Identification of Causal Genes, Networks, and Transcriptional Regulators of REM Sleep and Wake
| Autor: | Bin Zhang, Joshua Millstein, Andrew Kasarskis, Joseph R. Owens, John J. Renger, Lili Zhou, Keith C. Summa, Christopher J. Winrow, Karrie Fitzpatrick, Fred W. Turek, Eric E. Schadt, Martha Hotz Vitaterna |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Candidate gene Genotype Quantitative Trait Loci Hypothalamus Gene regulatory network Sleep REM Quantitative trait locus Biology Mice Thalamus Mesencephalon Physiology (medical) Animals Regulatory Elements Transcriptional Wakefulness Gene Cerebral Cortex Regulation of gene expression Mice Inbred BALB C Gene Expression Profiling Sleep in non-human animals Mice Inbred C57BL Gene expression profiling Gene Expression Regulation Commentary Neurology (clinical) Causal Genes Networks and Regulators of Sleep and Wake Neuroscience |
| Popis: | Study objective Sleep-wake traits are well-known to be under substantial genetic control, but the specific genes and gene networks underlying primary sleep-wake traits have largely eluded identification using conventional approaches, especially in mammals. Thus, the aim of this study was to use systems genetics and statistical approaches to uncover the genetic networks underlying 2 primary sleep traits in the mouse: 24-h duration of REM sleep and wake. Design Genome-wide RNA expression data from 3 tissues (anterior cortex, hypothalamus, thalamus/midbrain) were used in conjunction with high-density genotyping to identify candidate causal genes and networks mediating the effects of 2 QTL regulating the 24-h duration of REM sleep and one regulating the 24-h duration of wake. Setting Basic sleep research laboratory. Patients or participants Male [C57BL/6J × (BALB/cByJ × C57BL/6J*) F1] N(2) mice (n = 283). Interventions None. Measurements and results The genetic variation of a mouse N2 mapping cross was leveraged against sleep-state phenotypic variation as well as quantitative gene expression measurement in key brain regions using integrative genomics approaches to uncover multiple causal sleep-state regulatory genes, including several surprising novel candidates, which interact as components of networks that modulate REM sleep and wake. In particular, it was discovered that a core network module, consisting of 20 genes, involved in the regulation of REM sleep duration is conserved across the cortex, hypothalamus, and thalamus. A novel application of a formal causal inference test was also used to identify those genes directly regulating sleep via control of expression. Conclusion Systems genetics approaches reveal novel candidate genes, complex networks and specific transcriptional regulators of REM sleep and wake duration in mammals. |
| Databáze: | OpenAIRE |
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