Abstract
There is considerable variation in sleep duration, timing and quality in human populations, and sleep dysregulation has been implicated as a risk factor for a range of health problems. Human sleep traits are known to be regulated by genetic factors, but also by an array of environmental and social factors. These uncontrolled, non-genetic effects complicate powerful identification of the loci contributing to sleep directly in humans. The model system, Drosophila melanogaster, exhibits a behavior that shows the hallmarks of mammalian sleep, and here we use a multitiered approach, encompassing high-resolution QTL mapping, expression QTL data, and functional validation with RNAi to investigate the genetic basis of sleep under highly controlled environmental conditions. We measured a battery of sleep phenotypes in >750 genotypes derived from a multiparental mapping panel and identified several, modest-effect QTL contributing to natural variation for sleep. Merging sleep QTL data with a large head transcriptome eQTL mapping dataset from the same population allowed us to refine the list of plausible candidate causative sleep loci. This set includes genes with previously characterized effects on sleep and circadian rhythms, in addition to novel candidates. Finally, we employed adult, nervous system-specific RNAi on the Dopa decarboxylase, dyschronic, and timeless genes, finding significant effects on sleep phenotypes for all three. The genes we resolve are strong candidates to harbor causative, regulatory variation contributing to sleep.
Highlights
Sleep is a phenomenon that has been recognized in a variety of vertebrate and invertebrate systems [1,2]
Using RNAi, we provide independent evidence that the genes Dopa decarboxylase (Ddc), dyschronic, and timeless, all previously recognized as mediators of circadian rhythm or sleep, impact sleep phenotypes
We measured a suite of phenotypes in 787 F1 heterozygous genotypes derived from the DSPR [23], using an average of 8.7 virgin females per DSPRF1 genotype, and averaging phenotype over four sequential 24 h periods of data collection while flies were 3–9 d old
Summary
Sleep is a phenomenon that has been recognized in a variety of vertebrate and invertebrate systems [1,2]. Natural variation among individuals in the duration and quality of sleep is extensive, with evidence available from humans, as well as from model systems such as mice [5] and flies [6,7]. GWAS employ hundreds of thousands of individuals, human geneticists have successfully identified, and in many cases replicated small-effect loci contributing to variation in sleep parameters in human populations. Such studies, conducted directly in humans, have implicated a number of biological pathways in the control of sleep variation, and have made connections between disease risk and
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