SARS-CoV-2 evasion from ADAR hyper-editing is both genome-encoded and sustained by the virus replication strategy

Abstract SARS-CoV-2 is threatening the human society because of its capability to subvert antiviral defenses, causing cytokine hyper-activation and prolonged damage in multiple tissues with unpredictable outcomes in the mid-long term. Here, we evaluated the role of ADAR, an interferon-stimulated gene able to control the activation of the immune system and to directly modify exogenous dsRNAs, during in-vivo infection by SARS-CoV-2. After accurate analysis of 863 RNA-seq samples from different species, we identified ADAR-mediated hyper-editing of SARS-CoV-2 only in 49 human datasets at a low level (0.036‰ hyper edited reads on average) and preferentially on ORF6. Conversely, in mouse datasets we found abundant hyper-editing of viral reads (up to 1.16‰). The analysis of dinucleotide frequency along the ORFs of α, β, δ and γ coronaviruses highlighted the evolutionary pressure of ADAR enzymes, suggesting that the SARS-CoV-2 resistance to hyper-editing is both genome-encoded and supported by the viral transcription strategy.