Paleo-Immunology: Evidence Consistent with Insertion of a Primordial Herpes Virus-Like Element in the Origins of Acquired Immunity

David H Dreyfus,Sebastian D Fugmann

doi:10.1371/journal.pone.0005778

Abstract

BackgroundThe RAG encoded proteins, RAG-1 and RAG-2 regulate site-specific recombination events in somatic immune B- and T-lymphocytes to generate the acquired immune repertoire. Catalytic activities of the RAG proteins are related to the recombinase functions of a pre-existing mobile DNA element in the DDE recombinase/RNAse H family, sometimes termed the “RAG transposon”.Methodology/Principal FindingsNovel to this work is the suggestion that the DDE recombinase responsible for the origins of acquired immunity was encoded by a primordial herpes virus, rather than a “RAG transposon.” A subsequent “arms race” between immunity to herpes infection and the immune system obscured primary amino acid similarities between herpes and immune system proteins but preserved regulatory, structural and functional similarities between the respective recombinase proteins. In support of this hypothesis, evidence is reviewed from previous published data that a modern herpes virus protein family with properties of a viral recombinase is co-regulated with both RAG-1 and RAG-2 by closely linked cis-acting co-regulatory sequences. Structural and functional similarity is also reviewed between the putative herpes recombinase and both DDE site of the RAG-1 protein and another DDE/RNAse H family nuclease, the Argonaute protein component of RISC (RNA induced silencing complex).Conclusions/SignificanceA “co-regulatory” model of the origins of V(D)J recombination and the acquired immune system can account for the observed linked genomic structure of RAG-1 and RAG-2 in non-vertebrate organisms such as the sea urchin that lack an acquired immune system and V(D)J recombination. Initially the regulated expression of a viral recombinase in immune cells may have been positively selected by its ability to stimulate innate immunity to herpes virus infection rather than V(D)J recombination Unlike the “RAG-transposon” hypothesis, the proposed model can be readily tested by comparative functional analysis of herpes virus replication and V(D)J recombination.

Highlights

Biological systems can share a common mechanism either because of descent from a common ancestral system or molecule, or because of convergent evolution of two unrelated systems or molecules
Does the RAG transposon exist, or is it like the Unicorn, a literary icon for the faithful [14]? This is not an unimportant question, because the ‘‘RAG transposon model’’ is currently the only published model of the origins of the acquired immune system, and yet the RAG transposon has not been located despite an intensive search as reviewed in this manuscript
Additional co-regulation of the pRAG-1 protein in somatic tissues was provided by amino terminal regulatory sequences similar to those shared between the modern herpes DNA binding protein (DBP) and RAG proteins (Figure 6)

Summary

Introduction

Biological systems can share a common mechanism either because of descent from a common ancestral system or molecule (termed homology), or because of convergent evolution of two unrelated systems or molecules (termed analogy).

Results

Conclusion