RT Journal Article SR Electronic T1 The Reading Frame Surveillance Hypothesis and the Origins of RNAi JF bioRxiv FD Cold Spring Harbor Laboratory SP 071985 DO 10.1101/071985 A1 John T. Gray YR 2016 UL http://biorxiv.org/content/early/2016/08/29/071985.abstract AB Pathways of gene regulation mediated by Argonaute proteins derive specificity from short, bound RNA molecules and are increasingly implicated in broad areas of biology, however a unifying principle for the origin of these pathways has been lacking. I here present a hypothetical Reading Frame Surveillance (RFS) model which proposes that primordial ribosomes utilized evenly spaced cleavage of a complementary RNA to monitor and preserve the reading frame during translation of a message. Furthermore, I show how published data from the fields of gene silencing, RNA processing, antigen presentation, development, and oncogenesis support the possibility that vestiges of this primordial pathway are extant and contribute to these processes. The model provides rational mechanistic interpretations of the data leading to multiple testable hypotheses in each of these areas. In particular, the argument is put forward that not only does an RNA dependent RNA polymerase likely exist today in vertebrates, as has been proposed previously, but that it also routinely copies transcribed RNAs in the nucleus, and is likely a ribozyme.