Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

Autor:	Collins RL; 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., Brand H; 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., Redin CE; 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., Hanscom C; 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., Antolik C; 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., Stone MR; 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., Glessner JT; 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., Mason T; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Pregno G; Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy., Dorrani N; 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., Mandrile G; Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy., Giachino D; Medical Genetics Unit, Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy., Perrin D; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Walsh C; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Cipicchio M; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Costello M; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Stortchevoi A; 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., An JY; Department of Psychiatry, University of California San Francisco, San Francisco, CA, 94103, USA., Currall BB; 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., Seabra CM; 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., Ragavendran A; 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., Margolin L; Program in Population and Medical Genetics and Genomics Platform, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA., Martinez-Agosto JA; 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., Lucente D; Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA., Levy B; Department of Pathology, Columbia University, New York, NY, 10032, USA., Sanders SJ; Department of Psychiatry, University of California San Francisco, San Francisco, CA, 94103, USA., Wapner RJ; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, 10032, USA., Quintero-Rivera F; 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., Kloosterman W; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CG, The Netherlands., Talkowski ME; 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.
Jazyk:	angličtina
Zdroj:	Genome biology [Genome Biol] 2017 Mar 06; Vol. 18 (1), pp. 36. Date of Electronic Publication: 2017 Mar 06.
DOI:	10.1186/s13059-017-1158-6
Abstrakt:	Background: 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. Results: 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. Conclusions: 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.
Databáze:	MEDLINE
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