title: Origin of immunoglobulin isotype switching.
abstract: BACKGROUND
  From humans to frogs, immunoglobulin class switching introduces different effector functions to antibodies through an intrachromosomal DNA recombination process at the heavy-chain locus. Although there are two conventional antibody classes (IgM, IgW) in sharks, their heavy chains are encoded by 20 to >100 miniloci. These representatives of the earliest jawed vertebrates possess a primordial immunoglobulin gene organization where each gene cluster is autonomous and contains a few rearranging gene segments (VH-D1-D2-JH) with one constant region, μ or ω.
  
  
  RESULTS
  V(D)J rearrangement always takes place within the μ cluster, but here we show that the VDJ can be expressed with constant regions from different clusters, although IgH genes are spatially distant, at >120 kb. Moreover, reciprocal exchanges take place between Igω and Igμ genes. Switching is augmented with deliberate immunization and is concomitant with somatic hypermutation activity. Because switching occurs independently of the partners' linkage position, some events involve transchromosomal recombination. The switch sites consist of direct joins between two genes in the 3' intron flanking JH.
  
  
  CONCLUSIONS
  Our data are consistent with a mechanism of cutting or joining of distal DNA lesions initiated by activation-induced cytidine deaminase (AID), in the absence of mammalian-type switch regions. We suggest that, in shark, with its many autonomous IgH targeted by programmed DNA breakage, factors predisposing broken DNA ends to translocate configured the earliest version of class switch recombination.
authors.affiliation: Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, NY 11203, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Zhu
authors.forename: Victor
authors.initials: V
authors.lastname: Lee
authors.forename: Alyssa
authors.initials: A
authors.lastname: Finn
authors.forename: Kate
authors.initials: K
authors.lastname: Senger
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.forename: Louis
authors.initials: L
authors.lastname: Du Pasquier
authors.forename: Ellen
authors.initials: E
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001483:Base Sequence; D015151:Immunoblotting; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D007075:Immunoglobulin M / Q000235:genetics; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012754:Sharks / Q000235:genetics*; D060152:V(D)J Recombination
chemical_list: D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M