RT Journal Article
SR Electronic
T1 Common genomic regions underlie natural variation in diverse toxin responses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 325399
DO 10.1101/325399
A1 Kathryn S. Evans
A1 Shannon C. Brady
A1 Joshua S. Bloom
A1 Robyn E. Tanny
A1 Daniel E. Cook
A1 Sarah E. Giuliani
A1 Stephen W. Hippleheuser
A1 Mostafa Zamanian
A1 Erik C. Andersen
YR 2018
UL http://biorxiv.org/content/early/2018/08/21/325399.abstract
AB Phenotypic complexity is caused by the contributions of environmental factors and multiple genetic loci, interacting or acting independently. Studies of yeast and Arabidopsis found that the majority of natural variation across phenotypes is attributable to independent additive quantitative trait loci (QTL). Detected loci in these organisms explain most of the estimated heritable variation. By contrast, many heritable components underlying phenotypic variation in metazoan models remain undetected. Before the relative impacts of additive and interactive variance components on metazoan phenotypic variation can be dissected, high replication and precise phenotypic measurements are required to obtain sufficient statistical power to detect loci contributing to this missing heritability. Here, we used a panel of 296 recombinant inbred advanced intercross lines of Caenorhabditis elegans and a high-throughput fitness assay to detect loci underlying responses to 16 different toxins, including heavy metals, chemotherapeutic drugs, pesticides, and neuropharmaceuticals. Using linkage mapping, we identified 82 QTL that underlie variation in responses to these toxins and predicted the relative contributions of additive loci and genetic interactions across various growth parameters. Additionally, we identified three genomic regions that impact responses to multiple classes of toxins. These QTL hotspots could represent common factors impacting toxin responses. We went further to generate near-isogenic lines and chromosome-substitution strains and then experimentally validated these QTL hotspots, implicating additive and interactive loci that underlie toxin-response variation.