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The team of researchers used two techniques to sequence the RNAs - DNA nanoball sequencing and nanopore direct RNA sequencing (nanopore DRS). The first is capable of accurately sequencing short fragments, at high speed, yielding a large number of such reads. The latter allows the direct sequencing of the entire RNA molecule, in contrast to the conventional procedures that require the RNA to be first cut into pieces and then reverse-transcribed to DNA before a readout can be done. Though nanopore DRS is less accurate, the long-read sequencing allows long nested transcripts to be read. It also provides data on chemical modifications directly because of its detection of RNA rather than cDNA. The two methods pair beautifully to result in a complementary analysis of the viral RNAs. What did the study show?
The detailed map shows the entire transcriptome (viral genes) as well as the epitranscriptome (the chemical modifications on the RNA strand that do not affect the base sequence).
Earlier, researchers thought that the viral particle contained ten such subgenomic RNAs, but it is now known, as a result of this study, that there are only 9. The DNA nanoball sequencing technique showed that the viral transcriptome is composed of a large number of discontinuous transcription events.
They also had unexpected gains from the study, which revealed dozens of hitherto unknown subgenomic RNAs formed by the fusion and deletion of nucleotides on the RNA strand, as well as frameshift mutations, often accompanying the former. They also found several new chemical modifications. These epigenetic changes could be the reasons for the rapid alterations in the genetic make-up of the virus, they say. The chemical modifications could be the key to the virus’s resistance to host immune attack. Earlier research has shown that a host of RNA modifications regulate RNAs in both eukaryotes and viruses.
Furthermore, they postulate the presence of novel properties for these modified RNAs compared to the original fragments, despite the identical base sequence information for either. They aim to decipher the meaning of these changes, for instance, in the replication of the virus and in the resulting host immune responses, and to explore its lifecycle. The consistent presence of tail shortening, for instance, in modified RNA molecules, could mean an effect on the control of viral RNA stability.
The researchers sum up: “Our work provides a high-resolution map of SARS-CoV-2. This map will help understand how the virus replicates and how it escapes the human defense system.”“We firmly believe that our study will contribute to the development of diagnostics and therapeutics to combat the virus more effectively,” says Narry. Journal reference:
Kim, D., Lee, J. Y., Yang, J. S., Kim, J. W., Kim, V. N., & Chang, H. (2020). The architecture of SARS-CoV-2 transcriptome. Cell. In press. DOI: 10.1016/j.cell.2020.04.011, https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00765.pdf
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