Leishmania genome dynamics during environmental adaptation in culture
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ABSTRACT:
PROVIDER: PRJEB23832 | ENA |
REPOSITORIES: ENA
Similar Datasets
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Project description:Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth (fitness gain) impairing differentiation of infectious metacyclic parasites, hence infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network driving parasite fitness, with genome instability causing gene dosage-dependent changes in proteins linked to post-transcriptional regulation. These in turn caused gene dosage-independent changes in transcripts associated with fitness tradeoff, including coordinated degradation of flagellar transcripts and stabilization of coding and non-coding RNAs regulating ribosomal biogenesis and protein translation, including small nucleolar RNAs (snoRNAs).
2022-02-22 | GSE165615 | GEO
Project description:Purpose: Monitor modulation of aneuploidy in Leishmania donovani during adaptation to different in vitro and in vivo environments, and its impact on gene expression Importance: Aneuploidy is usually detrimental in multicellular organisms, but in several micro-organisms (fungi being the best-studied) it can be tolerated and even beneficial. Leishmania – a protozoan parasite killing more than 30,000 persons each year – is emerging as a new model for aneuploidy studies: unexpectedly high levels of aneuploidy are found in clinical isolates. Leishmania lacks classical regulation of transcription through inducible promoters, so aneuploidy could represent a major adaptive strategy of this parasite to modulate gene dosage in response to stressful environments. For the first time, we document the dynamics of aneuploidy throughout the life cycle of the parasite, in vitro and in vivo. We show its adaptive impact on transcription and its intertwinement with regulation. Besides offering a new model for aneuploidy studies, we show that further genomic studies should be done directly in clinical samples (without parasite isolation) and that adequate methods should be developed for this.
2017-04-10 | GSE97453 | GEO
Project description:The genomic DNAs of strains JPCM5 and 263 of L. infantum, strains LV39 and Friedlin of L. major and strains Parrot-TarII and S125 of L. tarentolae were used in comparative genomic hybridizations to reveal the intra-species and inter-species gene content, and to validate L. tarentolae Parrot-TarII genome sequencing results. Leishmania (Sauroleishmania) tarentolae was first isolated in the lizard Tarentola mauritanica. This species is not known to be pathogenic to humans but is often used as a model organism for molecular analyses or protein overproduction. The Leishmania tarentolae Parrot-TarII strain genome sequence was resolved by high-throughput sequencing technologies. The L. tarentolae genome was first assembled de novo and then aligned against the reference L. major Friedlin genome to facilitate contig positioning and annotation, providing a 23-fold coverage of the genome. This is the first non-pathogenic to humans kinetoplastid protozoan genome to be described, and it provides an opportunity for comparison with the completed genomes of the pathogenic Leishmania species. A high synteny was observed in de novo assembled contigs between all sequenced Leishmania species. A number of limited chromosomal regions diverged between L. tarentolae and L. infantum, while remaining syntenic with L. major. Globally, over 90% of the L. tarentolae gene content was shared with the other Leishmania species. There were 250 L. major genes absent from L. tarentolae, and interestingly these missing genes were primarily expressed in the intracellular amastigote stage of the pathogenic parasites. This implies that L. tarentolae may have impaired ability to survive as an intracellular parasite. In contrast to other Leishmania genomes, two gene families were expanded in L. tarentolae, namely the leishmanolysin (GP63) and a gene related to the promastigote surface antigen (PSA31C). Overall, L. tarentolae appears to have a gene content more adapted to the insect stage rather than the mammalian one. This may partly explain its inability to replicate within mammalian macrophages and its suspected preferred life style as promastigote in the lizards.
2011-10-21 | GSE27184 | GEO
Project description:Leishmania survival inside insect and mammalian hosts depends on the parasite’s capacity to develop into promastigote and amastigote stages, respectively. Promastigotes can be maintained in vitro in culture medium mimicking the insect milieu in which the parasites are surviving, differentiating and proliferating. We previously showed that the maintenance of the parasites in this in vitro environment lead to a progressive loss of infectivity together with genomic changes, notably chromosome amplifications. In contrast to classical eukaryotes Leishmania do not regulate expression of protein coding genes by transcriptional control, thus ruling out regulated gene expression changes in adaptation. In the absence of classical transcriptional regulation, Leishmania has evolved and emphasized other forms of control that are relevant for evolutionary adaptation, notably regulation of RNA abundance by gene dosage variation. In order to identify the biological signals that correlate with the observed fitness trade off we observed during L. donovani culture adaptation we combined DNAseq and RNAseq with label-free quantitative proteomics. Promastigotes freshly derived from splenic amastigotes purified from the spleen of infected hamsters were maintained in culture for 2 (EP) and 20 (LP) passages. Total protein extracts from four EP and four LP promastigotes were prepared for label free MS analysis.
2022-03-03 | PXD020236 | Pride
Project description:Leishmania donovani isolate:laboratory culture Genome sequencing
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Project description:Telomere attrition ultimately leads to the activation of protective cellular responses such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we employ a liposarcoma model system to assay telomere maintenance mechanism-specific genetic alterations. A multiassay approach was used to assess the telomere maintenance mechanism(s) active in tumors. Genomic DNA from these samples was then analyzed by high resolution DNA mapping array in order to identify genetic alterations. Our data reveal a higher level of genome instability in ALT-positive tumors as compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance employed. We also identified genetic changes specific to the ALT mechanism, e.g., deletion of chromosome 1q32.2-q44, as well as changes that are underrepresented amongst ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. Keywords: genotype, genome instability, copy number alteration, liposarcoma, ALT, telomerase, telomere
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