Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201

We estimate there are 15 IgM H chain loci in the nurse shark genome and have characterized one locus. It consists of one V, two D, and one J germline gene segments, and the constant (C) region can be distinguished from all of the others by a unique combination of restriction endonuclease sites in Cµ2. On the basis of these Cµ2 markers, 22 cDNA clones were selected from an epigonal organ cDNA library from the same individual; their C region sequences proved to be the same up to the polyadenylation site. With the identification of the corresponding germline gene segments, CDR3 from shark H chain rearrangements could be analyzed precisely, for the first time. Considerable diversity was generated by trimming and N addition at the three junctions and by varied recombination patterns of the two D gene segments. The cDNA sequences originated from independent rearrangements events, and most carried both single and contiguous substitutions. The 53 point mutations occurred with a bias for transition changes (53%), whereas the 78 tandem substitutions, mostly 2–4 bp long, do not (36%). The nature of the substitution patterns is the same as for mutants from six loci of two nurse shark L chain isotypes, showing that somatic hypermutation events are very similar at both H and L chain genes in this early vertebrate. The cis-regulatory elements targeting somatic hypermutation must have already existed in the ancestral Ig gene, before H and L chain divergence.

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