Selection for long and short sleep duration in Drosophila melanogaster reveals the complex genetic network underlying natural variation in sleep

Abstract

Why do some individuals need more sleep than others? Forward mutagenesis screens in flies using engineered mutations have established a clear genetic component to sleep duration, revealing mutants that convey very long or short sleep. Whether such extreme long or short sleep could exist in natural populations was unknown. We applied artificial selection for high and low night sleep duration to an outbred population of Drosophila melanogaster for 13 generations. At the end of the selection procedure, night sleep duration diverged by 9.97 hours in the long and short sleeper populations, and 24-hour sleep was reduced to 3.3 hours in the short sleepers. Neither long nor short sleeper lifespan differed appreciably from controls, suggesting little physiological consequences to being an extreme long or short sleeper. Whole genome sequence data from seven generations of selection revealed several hundred thousand changes in allele frequencies at polymorphic loci across the genome. Combining the data from long and short sleeper populations across generations in a logistic regression implicated 126 polymorphisms in 80 candidate genes, and we confirmed three of these genes and a larger genomic region with mutant and chromosomal deficiency tests, respectively. Many of these genes could be connected in a single network based on previously known physical and genetic interactions. Candidate genes have known roles in several classic, highly conserved developmental and signaling pathways—EGFR, Wnt, Hippo, and MAPK. The involvement of highly pleiotropic pathway genes suggests that sleep duration in natural populations can be influenced by a wide variety of biological processes, which may be why the purpose of sleep has been so elusive.

Dissecting the Genetic Basis of Variation in Drosophila Sleep Using a Multiparental QTL Mapping Resource

“…This view is supported by the observation that our study reveals a largely distinct genetic architecture from a previous sleep genomewide mapping study employing the DGRP lines [6]. Similarly, an artificial selection study initiated from DGRP strains with extreme sleep phenotypes observed little overlap at the polymorphism or gene level between loci identified in the GWAS and loci showing allele frequency changes following selection [22]. Nonetheless, we leveraged our mapping data, together with extant expression data, to point to three strong candidate genes, and our data suggest there is a link between natural variation in these genes and sleep phenotypes in flies.…”

“…These heritability values are generally consistent with those obtained for the same traits in the DGRP inbred line GWAS panel [6] and demonstrate that considerable segregating variation for sleep and activity parameters exists within Drosophila populations. Indeed, recent work by Harbison et al [22] has leveraged this genetic variation to create long-and short-sleeping Drosophila lines via artificial selection and saw a rapid divergence in phenotype over a modest number of generations of selection.…”

“…As a result of the correlations among traits, we expect some overlap in the mapped loci contributing to variation in the individual sleep and activity traits we assay. [22] has leveraged this genetic variation to create long-and short-sleeping Drosophila lines via artificial selection and saw a rapid divergence in phenotype over a modest number of generations of selection. Among-trait correlations in the DSPRF1 genotype panel are generally modest, but extremely significant given the size of the dataset (Supplementary Table S2).…”

“…Many studies of sleep in flies leverage mutations identified in forward genetic screens (e.g., [16]), but it is also feasible to dissect naturally-occurring genetic variation contributing to fly sleep using sets of wildtype genotypes [6,21,22]. Such studies are complementary since genes that yield large-effect, loss-of-function mutant alleles may not necessarily be those that also contribute to naturally-segregating allelic variation.…”

Most sleep does not serve a vital function. Evidence from Drosophila melanogaster

“…Likewise, artificially selected short-sleeping fruit flies have unaltered longevity (32). With flies joining pigeons in the list of animals surviving chronic sleep deprivation, the only solid evidence in favour of lethality upon sleep deprivation lays with the chronic sleep deprivation in rats using the disc-over-water system.…”