Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep
Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep
ABSTRACT Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a ‘variant-to-gene’ mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly, Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q), a gene that encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)- anchor biosynthesis. We show that flies deficient for PIG-Q have longer sleep during both day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated the PIG-Q locus in zebrafish and identified similar increases in sleep to those observed in Drosophila, confirming deep homology of PIG-Q mediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism-based prioritization, revealing a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.
Wells Andrew D.、Gehrman Phillip R.、Grant Struan F.A.、Doldur-Balli Fusun、Chesi Alessandra、Sonti Shilpa、Zimmerman Amber、Keene Alex C.、Brown Elizabeth B.、Palermo Justin、Pippin James A.、Pack Allan I.、Lasconi Chiara、Mazzotti Diego R.
Center for Spatial and Functional Genomics, Children?ˉs Hospital of Philadelphia||Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia||Division of Sleep Medicine/Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Psychiatry, Perelman School of Medicine, University of PennsylvaniaCenter for Spatial and Functional Genomics, Children?ˉs Hospital of Philadelphia||Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine||Division of Human Genetics, Children?ˉs Hospital of Philadelphia||Department of Genetics, University of PennsylvaniaDivision of Sleep Medicine/Department of Medicine, Perelman School of Medicine, University of PennsylvaniaCenter for Spatial and Functional Genomics, Children?ˉs Hospital of Philadelphia||Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine PhiladelphiaCenter for Spatial and Functional Genomics, Children?ˉs Hospital of PhiladelphiaCenter for Spatial and Functional Genomics, Children?ˉs Hospital of Philadelphia||Division of Sleep Medicine/Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Biology, Texas A&M UniversityDepartment of Biology, Texas A&M UniversityDepartment of Biology, Texas A&M UniversityCenter for Spatial and Functional Genomics, Children?ˉs Hospital of PhiladelphiaDivision of Sleep Medicine/Department of Medicine, Perelman School of Medicine, University of PennsylvaniaCenter for Spatial and Functional Genomics, Children?ˉs Hospital of PhiladelphiaDivision of Medical Informatics, Department of Internal Medicine, University of Kansas Medical Center||Division of Pulmonary Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kansas Medical Center
基础医学生物科学研究方法、生物科学研究技术神经病学、精神病学
Wells Andrew D.,Gehrman Phillip R.,Grant Struan F.A.,Doldur-Balli Fusun,Chesi Alessandra,Sonti Shilpa,Zimmerman Amber,Keene Alex C.,Brown Elizabeth B.,Palermo Justin,Pippin James A.,Pack Allan I.,Lasconi Chiara,Mazzotti Diego R..Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep[EB/OL].(2025-03-28)[2025-05-03].https://www.biorxiv.org/content/10.1101/2021.12.19.472248.点此复制
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