Background: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host’s anti-viral immune response, in turn affecting the frequency of variants over time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. Methods: Deep-sequencing data of SARS-CoV-2 from public databases and from clinical samples were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Results: Sequence analysis suggests that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep-sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. Conclusions: The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans, resulting in both coding changes and novel sub-genomic RNA transcripts, suggests this as a mechanism for diversification and adaptation within its new host.
【저자키워드】 COVID-19, SARS-CoV-2, transcription-regulating sequence, Homologous recombination, sub-genomic RNA transcript, viral polymorphism, 【초록키워드】 immune response, Mutation, Variation, Genome, variant, polymorphism, virus, database, Anti-viral, RNA, Transmissibility, nucleocapsid, humans, D614G, Genetic variant, change, mechanism, Amino acid, Frequency, Analysis, strain, open reading frames, increased expression, individual, domain, sequence, coding, circulating, dominant, Host, TRS, RNA transcripts, clinical sample, resulting, analyzed, identify, occurred, examined, generate, indicate, turn, C-terminal, affecting, RNA transcript, nucleotide change, the SARS-CoV-2 genome, 【제목키워드】 RNA, novel, change, Generation, Level, Potential,