title: Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.
abstract: Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.
authors.affiliation: Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Dennis
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
authors.forename: John
authors.initials: J
authors.lastname: Huddleston
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.affiliation: Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Karyn Meltz
authors.initials: KM
authors.lastname: Steinberg
authors.affiliation: Signature Genomic Laboratories, LLC, Spokane, Washington, USA.
authors.forename: Jill A
authors.identifier: 0000000156647987
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Miroballo
authors.affiliation: Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tina A
authors.initials: TA
authors.lastname: Graves
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Denman
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Raja
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stuart
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Brenton
authors.initials: B
authors.lastname: Munson
authors.affiliation: 1] Signature Genomic Laboratories, LLC, Spokane, Washington, USA. [2] Genetic Veterinary Sciences, Inc., Paw Print Genetics, Spokane, Washington, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Amemiya
authors.affiliation: Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D022202:Chromosomes, Artificial, Bacterial; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D011323:Primates; D012091:Repetitive Sequences, Nucleic Acid; D056916:Segmental Duplications, Genomic; D012640:Seizures / Q000235:genetics*; D017422:Sequence Analysis, DNA