Harbison, S.T. & Sehgal, A. Quantitative genetic analysis of sleep in Drosophila melanogaster. Genetics 178, 2341-2360

Howard Hughes Medical Institute, Department of Neuroscience, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genetics (Impact Factor: 5.96). 05/2008; 178(4):2341-60. DOI: 10.1534/genetics.107.081232
Source: PubMed


Although intensively studied, the biological purpose of sleep is not known. To identify candidate genes affecting sleep, we assayed 136 isogenic P-element insertion lines of Drosophila melanogaster. Since sleep has been negatively correlated with energy reserves across taxa, we measured energy stores (whole-body protein, glycogen, and triglycerides) in these lines as well. Twenty-one insertions with known effects on physiology, development, and behavior affect 24-hr sleep time. Thirty-two candidate insertions significantly impact energy stores. Mutational genetic correlations among sleep parameters revealed that the genetic basis of the transition between sleep and waking states in males and females may be different. Furthermore, sleep bout number can be decoupled from waking activity in males, but not in females. Significant genetic correlations are present between sleep phenotypes and glycogen stores in males, while sleep phenotypes are correlated with triglycerides in females. Differences observed in male and female sleep behavior in flies may therefore be related to sex-specific differences in metabolic needs. Sleep thus emerges as a complex trait that exhibits extensive pleiotropy and sex specificity. The large mutational target that we observed implicates genes functioning in a variety of biological processes, suggesting that sleep may serve a number of different functions rather than a single purpose.

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Available from: Susan T Harbison, Oct 07, 2014
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    • "A P-element insertional mutagenesis screen for alcohol sensitivity revealed that almost 30 % of the P-element insertions tested affected the trait, indicating that a large fraction of the genome contributes to alcohol sensitivity and predicting extensive pleiotropy (Morozova et al. 2011; Fig. 2). Indeed, most of the mutations that affect alcohol sensitivity in Drosophila have pleiotropic effects on other complex traits (Harbison and Sehgal 2008; edwards et al. 2009; Magwire et al. 2010). "
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    ABSTRACT: Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00438-013-0808-y) contains supplementary material, which is available to authorized users.
    MGG Molecular & General Genetics 01/2014; 289(3). DOI:10.1007/s00438-013-0808-y · 2.73 Impact Factor
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    • "Several studies have already capitalized on community resources, together screening more than 15,000 mutations for their effects on sleep [13-15]. A small number of mutations (e.g., in Shaker, fumin, and sleepless) have major effects on sleep [13-16], but many mutations have more subtle quantitative effects [17]. A complementary approach to mutagenesis is to identify loci at which alleles with more subtle effects segregate in natural populations [18,19]. "
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    ABSTRACT: Background Sleep is a highly conserved behavior, yet its duration and pattern vary extensively among species and between individuals within species. The genetic basis of natural variation in sleep remains unknown. Results We used the Drosophila Genetic Reference Panel (DGRP) to perform a genome-wide association (GWA) study of sleep in D. melanogaster. We identified candidate single nucleotide polymorphisms (SNPs) associated with differences in the mean as well as the environmental sensitivity of sleep traits; these SNPs typically had sex-specific or sex-biased effects, and were generally located in non-coding regions. The majority of SNPs (80.3%) affecting sleep were at low frequency and had moderately large effects. Additive models incorporating multiple SNPs explained as much as 55% of the genetic variance for sleep in males and females. Many of these loci are known to interact physically and/or genetically, enabling us to place them in candidate genetic networks. We confirmed the role of seven novel loci on sleep using insertional mutagenesis and RNA interference. Conclusions We identified many SNPs in novel loci that are potentially associated with natural variation in sleep, as well as SNPs within genes previously known to affect Drosophila sleep. Several of the candidate genes have human homologues that were identified in studies of human sleep, suggesting that genes affecting variation in sleep are conserved across species. Our discovery of genetic variants that influence environmental sensitivity to sleep may have a wider application to all GWA studies, because individuals with highly plastic genotypes will not have consistent phenotypes.
    BMC Genomics 04/2013; 14(1):281. DOI:10.1186/1471-2164-14-281 · 3.99 Impact Factor
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    • ", 2011 ) . Previously a P - element insertion allele at Crc ( Crc BG02566 ) was found to affect sleep phenotypes ( Harbison & Sehgal , 2008 ) , but this insertion was at a different site than the P - element insertion allele ( Crc BG01724 ) previously im - plicated in startle behaviour ( Yamamoto et al . , 2009 ) . "
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    ABSTRACT: Epistasis is an important feature of the genetic architecture of quantitative traits, but the dynamics of epistatic interactions in natural populations and the relationship between epistasis and pleiotropy remain poorly understood. Here, we studied the effects of epistatic modifiers that segregate in a wild-derived Drosophila melanogaster population on the mutational effects of P-element insertions in Semaphorin-5C (Sema-5c) and Calreticulin (Crc), pleiotropic genes that affect olfactory behaviour and startle behaviour and, in the case of Crc, sleep phenotypes. We introduced Canton-S B (CSB) third chromosomes with or without a P-element insertion at the Crc or Sema-5c locus in multiple wild-derived inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and assessed the effects of epistasis on the olfactory response to benzaldehyde and, for Crc, also on sleep. In each case, we found substantial epistasis and significant variation in the magnitude of epistasis. The predominant direction of epistatic effects was to suppress the mutant phenotype. These observations support a previous study on startle behaviour using the same D. melanogaster chromosome substitution lines, which concluded that suppressing epistasis may buffer the effects of new mutations. However, epistatic effects are not correlated among the different phenotypes. Thus, suppressing epistasis appears to be a pervasive general feature of natural populations to protect against the effects of new mutations, but different epistatic interactions modulate different phenotypes affected by mutations at the same pleiotropic gene.
    Genetics Research 02/2012; 94(1):9-20. DOI:10.1017/S001667231200002X · 1.47 Impact Factor
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