High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology.
Balanced chromosomal rearrangements can cause disease, but techniques for their rapid and accurate identification are missing. Here we demonstrate that chromatin conformation capture on chip (4C) technology can be used to screen large genomic regions for balanced and complex inversions and translocations at high resolution. The 4C technique can be used to detect breakpoints also in repetitive DNA sequences as it uniquely relies on capturing genomic fragments across the breakpoint. Using 4C, we uncovered LMO3 as a potentially leukemogenic translocation partner of TRB@. We developed multiplex 4C to simultaneously screen for translocation partners of multiple selected loci. We identified unsuspected translocations and complex rearrangements. Furthermore, using 4C we detected translocations even in small subpopulations of cells. This strategy opens avenues for the rapid fine-mapping of cytogenetically identified translocations and inversions, and the efficient screening for balanced rearrangements near candidate loci, even when rearrangements exist only in subpopulations of cells.
Simonis
Marieke
M
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands.
Klous
Petra
P
Homminga
Irene
I
Galjaard
Robert-Jan
RJ
Rijkers
Erik-Jan
EJ
Grosveld
Frank
F
Meijerink
Jules P P
JP
de Laat
Wouter
W
D002843:Chromatin / Q000737:chemistry*; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D007446:Chromosome Inversion; D002874:Chromosome Mapping / Q000379:methods*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D009690:Nucleic Acid Conformation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D017689:Polydactyly / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011487:Protein Conformation; D014178:Translocation, Genetic
D002843:Chromatin