The gene scb-1 underlies variation in caenorhabditis elegans chemotherapeutic responses

Kathryn S. Evans, Erik C. Andersen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Pleiotropy, the concept that a single gene controls multiple distinct traits, is prevalent in most organisms and has broad implications for medicine and agriculture. The identification of the molecular mechanisms underlying pleiotropy has the power to reveal previously unknown biological connections between seemingly unrelated traits. Additionally, the discovery of pleiotropic genes increases our understanding of both genetic and phenotypic complexity by characterizing novel gene functions. Quantitative trait locus (QTL) mapping has been used to identify several pleiotropic regions in many organisms. However, gene knockout studies are needed to eliminate the possibility of tightly linked, non-pleiotropic loci. Here, we use a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to identify a single large-effect QTL on the center of chromosome V associated with variation in responses to eight chemotherapeutics. We validate this QTL with near-isogenic lines and pair genome-wide gene expression data with drug response traits to perform mediation analysis, leading to the identification of a pleiotropic candidate gene, scb-1, for some of the eight chemotherapeutics. Using deletion strains created by genome editing, we show that scb-1, which was previously implicated in response to bleomycin, also underlies responses to other double-strand DNA break-inducing chemotherapeutics. This finding provides new evidence for the role of scb-1 in the nematode drug response and highlights the power of mediation analysis to identify causal genes.

Original languageEnglish (US)
Pages (from-to)2353-2364
Number of pages12
JournalG3: Genes, Genomes, Genetics
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2020

Funding

We would like to thank members of the Andersen Lab for helpful comments on the manuscript. This work was supported by an American Cancer Society Research Scholar Grant (127313-RSG-15-135-01-DD) to E.C.A. Additionally, K.S.E. received support from the NSF-Simons Center for Quantitative Biology at Northwestern University (awards Simons Foundation/SFARI 597491-RWC and the National Science Foundation 1764421).

Keywords

  • C. elegans
  • Chemotherapeutics
  • Mediation
  • Pleiotropy
  • QTL

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology

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