Source: School of Life Sciences
Written by: Dr. Shengfeng Huang
Edited by: Wang Dongmei

In the latest issue of Cell, Dr. Anlong Xu and his colleagues report the discovery of the long-sought RAG transposon from a basal chordate called lancelet or amphioxus. This work provides the strongest evidence supporting the transposon hypothesis that has been used to explain the origins of the V(D)J rearrangement for the human B/T-cell receptors in the last four decades. Dr. Xu is the corresponding author, while his three colleagues, Dr. Shengfeng Huang, Dr. Xin Tao, and Dr. Shaochun Yuan are the co-first authors.

In late 1970s, Nobel Prize laureate Susumu Tonegawa proposed the transposon hypothesis to explain the origins of the V(D)J rearrangement for the human B/T-cell receptors (Sakano et al., 1979). Later, the host gene pair of RAG1 and RAG2 responsible for the V(D)J rearrangement have been discovered by David Schatz and colleagues (Oettinger et al., 1990; Schatz et al., 1989). Since then, the host domestication of a RAG transposon is considered a milestone event in the genesis of the adaptive immune system in jawed vertebrates (Flajnik and Kasahara, 2010). However, despite huge efforts made during the last nearly four decades, there is no solid evidence to support the hypothesis. Indeed, the legendary “RAG transposon” has long been considered lost several hundred million years ago.

In the latest issue of Cell, Dr. Anlong Xu and colleagues report the discovery of ProtoRAG, a novel DNA transposon family from lancelets, the most basal extant chordate. A typical ProtoRAG is flanked by 5 bptarget site duplications (TSDs) and a pair of terminal inverted repeats (TIRs) resembling the V(D)J recombination signal sequences. The tail-to-tail oriented and intron-containing RAG1-like and RAG2-like genes are located between the TIRs. They demonstrate that ProtoRAG was transcribed in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and even low-frequency TIR-to-TIR rejoining using the molecular mechanisms similar to those used by human RAG. These data show that ProtoRAG represent a molecular "living fossil” of the long-sought RAG transposon, and provide powerful evidence in favor of the RAG transposon hypothesis for the origins of jawed vertebrate adaptive immunity.

Paper links:
http://dx.doi.org/10.1016/j.cell.2016.05.032
Shengfeng Huang, Xin Tao, Shaochun Yuan, Yuhang Zhang, Peiyi Li, Helen A. Beilinson, Ya Zhang, Wenjuan Yu, Pierre Pontarotti, Hector Escriva, Yann Le Petillon, Xiaolong Liu, Shangwu Chen, David G. Schatz, Anlong Xu. Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination. Cell. 2016. In press.

http://dx.doi.org/10.1038/ncomms6896
Shengfeng Huang, Zelin Chen, Xinyu Yan, Ting Yu, Guangrui Huang, Pierre Antoine Pontarotti, Qingyu Yan, Hongchen Zhao, Jie Li, Ping Yang, Ruihua Wang, Rui Li, Xin Tao, Ting Deng, Yiquan Wang, Guang Li, Qiujin Zhang, Sisi Zhou, Leiming You, Shaochun Yuan, Yonggui Fu, Fenfang Wu, Meiling Dong, Shangwu Chen, Anlong Xu. Decelerated genome evolution in modern vertebrates revealed by analysis of multiple lancelet genomes. Nature Communications. 2014 Dec 19; 5:5896.

Reference:
Sakano, H., Huppi, K., Heinrich, G., and Tonegawa, S. (1979). Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280, 288-294.
Schatz, D.G., Oettinger, M.A., and Baltimore, D. (1989). The V(D)J recombination activating gene, RAG-1. Cell 59, 1035-1048.
Oettinger, M.A., Schatz, D.G., Gorka, C., and Baltimore, D. (1990). RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517-1523.
Flajnik, M.F., and Kasahara, M. (2010). Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11, 47-59.