TY - JOUR
T1 - FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation
AU - Koumbaris, George
AU - Hatzisevastou-Loukidou, Hariklia
AU - Alexandrou, Angelos
AU - Ioannides, Marios
AU - Christodoulou, Christodoulos
AU - Fitzgerald, Tomas
AU - Rajan, Diana
AU - Clayton, Stephen
AU - Kitsiou-Tzeli, Sophia
AU - Vermeesch, Joris R.
AU - Skordis, Nicos
AU - Antoniou, Pavlos
AU - Kurg, Ants
AU - Georgiou, Ioannis
AU - Carter, Nigel P.
AU - Patsalis, Philippos C.
PY - 2011/5
Y1 - 2011/5
N2 - 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 microhomologyassociated 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.
AB - 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 microhomologyassociated 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.
UR - http://www.scopus.com/inward/record.url?scp=79955414171&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr074
DO - 10.1093/hmg/ddr074
M3 - Article
C2 - 21349920
AN - SCOPUS:79955414171
SN - 0964-6906
VL - 20
SP - 1925
EP - 1936
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
M1 - ddr074
ER -