Unknown,Transcriptomics,Genomics,Proteomics

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Evolution of monoclonal zebrafish Myc-induced T-ALL, assessed by copy number variant analysis

ABSTRACT: Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T-cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia propagating potential with time. We analyzed CNVs between monoclonal primary transplants and secondary transplants of clones that evovled increased leukemia propagating potential, and well as non-evovled clones with inherently high and low leukemia propagating potential. The goal of this study was to identify CNVs commonly assoicated with increased leukemia propagating cell frequency. Myc-induced T-ALL were generated in syngenic CG1. Single T-ALL cells were transplanted into recipitent CG1, resulting in monoclonal T-ALL. In some instances, the monoclonal T-ALL were serially passaged. Leukemia propagating frequency was calculated for each T-ALL clone, at each passage. In this analysis, 9 primary T-ALL and 35 monoclonal T-ALL were individually run against a CG1 control.

ORGANISM(S): Danio rerio

SUBMITTER: David Langenau

PROVIDER: E-GEOD-54482 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Gene copy-number variation, which provides the raw material for the evolution of novel genes, is surprisingly widespread in natural populations. Experimental evolution studies have demonstrated an extremely high spontaneous rate of origin of gene duplications. When organisms are suboptimally adapted to their environment, gene duplication may compensate for reduced fitness by amplifying promiscuous activity of a gene, or increasing dosage of a suboptimal gene. The overarching goal of this study is to inverstigate whether CNVs constitute a common mechanism of adaptive genetic change during compensatory evolution and to further characterize the role of natural selection in dictating their evolutionary spread at a population-genomic level. Outcrossing populations of C. elegans with low fitness were evolved for >200 generations and the frequencies of CNVs in these populations were analyzed by oligonucleotide array comparative genome hybridization, quantitative PCR, and single-worm PCR. Multiple duplications and deletions were detected in intermediate to high frequencies and several lines of evidence suggest that the changes in frequency were adaptive. 1) Many copy-number changes reached high frequency, were near fixation, or were fixed in a short time. 2) Many independent duplications and deletions in high frequency harbor overlapping regions which likely include genes that are under selection for either higher or lower rates of expression. 3) The size spectrum of deuplications and deletions in the adaptive recovery populations is significantly larger than that of spontaneous copy-number variants in mutation accumulation experiments. This is expected if larger CNVs are more likely to encompass genes that are being selected for altered gene dosage. Out results validate the great potential borne by gene copy-number changes for compensatory evolution and adaptation. Experimental genome evolution of copy-number variants in 25 experimental lines compared to 5 ancestral control lines.

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Evolution of monoclonal zebrafish Myc-induced T-ALL, assessed by copy number variant analysis

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