title: Sequencing human-gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites.
abstract: The gibbon genome exhibits extensive karyotypic diversity with an increased rate of chromosomal rearrangements during evolution. In an effort to understand the mechanistic origin and implications of these rearrangement events, we sequenced 24 synteny breakpoint regions in the white-cheeked gibbon (Nomascus leucogenys, NLE) in the form of high-quality BAC insert sequences (4.2 Mbp). While there is a significant deficit of breakpoints in genes, we identified seven human gene structures involved in signaling pathways (DEPDC4, GNG10), phospholipid metabolism (ENPP5, PLSCR2), beta-oxidation (ECH1), cellular structure and transport (HEATR4), and transcription (ZNF461), that have been disrupted in the NLE gibbon lineage. Notably, only three of these genes show the expected evolutionary signatures of pseudogenization. Sequence analysis of the breakpoints suggested both nonclassical nonhomologous end-joining (NHEJ) and replication-based mechanisms of rearrangement. A substantial number (11/24) of human-NLE gibbon breakpoints showed new insertions of gibbon-specific repeats and mosaic structures formed from disparate sequences including segmental duplications, LINE, SINE, and LTR elements. Analysis of these sites provides a model for a replication-dependent repair mechanism for double-strand breaks (DSBs) at rearrangement sites and insights into the structure and formation of primate segmental duplications at sites of genomic rearrangements during evolution.
authors.affiliation: Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Tina
authors.initials: T
authors.lastname: Graves
authors.forename: Tomas
authors.initials: T
authors.lastname: Marques-Bonet
authors.forename: Mario
authors.initials: M
authors.lastname: Ventura
authors.forename: Catrina
authors.initials: C
authors.lastname: Fronick
authors.forename: Lucinda
authors.initials: L
authors.lastname: Fulton
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000818:Animals; D001483:Base Sequence; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial; D002877:Chromosomes, Human; D006801:Humans; D006922:Hylobates / Q000235:genetics*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009030:Mosaicism / Q000662:veterinary; D016254:Mutagenesis, Insertional / Q000502:physiology*; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D026801:Synteny