title: FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.
abstract: The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: George
authors.initials: G
authors.lastname: Koumbaris
authors.forename: Hariklia
authors.initials: H
authors.lastname: Hatzisevastou-Loukidou
authors.forename: Angelos
authors.initials: A
authors.lastname: Alexandrou
authors.forename: Marios
authors.initials: M
authors.lastname: Ioannides
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Christodoulou
authors.forename: Tomas
authors.initials: T
authors.lastname: Fitzgerald
authors.forename: Diana
authors.initials: D
authors.lastname: Rajan
authors.forename: Stephen
authors.initials: S
authors.lastname: Clayton
authors.forename: Sophia
authors.initials: S
authors.lastname: Kitsiou-Tzeli
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
authors.forename: Pavlos
authors.initials: P
authors.lastname: Antoniou
authors.forename: Ants
authors.initials: A
authors.lastname: Kurg
authors.forename: Ioannis
authors.initials: I
authors.lastname: Georgiou
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Philippos C
authors.initials: PC
authors.lastname: Patsalis
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D041321:Chromosomes, Human, X / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004261:DNA Replication / Q000235:genetics*; D006801:Humans; D018404:Isochromosomes / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D016415:Sequence Alignment; D020080:Tandem Repeat Sequences / Q000235:genetics