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

Koumbaris, G./ Hatzisevastou-Loukidou, H./ Alexandrou, A./ Ioannides, M./ Christodoulou, C./ Fitzgerald, T./ Rajan, D./ Clayton, S./ Kitsiou-Tzeli, S./ Vermeesch, J. R./ Skordis, N./ Antoniou, P./ Kurg, A./ Georgiou, I./ Carter, N. P./ Patsalis, P. C.

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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιών
Keywords: serial replication slippage,nearby inverted repeats,alpha-satellite DNA,human genome,copy number,chromosome centromere,meiotic recombination,structural variation,mental-retardation,turner syndrome
URI: https://olympias.lib.uoi.gr/jspui/handle/123456789/16111
ISSN: 0964-6906
Link: <Go to ISI>://000289837400006
http://hmg.oxfordjournals.org/content/20/10/1925.full.pdf
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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