Expression Profiling of a Recombinant Inbred Line Panel Identifies the
                    <i>dod‐19</i>
                    Gene as a Regulator of Ethanol Response Behaviors in
                    <scp>
                      <i>C. elegans</i>

doi:10.1111/acer.70432

DOI: 10.1111/acer.70432 ISSN: 2993-7175

Expression Profiling of a Recombinant Inbred Line Panel Identifies the dod‐19 Gene as a Regulator of Ethanol Response Behaviors in C. elegans

Marijke H. van Wijk, Mark G. Sterken, Elizabeth C. Quamme, Joost A. G. Riksen, Basten L. Snoek, Stefan J. S. van de Ruitenbeek, Laura D. Mathies, Andrew G. Davies, Jill C. Bettinger, Jan E. Kammenga

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ABSTRACT

Background

Variation in gene expression is hypothesized to be a major source of phenotypic variation underlying the liability for alcohol misuse. Caenorhabditis elegans ( C. elegans ) has proven to be a valuable model in the identification of genes that modify behavioral responses to alcohol. Genetic variation in wild strains represents allelic differences that are tolerated by natural selection pressures and, therefore, are more likely to model the allelic differences that are present in humans compared with laboratory‐generated mutations.

Methods

We examined the influence of natural alleles on gene expression in response to ethanol by mapping eQTL in C. elegans . We used a recombinant inbred panel derived from four wild strains to examine the regulation of ethanol exposure‐induced gene expression. We performed differential gene expression analyses and mapped eQTL. Detailed examination of trans‐ band _{ChrV‐0:3 Mb} included quantification of the behavioral responses to ethanol for top candidate genes in the trans ‐band.

Results

Ethanol exposure increased trans‐ eQTL and decreased cis‐ eQTL. We observed the largest shift in distantly regulated transcripts on the first three Mb on chromosome V that contained 355 trans‐ eQTL in a single trans‐ band. The eQTL group in this trans‐ band was involved in processes implicated in alcohol use disorder and its gene ontology terms included unsaturated fatty acids, responses to stress and environment, and immune and defense responses. We validated this genomic region using an introgression line and identified nhr‐131 and dod‐19 as potential polymorphic modifiers of trans‐ band _{ChrV‐0:3 Mb} . We tested null mutations in nhr‐131 and dod‐19 and found that dod‐19 is required for the normal development of acute functional tolerance (AFT) to ethanol.

Conclusions

Natural genetic variation in these wild strains primarily affected trans ‐regulated gene expression. Examination of trans‐ band _{ChrV‐0:3 Mb} identified dod‐19 as a candidate expression modifier gene that regulates the development of AFT to ethanol and further implicates membrane biology in this process.