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Expression Analysis of Whole Thymus and Thymic Tumors on the Sdl Mouse Model

ABSTRACT: Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance; while mice homozygous for the mutation die early during embryonic development. Sdl mice harbor increased numbers of spontaneous micronuclei, and Sdl T-ALLs harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4D573H). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at the replication fork. This exon array was conducted to determine the expression changes that occur in pre-leukemic thymus samples at 21 days of age, as well as thymic tumors in the Sdl model.

ORGANISM(S): Mus musculus

PROVIDER: GSE40527 | GEO | 2012/09/01

SECONDARY ACCESSION(S): PRJNA174221

REPOSITORIES: GEO

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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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Expression Analysis of Whole Thymus and Thymic Tumors on the Sdl Mouse Model

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