Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder.
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Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder. / Vogt, Julia; Mussotter, Tanja; Bengesser, Kathrin; Claes, Kathleen; Högel, Josef; Chuzhanova, Nadia; Fu, Chuanhua; van den Ende, Jenneke; Mautner, Viktor Felix; Cooper, David N; Messiaen, Ludwine; Kehrer-Sawatzki, Hildegard.
In: HUM MUTAT, Vol. 33, No. 11, 11, 2012, p. 1599-1609.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder.
AU - Vogt, Julia
AU - Mussotter, Tanja
AU - Bengesser, Kathrin
AU - Claes, Kathleen
AU - Högel, Josef
AU - Chuzhanova, Nadia
AU - Fu, Chuanhua
AU - van den Ende, Jenneke
AU - Mautner, Viktor Felix
AU - Cooper, David N
AU - Messiaen, Ludwine
AU - Kehrer-Sawatzki, Hildegard
PY - 2012
Y1 - 2012
N2 - Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.
AB - Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.
KW - Humans
KW - Molecular Sequence Data
KW - Base Sequence
KW - Chromosome Deletion
KW - Sequence Deletion
KW - Sequence Homology, Nucleic Acid
KW - Genes, Neurofibromatosis 1
KW - Mosaicism
KW - DNA Copy Number Variations
KW - Intellectual Disability/genetics
KW - Multiplex Polymerase Chain Reaction
KW - Polycomb Repressive Complex 2/genetics
KW - Chromosomes, Human, Pair 17/genetics
KW - Craniofacial Abnormalities/genetics
KW - DNA Breaks
KW - Homologous Recombination
KW - Learning Disorders/genetics
KW - Mitosis/genetics
KW - Neurofibromatoses/genetics
KW - Neurofibromatosis 1/genetics
KW - Pseudogenes
KW - Humans
KW - Molecular Sequence Data
KW - Base Sequence
KW - Chromosome Deletion
KW - Sequence Deletion
KW - Sequence Homology, Nucleic Acid
KW - Genes, Neurofibromatosis 1
KW - Mosaicism
KW - DNA Copy Number Variations
KW - Intellectual Disability/genetics
KW - Multiplex Polymerase Chain Reaction
KW - Polycomb Repressive Complex 2/genetics
KW - Chromosomes, Human, Pair 17/genetics
KW - Craniofacial Abnormalities/genetics
KW - DNA Breaks
KW - Homologous Recombination
KW - Learning Disorders/genetics
KW - Mitosis/genetics
KW - Neurofibromatoses/genetics
KW - Neurofibromatosis 1/genetics
KW - Pseudogenes
M3 - SCORING: Journal article
VL - 33
SP - 1599
EP - 1609
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 11
M1 - 11
ER -
