RNA-templated diversity generation via reverse transcription and homologous recombination: an evolutionary hypothesis.

It is commonly believed that organisms diversify their genomes primarily through point mutations, insertions, and deletions. Here, I propose a complementary mechanism: Diversity Generation by Reverse Transcriptase (DGbyRT), in which cellular or exogenous RNAs are reverse transcribed into cDNA and integrated into the genome via homology-directed recombination. This process enables the reuse of modular genetic information-derived from both coding and non-coding transcripts-thereby biasing variation toward regions already represented in the transcriptome and potentially altering the statistical distribution of the explored sequence space. DGbyRT draws on mechanisms observed across life, including diversity-generating retroelements, retrotransposons, telomerase, and somatic hypermutation, and may involve endogenous RTs such as Pol-θ. I hypothesise that transcribed pseudogenes and duplicated sequences may serve as reservoirs for recombinable modules. DGbyRT may also contribute to somatic-to-germline communication, with reverse-transcribed RNAs crossing the Weismann barrier to influence heritable change. Inspired by synthetic biology tools such as the AutoDiMe method, DGbyRT is presented as a context-dependent diversification mechanism whose frequency may be modulated by cellular regulation of reverse transcriptase activity. As RNA-based technologies advance, understanding natural reverse transcription becomes increasingly relevant to both evolutionary biology and therapeutic innovation.