Guardian of the Genome: An Alternative RAG/Transib Co-Evolution Hypothesis for the Origin of V(D)J Recombination.

Iryna Yakovenko,Matan Oren,L Courtney Smith,Jacob Agronin

doi:10.3389/fimmu.2021.709165

Iryna Yakovenko, Matan Oren + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2021.709165

Copy DOI

Abstract

The appearance of adaptive immunity in jawed vertebrates is termed the immunological ‘Big Bang’ because of the short evolutionary time over which it developed. Underlying it is the recombination activating gene (RAG)-based V(D)J recombination system, which initiates the sequence diversification of the immunoglobulins and lymphocyte antigen receptors. It was convincingly argued that the RAG1 and RAG2 genes originated from a single transposon. The current dogma postulates that the V(D)J recombination system was established by the split of a primordial vertebrate immune receptor gene into V and J segments by a RAG1/2 transposon, in parallel with the domestication of the same transposable element in a separate genomic locus as the RAG recombinase. Here, based on a new interpretation of previously published data, we propose an alternative evolutionary hypothesis suggesting that two different elements, a RAG1/2 transposase and a Transib transposon invader with RSS-like terminal inverted repeats, co-evolved to work together, resulting in a functional recombination process. This hypothesis offers an alternative understanding of the acquisition of recombinase function by RAGs and the origin of the V(D)J system.

Highlights

An outstanding feature of the jawed vertebrates is their adaptive immune system that is capable of recombining gene segments to create a diverse repertoire of immunoglobulins (Igs) [1, 2] and T cell receptors (TCRs) [3]
We suggest that the N-recombination activating gene (RAG)-TP transposon was inserted into the 5′ end of the Transib sequence and not vice versa, keeping the original Transib terminal inverted repeats (TIRs) on both sides of the recombined sequence without interrupting the transposase function (Figure 3)
When including the match in the asymmetric spacer sizes of the 5ʹ and 3ʹ TIRs, the resemblance seems too great to be a coincidence. We propose that this unique asymetrical TIR structure has a functional role for the recombination signal sequences (RSSs) mediated recombination, and in Transib transposition as is known for other TIR transposons [44, 45]

Summary

Introduction

V(D)J RECOMBINATION AND RAGSAn outstanding feature of the jawed vertebrates is their adaptive immune system that is capable of recombining gene segments to create a diverse repertoire of immunoglobulins (Igs) [1, 2] and T cell receptors (TCRs) [3]. The current dogma postulates that the V(D)J recombination system was established by the split of a primordial vertebrate immune receptor gene into V and J segments by a RAG1/2 transposon, in parallel with the domestication of the same transposable element in a separate genomic locus as the RAG recombinase.

Results

Conclusion