Impact of ADAR-induced editing of minor viral RNA populations on replication and transmission of SARS-CoV-2

Abstract

Adenosine deaminases acting on RNA (ADAR) are RNA-editing enzymes that may restrict viral infection. We have utilized deep sequencing to determine adenosine to guanine (A→G) mutations, signifying ADAR activity, in clinical samples retrieved from 93 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected patients in the early phase of the COVID-19 pandemic. A→G mutations were detected in 0.035% (median) of RNA residues and were predominantly nonsynonymous. These mutations were rarely detected in the major viral population but were abundant in minor viral populations in which A→G was more prevalent than any other mutation (P < 0.001). The A→G substitutions accumulated in the spike protein gene at positions corresponding to amino acids 505 to 510 in the receptor binding motif and at amino acids 650 to 655. The frequency of A→G mutations in minor viral populations was significantly associated with low viral load (P < 0.001). We additionally analyzed A→G mutations in 288,247 SARS-CoV-2 major (consensus) sequences representing the dominant viral population. The A→G mutations observed in minor viral populations in the initial patient cohort were increasingly detected in European consensus sequences between March and June 2020 (P < 0.001) followed by a decline of these mutations in autumn and early winter (P < 0.001). We propose that ADAR-induced deamination of RNA is a significant source of mutated SARS-CoV-2 and hypothesize that the degree of RNA deamination may determine or reflect viral fitness and infectivity.

Buffy Coat Transcriptomic Analysis Reveals Alterations in Host Cell Protein Synthesis and Cell Cycle in Severe COVID-19 Patients

“…The up-regulated genes AGO4, STAT3, and ADAR were also found in this network, where the latter two have already been implicated as playing a role in the COVID-19 disease [ 33 , 34 ]. The down-regulated genes identified in the network included SLTM, RPS11, SBDS, LARP4, CPSF6, and EIF3H ( Figure 5 ).…”

Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission

“…Furthermore, the frequency of C>U and A>G mutations differed between hosts, which may reflect host cell activity, such as restriction factors (e.g. apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like or APOBEC family of mRNA editing proteins), RNA editing enzymes (ADAR1), and/or reactive oxygen species [41][42][43][44] . We also observed that the mutational spectrum of the Ontario WTD (and human) sequences is similar to that of other deer.…”

Divergent SARS-CoV-2 variant emerges in white-tailed deer with deer-to-human transmission

“…Importantly, this provides evidence supporting the hypothesis that mutational spectra can be used to infer viral host species 9,40 . Furthermore, the frequency of C > U and A > G mutations differed between hosts, which may reflect host cell activity, such as restriction factors (for example, apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like or APOBEC family of mRNA editing proteins), RNA editing enzymes (ADAR1) and reactive oxygen species [42][43][44][45] . We also observed that the mutational spectrum of B.…”