Project Summary/Abstract: We have identified genes that act in the maturation or presentation of siRNAs that mediate antiviral defense in C. elegans. We propose to discern how the siRNAs and other small RNAs may be edited analogous to the ancient editing of wobble base pairs in the anticodon loop of many tRNAs, to allow this system to anticipate infection with viruses related to virus infections recorded in the genome. Our saturation genetic analysis of these antiviral pathways has revealed new possibilities for how the genomic record of past viral infections via RNA editing and DNA recombination between repetitive elements can anticipate future viral variation. This is equivalent to wobble base pairing between tRNA and codons, which is mediated by very ancient RNA modification pathways. Thus the modern RNA world, which is heavily populated by parasitic RNA viruses such as Covid-19, may depend on ancient RNA editing. Our hypothesis that synMuv genes mediate gene amplification in the intestine and other tissues to produce substrates for unequal crossing over is very unorthodox, but intersects nicely with the translocations so common in tumor biology. It could be transformative for cancer biology.