Genome-Scale Patterns in The Loss of Heterozygosity Incidence in Saccharomyces cerevisiae
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PROVIDER: PRJNA791636 | ENA |
REPOSITORIES: ENA
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Project description:We applied extensive assays--repeated over several genetic backgrounds and environments--to reveal some general features of the loss of heterozygosity (LOH) in yeast. We found that LOH: was most frequent in homozygotes, was more densely distributed on shorter chromosomal arms, depended on the presence of some repetitive elements but not the intensity of transcription, occured also in absence of growth although at a low rate. Our findings uncover new features of LOH and help to interpret those already known.
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Project description:Chromosome arm deletions are frequently observed in human cancers. Such large-scale aberrations may trigger phenotypes distinct from those that arise by loss of single genes. Using TALEN-based genomic engineering, we generated cell models with targeted 8p loss-of-heterozygosity (LOH) that mimics an 8p deletion commonly found in breast cancer patients. 8p LOH triggered up-regulation of the mevalonate pathway. The alterations in lipid metabolism led to increased metastatic potential and drug resistance of 8p-deleted cells that are in agreement with poorer survival rates of breast cancer patients harbouting 8p LOH. Our findings also suggest novel therapeutic strategies for treatment of 8p LOH tumors.
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Project description:CGH arrays for Smukowski Heil, et al MBE 2017. Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we address these questions using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae x Saccharomyces uvarum and their parentals. We evolved these strains in nutrient limited conditions for hundreds of generations and sequenced the resulting cultures to identify genomic changes. Analysis of 16 hybrid clones and 16 parental clones identified numerous point mutations, copy number changes, and loss of heterozygosity events, including species biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated loss of heterozygosity at the high affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the loss of heterozygosity is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity, and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation.
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Project description:Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. It is unknown whether copy-neutral loss of heterozygosity (CN-LOH) contributes to the pathogenesis of this tumor. To get insight into the CN-LOH landscape of PMBL, we performed Single Nucleotide Polymorphism array (SNPa) analysis of two PMBL-derived cell lines and 33 primary tumors. The study uncovered large-scale CN-LOH lesions in both cell lines and 90.9% (30/33) of primary tumors. The latter cases showed 133 CN-LOH stretches of size >25Mb which affected up to 14 chromosomes per case (mean of 4.4). Involvement of chromosomal segments was predominant (81.2%), which, in a heterozygous diploid context, suggests the implication of B-cell specific crossover events. Further analysis indicated that the CN-LOH lesions were triggered by one or two consecutive molecular hits. Notably, CN-LOH segments were non-randomly clustered on chromosome 6p (60%), 15 (37.2%) and 17q (40%). Preliminary whole-exome sequencing data yielded coincidence of these lesions with mutations in MHC I and histon-related genes (6p21), B2M (15q15) and GNA13 (17q23), respectively. We hypothesize that CN-LOH-associated hits occurred early during lymphomagenesis, following mutagenesis but preceding genomic gains. Screening of the cohort of 2,658 cancer whole-genomes revealed that the CN-LOH landscape in PMBL is unique and distinguishes this tumor from other malignancies. Altogether, CN-LOH lesions rank as the most frequent genetic defect identified so far in this disease and the CN-LOH landscape suggest a hitherto undescribed mitotic recombinational driver. The aberrations affect the expression of key driver genes and functionally alternate genomic deletions which are infrequent in PMBL.
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