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The Effect of Translocation-Induced Nuclear Re-organization on Gene Expression

ABSTRACT: To study the effect of balanced chromosomal rearrangements on gene expression, we compared the transcriptomes of cell lines from control and t(11;22)(q23;q11) individuals. This translocation between chromosomes 11 and 22 is the only recurrent constitutional non-Robertsonian translocation in humans. The number of differentially expressed transcripts between the translocated and control cohort is significantly higher than that observed between control samples alone, suggesting that balanced rearrangements have a greater effect on gene expression than normal variation. Altered expression is not limited to genes close to the translocation breakpoint suggesting that a long-range effect is operating. Indeed we show that the nuclear position of the derivative chromosome is altered compared to the normal chromosomes. Our results are consistent with recent studies that indicate a functional role for nuclear position in regulating the expression of some genes in mammalian cells. They may also have implications on reproductive separation, as we show that reciprocal translocations not only provide partial isolation for speciation but also significant changes in transcriptional regulation through alteration of nuclear chromosomes territories. Keywords: Genetic modification

ORGANISM(S): Homo sapiens

PROVIDER: GSE13122 | GEO | 2010/03/05

SECONDARY ACCESSION(S): PRJNA109661

REPOSITORIES: GEO

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Robertsonian translocations modify genomic distribution of gH2AX and H3.3 in mouse germ cells

Project description:Purpose: determine if gH2AX and H3.3 are enriched at unsynapsed regions of chromosomes involved in translocations in mouse germ line (meiotic prophase I) Methods: testes were isolated from 4-week or 6-week old heterozygous carriers of a single Robertsonian translocation RB(8;12) or 3 Robertsonian translocations RB(8;12), RB(1;3) and RB(9;14) and controls. ChIP assays were conducted as described in Smagulova 2011. Experiments done in triplicate. Results: We find enrichment of gH2AX in the proximal gene-rich regions of translocation-associated chromosomes and reduced enrichment of gH2AX and H3.3 at sex chromosomes

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Non-allelic homologous recombination between retrotransposable elements is a major driver of de novo unbalanced translocations.

Project description:Large scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations. Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically. We analyzed 12 de novo translocations and mapped the breakpoints in 9. Surprisingly, in contrast to balanced translocations, we identify non-allelic homologous recombination (NAHR) between (retro)transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism. This finding implicates (retro)transposons to be a major driver of genomic rearrangements and exposes a profoundly different mutational mechanism compared to balanced chromosomal translocations. Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements.

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Non-allelic homologous recombination between retrotransposable elements is a major driver of de novo unbalanced translocations.

2012-07-12 | E-GEOD-39303 | biostudies-arrayexpress

Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation.

Project description:The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5M-bM-^@M-^S10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated. In this study, we performed gene expression microarrays analysis to compare CML patients bearing variant rearrangements and those with classic t(9;22)(q34;q11). We identified a list of 59 differentially expressed genes significantly associated with the two analyzed groups. These genes are mostly involved in the intracellular protein kinase cascade and their upregulation enhances cellular processes already known to sustain the CML pathogenesis. According to conventional and molecular cytogenetics (FISH) data, 12 CML cases with classic t(9;22) and of 8 cases with variant translocations were selected and analyzed by GEP.

2013-10-01 | E-GEOD-41375 | biostudies-arrayexpress

Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation.

Project description:The t(9;22)(q34;q11) generating the Philadelphia chromosome and the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5–10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The molecular bases of differences between CML patients with classic and variant t(9;22) have never been elucidated. In this study, we performed gene expression microarrays analysis to compare CML patients bearing variant rearrangements and those with classic t(9;22)(q34;q11). We identified a list of 59 differentially expressed genes significantly associated with the two analyzed groups. These genes are mostly involved in the intracellular protein kinase cascade and their upregulation enhances cellular processes already known to sustain the CML pathogenesis.

2013-10-01 | GSE41375 | GEO

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Project description:This was a retrospective comparison study of SNP-based preimplantation genetic screening (SNP-PGS) and FISH-based preimplantation genetic diagnosis (FISH-PGD) for 575 couples in total with chromosome translocations, including 169 couples treated by SNP-PGS between October 2011 and August 2012, and 406 couples treated by FISH- PGD between January 2005 and October 2011. In total, 773 blastocysts obtained from 169 couples were biopsied and frozen, embryo transfer was carried out on the balanced embryos. The PGS results and pregnancy outcomes were compared with those of FISH-PGD for 406 translocation carriers with 3,968 embryos biopsied on day 3. Of the 773 biopsied blastocysts, reliable SNP-PGS results were obtained for 717 (92.76%). For Robertsonian translocation carriers, the rate of normal/balanced embryos, embryos with translocation-related abnormalities, and embryos with abnormalities unrelated to a translocation were 57.80%, 23.39% and 18.81%, respectively. In reciprocal translocation carriers, the rate of normal/balanced embryos, embryos with translocation-related abnormalities and embryos with abnormalities unrelated to translocation were 35.47%, 52.10% and 12.42%, respectively. There was no significant differences in patient age, basal endocrine level and the average number of retrieved oocytes and good quality day 3 embryos before biopsy in the SNP-PGS group compared with the FISH-PGD group. The number of embryos biopsied in the FISH-PGD group was higher than in the SNP-PGS group. However, the pregnancy rate with successful delivery per oocyte retrieval and the implantation rate were both lower in the FISH-PGD group than in the SNP-PGS group. The spontaneous abortion rate was higher in the FISH-PGD group than in the SNP-PGS group. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from trophectoderm cells.

2013-03-11 | E-GEOD-44994 | biostudies-arrayexpress

The spatial position of budding yeast chromosomes affects gene expression

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2017-12-20 | GSE108261 | GEO

SNP microarray-based PGS significantly improves the clinical outcome for translocation carriers

2013-03-11 | GSE44994 | GEO

Use of single nucleotide polymorphism microarrays to distinguish between balanced and normal chromosomes in embryos from a translocation carrier

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2011-05-18 | GSE21732 | GEO

Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring [case 2]

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2015-01-31 | GSE65452 | GEO

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