RNA editing by the host ADAR system affects the molecular evolution of the Zika virus

Abstract

Zika virus (ZIKV) is a mosquito‐transmitted flavivirus, linked to microcephaly and fetal death in humans. Here, we investigate whether host‐mediated RNA editing of adenosines (ADAR) plays a role in the molecular evolution of ZIKV. Using complete coding sequences for the ZIKV polyprotein, we show that potential ADAR substitutions are underrepresented at the ADAR‐resistant GA dinucleotides of both the positive and negative strands, that these changes are spatially and temporally clustered (as expected of ADAR editing) for three branches of the viral phylogeny, and that ADAR mutagenesis can be linked to its codon usage. Furthermore, resistant GA dinucleotides are enriched on the positive (but not negative) strand, indicating that the former is under stronger purifying selection than the latter. ADAR editing also affects the evolution of the rhabdovirus sigma. Our study now documents that host ADAR editing is a mutation and evolutionary force of positive‐ as well as negative‐strand RNA viruses.

Mutation landscape of SARS-CoV-2 reveals five mutually exclusive clusters of leading and trailing single nucleotide substitutions

“…A similar trend has also been reported for SARS-CoV (22). Amongst host RNA editing enzymes, APOBECs (Apolipoprotein B mRNA editing complex) and ADARs (Adenosine Deaminases Acting on RNA) have been studied for their ability to edit virus genomes (23,24).…”

Explaining Pathogenicity of Congenital Zika and Guillain–Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

“…Our recent comparative work revealed a distinct ADAR editing signature in viral genomes, including ZIKV, suggesting that host ADAR editing plays a role in the molecular evolution of ZIKV . Our findings were corroborated by an independent evolutionary study that used a different approach from ours to identify ADAR editing footprints in ZIKV genomes.…”

“…Together, these results indicate that ADAR editing is active during ZIKV infection. While it remains to be determined whether observed ADAR editing footprints are due to ADAR action in the mosquito or mammalian host (or both), studies of the mammalian immune response support the hypothesis that ADAR (specifically, the IFN‐induced ADARp150 isoform) is activated in ZIKV infections.…”

A decade of RNA virus metagenomics is (not) enough

“…The ultimate immunoevasion strategy may be virally-encoded nucleotides (Bryson et al, 2015;Murphy et al, 2013;Weigele et al, 2017). Host and virallyencoded RNA editing already bedevils calling of accurate whole genome sequences in both positive-and negative-strand RNA viruses (Park et al, 2015;Pelet et al, 1991;Piontkivska et al, 2017;Vidal et al, 1990). Adenosine-based modifications of viral genomes have shown effects on viral and host biology, but detecting them requires additional modifications to most sequencing protocols (Gokhale and Horner, 2017;Gonzales-van Horn and Sarnow, 2017;Kennedy et al, 2016Kennedy et al, , 2017.…”