Hereditary Consequences of Small RNAs

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The “Modern synthesis”, which is a combination of Darwinian evolution with Mendelian and population genetics, dismisses the possibility that responses to environmental challenges can become heritable. According to this prevailing conceptual paradigm, genomes evolve due to selection or drift of mutations that accumulate randomly. Nonetheless, experiments conducted with C. elegans over the last 20 years have shown that small RNA-induced RNA interference (RNAi) mechanisms can transmit parental gene regulatory responses across generations; thus, while the original naïve ideas of Lamarck were dismissed, tractable genetic models now allow proper investigation of new mechanisms that, in certain cases, enable direct transgenerational transfer of acquired non-DNA-encoded information about the ancestral environment. Indeed, insight from multiple studies elucidated the conditions under which RNAi in C. elegans can trigger silencing effects that proceed for many generations, and the genetic mechanisms that enable this type of inheritance. Transcription is known to affect the capacity of DNA repair mechanisms, such as transcription-coupled nucleotide excision repair (TC-NER), to prevent mutations, and also the probability that a given locus would undergo recombination. Different mechanisms discovered in a wide range of organisms raise the provocative possibility that silencing genes over long periods of time could lead to a change in the number of mutations on the target, or alternate recombination frequencies. We present here a plan for testing the provocative hypothesis that small RNA inheritance affects genome evolution; Specifically, we will examine if small RNAs can change the propensity of genes to accrue germline mutations thus altering the genetic plasticity of their targets, ultimately giving rise to “hardwired” changes in the DNA sequence. We decided to synergize our expertise in RNAi mechanisms in transgenerational inheritance (Rechavi) and DNA repair mechanisms, specifically TC-NER (Schumacher), to addresses the fundamental question: Can temporary epigenetic responses become fixated in the genome? We will (1) examine whether heritable small RNA-induced silencing affects the likelihood that the target would acquire specific types of mutations, (2) test whether small RNA inheritance affects recombination frequencies, (3) perform a genome-wide assessment of the contribution of small RNAs in the germline to DNA repair and recombination, and (4) assess whether the levels of small RNAs, which are inherited as a response to environmental stress, correlate with DNA sequence changes.