{
  "abstract": "High-throughput sequencing has generated protein datasets whose scale increasingly exceeds the practical limits of conventional functional annotation workflows. We present Sma3s v3, a scalable reimplementation of the Sma3s three-step annotation strategy, which combines transfer from highly similar homologs, orthology-based inference, and functional enrichment among homologous proteins. Sma3s v3 replaces BLAST-based searches with MMseqs2 and introduces parallel processing, reusable SQLite caches, taxonomic filtering, and traceable outputs that retain the evidence underlying each assignment. We evaluated the method on a Vibrio cholerae pangenome comprising 50,415 gene clusters from 11,295 quality-filtered genomes and on a metagenomic catalogue containing 843,935 proteins. After excluding non-informative assignments, Sma3s v3 annotated 30,662 pangenome clusters (60.8%), comparable to InterProScan (60.2%) and exceeding eggNOG-mapper (41.4%), while providing 5,747 annotations not recovered by either comparator. Gene Ontology comparisons showed broad semantic agreement between methods, with Sma3s v3 frequently contributing more non-redundant information in Molecular Function and Biological Process. Within the pangenome, annotation coverage reached 97.1% for core clusters and approximately 59% for accessory and unique clusters. Exact protein matches to non-Vibrio genera identified 1,838 candidate horizontally transferred clusters enriched in genetic mobility, antimicrobial resistance, and metal tolerance functions. In the metagenomic catalogue, Sma3s v3 annotated 728,014 proteins (86.3%), compared with 616,895 (73.1%) using InterProScan 2026, and recovered approximately 20,000 unique functional terms. These results establish Sma3s v3 as a scalable and interpretable tool for functional annotation and re-annotation of proteomes, pangenomes, and metagenomic protein catalogues.",
  "abstract_shown": true,
  "affiliations": [
    "Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA), Faculty of Experimental Sciences (Genetics Area), University Pablo de Olavide, Avda. Rectora Ro"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "A. Rubio"
    },
    {
      "name": "J. L. Garcia-Junco"
    },
    {
      "name": "E. Luque-Jimenez"
    },
    {
      "name": "A. Martin Dominguez"
    },
    {
      "name": "J. Dopazo"
    },
    {
      "affs": [
        0
      ],
      "name": "A. J. Perez-Pulido"
    },
    {
      "name": "C. S. Casimiro-Soriguer"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cqe4qmnd3s59y.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.14.748778",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.748778v1.full",
  "id": "cqe4qmnd3s59y",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.748778v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "1312|Genomics and Phylogenetic Studies"
    ]
  ],
  "openalex": "W7213780244",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.14.748778v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cqe4qmnd3s59y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:19Z",
      "native_id": "10.64898/2026.09.14.748778",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.14.748778v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Scaling Functional Annotation Across Proteomes, Pangenomes and Metagenomes with Sma3s v3",
  "title_text": "Scaling Functional Annotation Across Proteomes, Pangenomes and Metagenomes with Sma3s v3",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:19Z",
  "url": "https://research.draconitic.com/paper/cqe4qmnd3s59y",
  "venue": "bioRxiv",
  "versions": []
}