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PMID: 21349920 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Human molecular genetics ·Vol. 20 ·No. 10 ·2011-05-15 ·Pages 1925-36

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

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.

MeSH Terms
Base Sequence Chromosome Breakage Chromosomes, Human, X/genetics Comparative Genomic Hybridization DNA Replication/genetics Humans Isochromosomes/genetics Models, Genetic Molecular Sequence Data Nucleic Acid Conformation Polymorphism, Genetic Recombination, Genetic Sequence Alignment Tandem Repeat Sequences/genetics
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Koumbaris George
Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Hatzisevastou-Loukidou Hariklia
Alexandrou Angelos
Ioannides Marios
Christodoulou Christodoulos
Fitzgerald Tomas
Rajan Diana
Clayton Stephen
Kitsiou-Tzeli Sophia
Vermeesch Joris R
Skordis Nicos
Antoniou Pavlos
Kurg Ants
Georgiou Ioannis
Carter Nigel P
Patsalis Philippos C
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddr074
Published
2011-05-15
Epub
2011-00-24
Pages
1925-36
Language
English
Region
England
NLM ID
9208958
PMCID
PMC3428953
Subset
IM
Grants
Wellcome Trust · 077008 · United Kingdom
External Links
PubMed source DOI: 10.1093/hmg/ddr074 PMC Full Text View journal details
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