{
  "abstract": "Genetic interactions contribute to phenotypic variation, yet most studies characterize them in a small number of reference backgrounds rather than across natural populations. Studying genetic interactions in Caenorhabditis elegans is facilitated by RNAi by feeding, which enables gene-specific knockdowns across many genetic backgrounds without the need to construct individual mutant lines. However, individually screening hundreds of isolates across many RNAi conditions is laborious. Here, we developed a pooled platform that uses whole-genome sequencing to quantify the fitness of hundreds of genetically distinct C. elegans strains competing in a single flask. We leveraged this platform to evaluate RNAi responses in a pooled population of RNAi-sensitive C. elegans strains and identified two classes of QTL that influence RNAi responses. The first class influences responses to knockdowns of specific genes and is exemplified by a QTL that is specific to knockdown of mig-6. The second class influences general RNAi-response across multiple knockdowns. One QTL in this class localized to the right arm of chromosome III and was detected by both GWA and xQTL mapping, which suggests that a common large-effect variant underlies this QTL. We identified a T96K missense change in the dsRNA receptor SID-2 as the underlying causal variant. The 96K allele resides in the extracellular domain of SID-2 and confers increased RNAi sensitivity relative to the 96T allele. We hypothesize that the 96K allele enables greater uptake of ingested lumenal dsRNA through higher-affinity binding to the dsRNA phosphate backbone. The platform we developed enables systematic mapping of genetic interactions across natural populations at a previously impractical scale.",
  "abstract_shown": true,
  "affiliations": [
    "University of California, Los Angeles"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "S. Zdraljevic"
    },
    {
      "name": "A. Lee"
    },
    {
      "name": "L. Walter-McNeill"
    },
    {
      "name": "H. Marquez"
    },
    {
      "name": "A. K. Webster"
    },
    {
      "name": "R. Chitrakar"
    },
    {
      "name": "J. Blount"
    },
    {
      "name": "L. R. Baugh"
    },
    {
      "name": "J. S. Bloom"
    },
    {
      "name": "L. Kruglyak"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f8xjg0q3epnnf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.08.757717",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757717v1.full",
  "id": "f8xjg0q3epnnf",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757717v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "genetics"
    ],
    [
      "openalex",
      "1311|Genetic Mapping and Diversity in Plants and Animals"
    ]
  ],
  "openalex": "W7221448930",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757717v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/f8xjg0q3epnnf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:11Z",
      "native_id": "10.64898/2026.10.08.757717",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757717v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:genetics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Large-scale pooled selection enables mapping of modifiers of RNAi gene knockdown effects in C. elegans",
  "title_text": "Large-scale pooled selection enables mapping of modifiers of RNAi gene knockdown effects in C. elegans",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:11Z",
  "url": "https://research.draconitic.com/paper/f8xjg0q3epnnf",
  "venue": "bioRxiv",
  "versions": []
}