title: Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.
abstract: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies.
  
  
  
  We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV.
  
  
  
  These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, 02115, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Collins
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Redin
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Antolik
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stone
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mason
authors.affiliation: Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pregno
authors.affiliation: Department of Pathology & Laboratory Medicine and UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California Los Angeles, UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Dorrani
authors.affiliation: Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giachino
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Perrin
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Cole
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cipicchio
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Costello
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Stortchevoi
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, 94103, USA.
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: An
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Currall
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.|GABBA Program, University of Porto, Porto, 4099-002, Portugal.
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Seabra
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Ragavendran
authors.affiliation: Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Margolin
authors.affiliation: Department of Pathology & Laboratory Medicine and UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California Los Angeles, UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Lucente
authors.affiliation: Department of Pathology, Columbia University, New York, NY, 10032, USA.
authors.forename: Brynn
authors.initials: B
authors.lastname: Levy
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, 94103, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wapner
authors.affiliation: Department of Pathology & Laboratory Medicine and UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California Los Angeles, UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CG, The Netherlands.
authors.forename: Wigard
authors.initials: W
authors.lastname: Kloosterman
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA. talkowski@chgr.mgh.harvard.edu.|Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, 02115, USA. talkowski@chgr.mgh.harvard.edu.|Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA. talkowski@chgr.mgh.harvard.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D000072837:Chromothripsis; D023061:Gene Order; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation
keywords: Autism; Chromoanagenesis; Chromothripsis; Complex chromosomal rearrangement; Copynumber variation; Germline mutation; Inversion; Neurodevelopmental disorders; Structural variation; Whole-genome sequencing