Co-regulated transcriptional networks contribute to natural genetic variation in Drosophila sleep

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Abstract
Trudy Mackay and colleagues measure sleep phenotypes in 40 wild-derived Drosophila lines, and report candidate genes and transcriptional networks associated with sleep regulation. Sleep disorders are common in humans, and sleep loss increases the risk of obesity and diabetes1. Studies in Drosophila2,3 have revealed molecular pathways4,5,6,7 and neural tissues8,9,10 regulating sleep; however, genes that maintain genetic variation for sleep in natural populations are unknown. Here, we characterized sleep in 40 wild-derived Drosophila lines and observed abundant genetic variation in sleep architecture. We associated sleep with genome-wide variation in gene expression11 to identify candidate genes. We independently confirmed that molecular polymorphisms in Catsup (Catecholamines up) are associated with variation in sleep and that P-element mutations in four candidate genes affect sleep and gene expression. Transcripts associated with sleep grouped into biologically plausible genetically correlated transcriptional modules. We confirmed co-regulated gene expression using P-element mutants. Quantitative genetic analysis of natural phenotypic variation is an efficient method for revealing candidate genes and pathways.