{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:35:13Z","timestamp":1792636513002,"version":"4.5.0"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), its genetic and geographical origins remain unclear, resulting in suspicions about its natural origin. In one of our previous studies, we reported the presence of a furin cleavage site RRAR in the junction region between S1 and S2 subunits of the spike protein, which was discovered as the first crucial clue for the origin tracing of SARS-CoV-2. In the present study, we conducted an integrative analysis of new genome data from bat <jats:italic>Sarbecovirus<\/jats:italic> strains reported after the COVID-19 outbreak. The primary results included the identification of BANAL-20-52, Rp22DB159, and S18CXBatR24 as three close relatives of SARS-CoV-2 and the successful detection of seven out of nine key genomic features (designated as RC0-7 and <jats:italic>ORF8<\/jats:italic>) observed in wild types of SARS-CoV-2 in the three close relatives from Laos, Vietnam, and Yunnan province of China, respectively. The most significant contribution of the present study lies in the detection of RC1 in wild genotype in a bat <jats:italic>Sarbecovirus<\/jats:italic> population BANAL-20-52 belonging to. Encoding a segment of the <jats:italic>NSP3<\/jats:italic> protein, RC1 was discovered as the second crucial clue for the origin tracing of SARS-CoV-2. Although RC0, encoding the junction furin cleavage site, remains undetected outside of the SARS-CoV-2 genome, Feuang of Laos is the sole place where eight of the nine wild-type features (RC1-7 and <jats:italic>ORF8<\/jats:italic>) have been detected.<\/jats:p>","DOI":"10.1371\/journal.pone.0309557","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T17:38:36Z","timestamp":1725039516000},"page":"e0309557","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Emergence of crucial evidence catalyzing the origin tracing of 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Hassanin","year":"2023","journal-title":"Research Square"},{"issue":"1","key":"pone.0309557.ref012","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.1038\/s41467-023-39835-1","article-title":"Individual bat virome analysis reveals co-infection and spillover among bats and virus zoonotic potential","volume":"14","author":"J Wang","year":"2023","journal-title":"Nat Commun"},{"key":"pone.0309557.ref013","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.virol.2016.10.017","article-title":"VirusDetect: An automated pipeline for efficient virus discovery using deep sequencing of small RNAs","volume":"500","author":"Y Zheng","year":"2017","journal-title":"Virology"},{"key":"pone.0309557.ref014","first-page":"44","article-title":"Fastq_clean: An optimized pipeline to clean the Illumina sequencing data with quality control","author":"M Zhang","year":"2014","journal-title":"IEEE International Conference on Bioinformatics and 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natural insertions at the S1\/S2 cleavage site of the spike protein","volume":"30","author":"H Zhou","year":"2020","journal-title":"Curr Biol"},{"issue":"D1","key":"pone.0309557.ref025","doi-asserted-by":"crossref","first-page":"D701","DOI":"10.1093\/nar\/gkad958","article-title":"COV2Var, a function annotation database of SARS-CoV-2 genetic variation","volume":"52","author":"YZ Feng","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pone.0309557.ref026","first-page":"1","article-title":"Using pan RNA-seq analysis to reveal the ubiquitous existence of 5\u2019 and 3\u2019 end small RNAs","volume":"10","author":"XF Xu","year":"2019","journal-title":"Front Genet"},{"issue":"5","key":"pone.0309557.ref027","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1080\/14728222.2024.2362675","article-title":"Novel benzimidazole angiotensin receptor blockers with anti-SARS-CoV-2 activity equipotent to that of nirmatrelvir: computational and enzymatic studies","volume":"28","author":"H Ridgway","year":"2024","journal-title":"Expert Opin Ther Tar"},{"issue":"5","key":"pone.0309557.ref028","doi-asserted-by":"crossref","first-page":"787","DOI":"10.3390\/biom13050787","article-title":"Role of angiotensin II in cardiovascular diseases: Introducing bisartans as a novel therapy for coronavirus 2019","volume":"13","author":"J Swiderski","year":"2023","journal-title":"Biomolecules"},{"issue":"5","key":"pone.0309557.ref029","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3390\/v14051029","article-title":"Understanding the driving forces that trigger mutations in SARS-CoV-2: mutational energetics and the role of arginine blockers in COVID-19 therapy","volume":"14","author":"H Ridgway","year":"2022","journal-title":"Viruses"},{"key":"pone.0309557.ref030","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1016\/j.csbj.2022.04.010","article-title":"Discovery of a new generation of angiotensin receptor blocking drugs: Receptor 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