Journal Article

FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation

George Koumbaris, Hariklia Hatzisevastou-Loukidou, Angelos Alexandrou, Marios Ioannides, Christodoulos Christodoulou, Tomas Fitzgerald, Diana Rajan, Stephen Clayton, Sophia Kitsiou-Tzeli, Joris R. Vermeesch, Nicos Skordis, Pavlos Antoniou, Ants Kurg, Ioannis Georgiou, Nigel P. Carter and Philippos C. Patsalis

in Human Molecular Genetics

Volume 20, issue 10, pages 1925-1936
Published in print May 2011 | ISSN: 0964-6906
Published online February 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr074
FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation

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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.

Journal Article.  7260 words.  Illustrated.

Subjects: Genetics and Genomics

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