New Insights on Gene by Environmental Effects of Drugs of Abuse in Animal Models Using GeneNetwork.

Abstract

Gene-by-environment interactions are important for all facets of biology, especially behaviour. Families of isogenic strains of mice, such as the BXD strains, are excellently placed to study these interactions, as the same genome can be tested in multiple environments. BXD strains are recombinant inbred mouse strains derived from crossing two inbred strains—C57BL/6J and DBA/2J mice. Many reproducible genometypes can be leveraged, and old data can be reanalysed with new tools to produce novel insights. We obtained drug and behavioural phenotypes from Philip et al. Genes, Brain and Behaviour 2010, and reanalysed their data with new genotypes from sequencing, as well as new models (Genome-wide Efficient Mixed Model Association (GEMMA) and R/qtl2). We discovered QTLs on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We reduced the candidate genes based on their ability to alter gene expression or protein function. Candidate genes included Slitrk6 and Cdk14. Slitrk6, in a Chromosome14 QTL for locomotion, was found to be part of a co-expression network involved in voluntary movement and associated with neuropsychiatric phenotypes. Cdk14, one of only three genes in a Chromosome5 QTL, is associated with handling induced convulsions after ethanol treatment, that is regulated by the anticonvulsant drug valproic acid. By using families of isogenic strains, we can reanalyse data to discover novel candidate genes involved in response to drugs of abuse.