FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation
Koumbaris, George × Hatzisevastou-Loukidou, Hariklia Alexandrou, Angelos Ioannides, Marios Christodoulou, Christodoulos Fitzgerald, Tomas Rajan, Diana Clayton, Stephen Kitsiou-Tzeli, Sophia Vermeesch, Joris Skordis, Nicos Antoniou, Pavlos Kurg, Ants Georgiou, Ioannis Carter, Nigel P Patsalis, Philippos C #
Human Molecular Genetics vol:20 issue:10 pages:1925-1936
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 (NAHR) between palindromic low copy repeats (LCRs) and highly homologous palindromic LINE elements. We also show that nonrecurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination (MMRDR) mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.