{"doi":"10.1101/2020.04.10.029454","title":"Generation of a novel SARS-CoV-2 sub-genomic RNA due to the R203K/G204R variant in nucleocapsid: homologous recombination has potential to change SARS-CoV-2 at both protein and RNA level","abstract":"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 three adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence (CS) 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":118947,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":500168,"name":"Silvana Gaudieri","orcid":null,"position":1,"is_corresponding":false},{"id":103731,"name":"Matthew Parker","orcid":"0000-0003-2999-3870","position":2,"is_corresponding":false},{"id":499245,"name":"Abha Chopra","orcid":"0000-0001-5008-9080","position":3,"is_corresponding":false},{"id":418026,"name":"Ian James","orcid":"0009-0008-7533-2751","position":4,"is_corresponding":false},{"id":552550,"name":"Suman Pakala","orcid":"0000-0001-5156-0823","position":5,"is_corresponding":false},{"id":552551,"name":"Eric Alves","orcid":"0000-0002-6072-708X","position":6,"is_corresponding":false},{"id":552552,"name":"Mina John","orcid":"0000-0002-6429-0719","position":7,"is_corresponding":false},{"id":103742,"name":"Benjamin B. Lindsey","orcid":"0000-0003-4227-2592","position":8,"is_corresponding":false},{"id":103741,"name":"Alexander J. Keeley","orcid":"0000-0001-9386-1157","position":9,"is_corresponding":false},{"id":56241,"name":"Sarah L. Rowland-Jones","orcid":null,"position":10,"is_corresponding":false},{"id":311456,"name":"Maurice S. Swanson","orcid":"0000-0001-6245-5367","position":11,"is_corresponding":false},{"id":34148,"name":"David A. Ostrov","orcid":"0000-0002-4696-875X","position":12,"is_corresponding":false},{"id":383337,"name":"Jodi L. Bubenik","orcid":"0000-0001-6575-9817","position":13,"is_corresponding":false},{"id":270036,"name":"Suman R. 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