Identification of natural variants that influence responses to ethanol in C. elegans

Background

Alcohol use disorder (AUD) is a worldwide problem that has social, health and financial consequences. The genetic component of developing this disease is estimated to be roughly 50%. Genetic variation, in the form of mild change- of- function alleles, of genes that contribute to the physiological response of alcohol use, are likely underlying the development of AUD. Because the genetic risk underlying AUD is highly polygenic, many investigations into natural variation of ethanol responses in human population have not yielded enough candidate genes to explain this large genetic component.

To investigate this missing heritability, we use the nematode C. elegans as model organism for investigating genotype phenotype relations in response to ethanol. C. elegans is an excellent model to study ethanol responses due to the conserved neuronal molecular machinery between worms and humans, conserved ethanol responses, and their rapid life cycle.

Project description

In this project we will behaviorally characterize a multi-parent recombinant inbred line (mpRIL) panel for several phenotypes that are relevant for AUD risk and map QTL. Furthermore, we will investigate the transcriptional architecture of ethanol responses by exposing a core set of mpRILs to ethanol and map eQTL. Loci that are implicated in ethanol responses will be validated by generating introgression lines. After validation, candidate genes will be prioritized, and alleles will be verified by performing allele swaps with CRISPR-cas9.