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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

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

doi

10.1093/hmg/ddr074

subject

Has Abstract

pub_date

2011-05-15 00:00:00

pages

1925-36

issue

10

eissn

0964-6906

issn

1460-2083

pii

ddr074

journal_volume

20

pub_type

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