{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T20:14:22Z","timestamp":1762460062808,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 genomic sequencing efforts have scaled dramatically to address the current global pandemic and aid public health. However, autonomous genome annotation of SARS-CoV-2 genes, proteins, and domains is not readily accomplished by existing methods and results in missing or incorrect sequences. To overcome this limitation, we developed a novel semi-supervised pipeline for automated gene, protein, and functional domain annotation of SARS-CoV-2 genomes that differentiates itself by not relying on the use of a single reference genome and by overcoming atypical genomic traits that challenge traditional bioinformatic methods. We analyzed an initial corpus of 66,000 SARS-CoV-2 genome sequences collected from labs across the world using our method and identified the comprehensive set of known proteins with 98.5% set membership accuracy and 99.1% accuracy in length prediction, compared to proteome references, including Replicase polyprotein 1ab (with its transcriptional slippage site). Compared to other published tools, such as Prokka (base) and VAPiD, we yielded a 6.4- and 1.8-fold increase in protein annotations. Our method generated 13,000,000 gene, protein, and domain sequences\u2014some conserved across time and geography and others representing emerging variants. We observed 3362 non-redundant sequences per protein on average within this corpus and described key D614G and N501Y variants spatiotemporally in the initial genome corpus. For spike glycoprotein domains, we achieved greater than 97.9% sequence identity to references and characterized receptor binding domain variants. We further demonstrated the robustness and extensibility of our method on an additional 4000 variant diverse genomes containing all named variants of concern and interest as of August 2021. In this cohort, we successfully identified all keystone spike glycoprotein mutations in our predicted protein sequences with greater than 99% accuracy as well as demonstrating high accuracy of the protein and domain annotations. This work comprehensively presents the molecular targets to refine biomedical interventions for SARS-CoV-2 with a scalable, high-accuracy method to analyze newly sequenced infections as they arise.<\/jats:p>","DOI":"10.3390\/v13122426","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T03:21:05Z","timestamp":1638847265000},"page":"2426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Semi-Supervised Pipeline for Autonomous Annotation of SARS-CoV-2 Genomes"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4603-0235","authenticated-orcid":false,"given":"Kristen L.","family":"Beck","sequence":"first","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2286-0226","authenticated-orcid":false,"given":"Edward","family":"Seabolt","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-0916","authenticated-orcid":false,"given":"Akshay","family":"Agarwal","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5819-7115","authenticated-orcid":false,"given":"Gowri","family":"Nayar","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3367-2084","authenticated-orcid":false,"given":"Simone","family":"Bianco","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"},{"name":"NSF Center for Cellular Construction, San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9932-0076","authenticated-orcid":false,"given":"Harsha","family":"Krishnareddy","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8006-3129","authenticated-orcid":false,"given":"Timothy A.","family":"Ngo","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4626-8972","authenticated-orcid":false,"given":"Mark","family":"Kunitomi","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8189-328X","authenticated-orcid":false,"given":"Vandana","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-7134","authenticated-orcid":false,"given":"James H.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"AI and Cognitive Software, IBM Almaden Research Center, San Jose, CA 95120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s10930-020-09901-4","article-title":"The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19","volume":"39","author":"Yoshimoto","year":"2020","journal-title":"Protein J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/s41588-020-0700-8","article-title":"The UCSC SARS-CoV-2 Genome Browser","volume":"52","author":"Fernandes","year":"2020","journal-title":"Nat. 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