Co-evolving pairs of complementary nucleotide sequence regions containing compensatory divergences and polymorphisms in rotavirus genomes

Group A rotavirus (RVA), possessing a genome of 11 segmented double-stranded RNAs, is considered to undergo selective packaging, in which one copy of each genomic segment is incorporated into a virion. The selective packaging is thought to be mediated by formation of supra-molecular complex for 11 positive-sense RNAs (+RNAs) through inter-segmental interaction of complementary nucleotide sequence regions, termed the bundling signal. Here, genomic sequences for mammalian and avian RVA isolates were analyzed to identify co-evolving pairs of complementary nucleotide sequence regions containing compensatory divergences and polymorphisms, allowing for existence of slightly deleterious mutations partially disrupting complementarity. In the predicted secondary structure of +RNAs, intra-segmental co-evolving pairs mostly constituted stems, and were involved in formation of pan-handle structure in the VP1, VP3, and NSP4 segments and stem-loop structure at the 5′ terminal region in the VP7 segment, at the 3′ terminal region in the VP6 and NSP4 segments, and in the middle of the NSP2 segment. Inter-segmental co-evolving pairs between the 5′ terminal region each in the VP3 and NSP3 segments, the middle and 5′ terminal regions in the NSP1 and NSP2 segments, respectively, and the 5′ and 3′ terminal regions in the NSP2 and NSP3 segments, respectively, tended to constitute loops, suggesting that these pairs may interact as bundling signals.