Genome evolution is driven by gene expression‐generated biophysical constraints through RNA‐directed genetic variation: A hypothesis

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co‐transcriptional and co‐translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti‐parasite genome defence systems, and implies that gene expression‐related biophysical constraints represent a driving force of genome evolution.