Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination

Cell. 2016 Jun 30;166(1):102-14. doi: 10.1016/j.cell.2016.05.032. Epub 2016 Jun 9.


Co-option of RAG1 and RAG2 for antigen receptor gene assembly by V(D)J recombination was a crucial event in the evolution of jawed vertebrate adaptive immunity. RAG1/2 are proposed to have arisen from a transposable element, but definitive evidence for this is lacking. Here, we report the discovery of ProtoRAG, a DNA transposon family from lancelets, the most basal extant chordates. A typical ProtoRAG is flanked by 5-bp target site duplications and a pair of terminal inverted repeats (TIRs) resembling V(D)J recombination signal sequences. Between the TIRs reside tail-to-tail-oriented, intron-containing RAG1-like and RAG2-like genes. We demonstrate that ProtoRAG was recently active in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and low-efficiency TIR rejoining using reaction mechanisms similar to those used by vertebrate RAGs. We propose that ProtoRAG represents a molecular "living fossil" of the long-sought RAG transposon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Transposable Elements*
  • DNA-Binding Proteins
  • Evolution, Molecular*
  • Homeodomain Proteins
  • Lancelets / genetics*
  • Terminal Repeat Sequences
  • V(D)J Recombination*


  • DNA Transposable Elements
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • V(D)J recombination activating protein 2
  • RAG-1 protein