{
  "abstract": "Long-context sequence-to-function models enable nucleotide-resolution prediction of regulatory variant effects, motivating comprehensive mutational interrogation across broad genomic contexts. Yet conventional in silico saturation mutagenesis (ISM) scores mutations one at a time, requiring millions of model evaluations for a single gene and billions to trillions at genome scales. Here, we introduce Multi-ISM, a scalable framework that reformulates ISM as a sparse recovery problem. Multi-ISM generates mutational maps using 45-fold fewer model evaluations than exhaustive single-variant ISM and matches or exceeds its accuracy on variant-effect benchmarks. Multi-ISM is architecture-agnostic and transfers across large-scale sequence-to-function models. We applied Multi-ISM to 5,000 protein-coding genes, including 3,317 OMIM disease genes, generating base-pair-resolution, tissue-resolved attribution maps across 500-kb windows. These maps supported enhancer--gene prioritization and identification of cell-type-specific regulatory elements. Gene-level summaries of the maps captured regulatory complexity and showed that more constrained genes had smaller predicted mutational effects. Aggregating Multi-ISM predictions into gene-level rare-variant burdens improved personalized expression prediction over a common-variant elastic net, with the largest gains at expression outliers. Multi-ISM makes nucleotide-resolution interpretation of long-context sequence models a routine computation rather than a dedicated effort, so that new architectures, functional readouts, and cellular contexts can be mapped as they appear.",
  "abstract_shown": true,
  "affiliations": [
    "Calico Life Sciences LLC"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "H. Yuan"
    },
    {
      "name": "X. Huang"
    },
    {
      "name": "B. Auerbach"
    },
    {
      "name": "J. Linder"
    },
    {
      "name": "D. Srivastava"
    },
    {
      "affs": [
        0
      ],
      "name": "D. R. Kelley"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cybd4vxjr13bw.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.30.755794",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755794v1.full",
  "id": "cybd4vxjr13bw",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755794v1",
  "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",
      "genomics"
    ],
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7215037267",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755794v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cybd4vxjr13bw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:39Z",
      "native_id": "10.64898/2026.09.30.755794",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755794v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:genomics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Scalable saturation mutagenesis reveals gene regulatory architecture and rare variant effects",
  "title_text": "Scalable saturation mutagenesis reveals gene regulatory architecture and rare variant effects",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:39Z",
  "url": "https://research.draconitic.com/paper/cybd4vxjr13bw",
  "venue": "bioRxiv",
  "versions": []
}