title: An integrative computational approach for prioritization of genomic variants.
abstract: An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America; Department of Energy Joint Genome Institute, Walnut Creek, California, United States of America.
authors.forename: Inna
authors.initials: I
authors.lastname: Dubchak
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Toyota Technological Institute at Chicago, Chicago, Illinois, United States of America.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Meydan
authors.initials: M
authors.lastname: Cem
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Cem
authors.initials: C
authors.lastname: Meyden
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Computation Institute, University of Chicago/Argonne National Laboratory, Chicago, Illinois, United States of America.
authors.forename: Dinanath
authors.initials: D
authors.lastname: Sulakhe
authors.affiliation: Department of Energy Joint Genome Institute, Walnut Creek, California, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Poliakov
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Toyota Technological Institute at Chicago, Chicago, Illinois, United States of America.
authors.forename: Daniela
authors.initials: D
authors.lastname: Börnigen
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Department of Computer Science, Illinois Institute of Technology, Chicago, Illinois, United States of America.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Toyota Technological Institute at Chicago, Chicago, Illinois, United States of America.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Ma
authors.affiliation: Departments of Neurology, Pediatrics, and Biomedical Genetics and Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.affiliation: Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ghayda M
authors.initials: GM
authors.lastname: Mirzaa
authors.affiliation: Computation Institute, University of Chicago/Argonne National Laboratory, Chicago, Illinois, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Dave
authors.affiliation: Department of Computer Science, Illinois Institute of Technology, Chicago, Illinois, United States of America.
authors.forename: Gady
authors.initials: G
authors.lastname: Agam
authors.affiliation: Toyota Technological Institute at Chicago, Chicago, Illinois, United States of America.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, UAE.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Laboratory of Neurogenetics and Development, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Ross
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Computation Institute, University of Chicago/Argonne National Laboratory, Chicago, Illinois, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Maltsev
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Computation Institute, University of Chicago/Argonne National Laboratory, Chicago, Illinois, United States of America.
authors.forename: T Conrad
authors.initials: TC
authors.lastname: Gilliam
mesh_terms: D002648:Child; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D023281:Genomics / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011247:Pregnancy; D011487:Protein Conformation; D058978:Reduced Folate Carrier Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012984:Software; D016135:Spinal Dysraphism / Q000235:genetics* / Q000378:metabolism
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid