The Impact of Monosomies, Trisomies and Segmental aneuploidies on Chromosomal stability
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA796230 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17547983.fastq.gz | Fastqsanger.gz | |||
| SRR17547984.fastq.gz | Fastqsanger.gz | |||
| SRR17547985.fastq.gz | Fastqsanger.gz | |||
| SRR17547986.fastq.gz | Fastqsanger.gz | |||
| SRR17547987.fastq.gz | Fastqsanger.gz |
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Project description:Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.
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Project description:Preservation of chromosome integrity is key for the survival of any organism. To assure segregation of intact chromosomes, cell division is presumed to be under strict control of cell-cycle checkpoints. Estimates of chromosomal mutation rates per generation based on cytogenetic analyses of newborns and products of conception, range between 4.57x10-5 and 3.42x10-4. In contrast, the high incidence of segmental imbalances detected by single-cell genome-wide copy number profiling indicates that the error rate per cell division might be more than an order of magnitude higher. To directly measure the de novo incidence of segmental chromosomal imbalances, we plated a single fibroblast and analyzed the genomes of the two sister cells following a single cell division. Analysis of 89 pairs of sister cells (178 single cells in total) from 5 different cell lines revealed megabase-sized chromosomal imbalances in 21 fibroblasts, 14 of which derived from 7 mitoses with complementary segmental aneuploidies in the two daughter cells. The mutation rate of segmental imbalances is thus at least 7.9%, indicating that compared to the per generation chromosome stability is at least 100 times lower in vitro and likely underestimated in vivo.
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Project description:Preservation of chromosome integrity is key for the survival of any organism. To assure segregation of intact chromosomes, cell division is presumed to be under strict control of cell-cycle checkpoints. Estimates of chromosomal mutation rates per generation based on cytogenetic analyses of newborns and products of conception, range between 4.57x10-5 and 3.42x10-4. In contrast, the high incidence of segmental imbalances detected by single-cell genome-wide copy number profiling indicates that the error rate per cell division might be more than an order of magnitude higher. To directly measure the de novo incidence of segmental chromosomal imbalances, we plated a single fibroblast and analyzed the genomes of the two sister cells following a single cell division. Analysis of 89 pairs of sister cells (178 single cells in total) from 5 different cell lines revealed megabase-sized chromosomal imbalances in 21 fibroblasts, 14 of which derived from 7 mitoses with complementary segmental aneuploidies in the two daughter cells. The mutation rate of segmental imbalances is thus at least 7.9%, indicating that compared to the per generation chromosome stability is at least 100 times lower in vitro and likely underestimated in vivo.
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Project description:Preservation of chromosome integrity is key for the survival of any organism. To assure segregation of intact chromosomes, cell division is presumed to be under strict control of cell-cycle checkpoints. Estimates of chromosomal mutation rates per generation based on cytogenetic analyses of newborns and products of conception, range between 4.57x10-5 and 3.42x10-4. In contrast, the high incidence of segmental imbalances detected by single-cell genome-wide copy number profiling indicates that the error rate per cell division might be more than an order of magnitude higher. To directly measure the de novo incidence of segmental chromosomal imbalances, we plated a single fibroblast and analyzed the genomes of the two sister cells following a single cell division. Analysis of 89 pairs of sister cells (178 single cells in total) from 5 different cell lines revealed megabase-sized chromosomal imbalances in 21 fibroblasts, 14 of which derived from 7 mitoses with complementary segmental aneuploidies in the two daughter cells. The mutation rate of segmental imbalances is thus at least 7.9%, indicating that compared to the per generation chromosome stability is at least 100 times lower in vitro and likely underestimated in vivo.
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