scholarly journals Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

2021 ◽  
Author(s):  
R. Gonzalo Parra ◽  
Moritz J Przybilla ◽  
Milena Simovic ◽  
Hana Susak ◽  
Manasi Ratnaparkhe ◽  
...  
Keyword(s):  
Single Cell ◽  
Genome Instability ◽  
Response To Treatment ◽  
Genomic Rearrangements ◽  
Causative Role ◽  
Fitness Consequences ◽  
Double Minute ◽  
Cancer Drivers ◽  
Druggable Targets ◽  
Double Minute Chromosomes

Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.

scholarly journals Conditional out-of-distribution generation for unpaired data using transfer VAE

2020 ◽  
Vol 36 (Supplement_2) ◽  
pp. i610-i617
Author(s):  
Mohammad Lotfollahi ◽  
Mohsen Naghipourfar ◽  
Fabian J Theis ◽  
F Alexander Wolf
Keyword(s):  
Single Cell ◽  
Generative Models ◽  
Response To Treatment ◽  
High Dimensional ◽  
Compact Representation ◽  
Hair Color ◽  
Great Success ◽  
Cell Type ◽  
Style Transfer ◽  
Cell Type Specific

Abstract Motivation While generative models have shown great success in sampling high-dimensional samples conditional on low-dimensional descriptors (stroke thickness in MNIST, hair color in CelebA, speaker identity in WaveNet), their generation out-of-distribution poses fundamental problems due to the difficulty of learning compact joint distribution across conditions. The canonical example of the conditional variational autoencoder (CVAE), for instance, does not explicitly relate conditions during training and, hence, has no explicit incentive of learning such a compact representation. Results We overcome the limitation of the CVAE by matching distributions across conditions using maximum mean discrepancy in the decoder layer that follows the bottleneck. This introduces a strong regularization both for reconstructing samples within the same condition and for transforming samples across conditions, resulting in much improved generalization. As this amount to solving a style-transfer problem, we refer to the model as transfer VAE (trVAE). Benchmarking trVAE on high-dimensional image and single-cell RNA-seq, we demonstrate higher robustness and higher accuracy than existing approaches. We also show qualitatively improved predictions by tackling previously problematic minority classes and multiple conditions in the context of cellular perturbation response to treatment and disease based on high-dimensional single-cell gene expression data. For generic tasks, we improve Pearson correlations of high-dimensional estimated means and variances with their ground truths from 0.89 to 0.97 and 0.75 to 0.87, respectively. We further demonstrate that trVAE learns cell-type-specific responses after perturbation and improves the prediction of most cell-type-specific genes by 65%. Availability and implementation The trVAE implementation is available via github.com/theislab/trvae. The results of this article can be reproduced via github.com/theislab/trvae_reproducibility.

Induction of metallothionein-I mRNA in cultured cells by heavy metals and iodoacetate: evidence for gratuitous inducers

1984 ◽  
Vol 4 (3) ◽  
pp. 484-491
Author(s):  
D M Durnam ◽  
R D Palmiter
Keyword(s):  
Heavy Metals ◽  
Cultured Cells ◽  
Mrna Accumulation ◽  
Mouse Hepatocyte ◽  
Hepatocyte Cell Line ◽  
Regulatory Molecule ◽  
Heavy Metal Detoxification ◽  
Double Minute ◽  
Double Minute Chromosomes

A mouse hepatocyte cell line selected for growth in 80 microM CdSO4 (Cdr80 cells) was used to test the role of metallothioneins in heavy metal detoxification. The cadmium-resistant (Cdr80) cells have double minute chromosomes carrying amplified copies of the metallothionein-I gene and accumulate ca. 20-fold more metallothionein-I mRNA than unselected cadmium-sensitive (Cds) cells after optimal Cd stimulation. As a consequence, the amount of Cd which inhibits DNA synthesis by 50% is ca. 7.5-fold higher in Cdr80 cells than in Cds cells. Cds and Cdr80 cells were compared in terms of their resistance to other heavy metals. The results indicate that although Zn, Cu, Hg, Ag, Co, Ni, and Bi induce metallothionein-I mRNA accumulation in both Cdr80 and Cds cells, the Cdr80 cells show increased resistance to only a subset of these metals (Zn, Cu, Hg, and Bi). This suggests that not all metals which induce metallothionein mRNA are detoxified by metallothionein and argues against autoregulation of metallothionein genes. Metallothionein-I mRNA is also induced by iodoacetate, suggesting that the regulatory molecule has sensitive sulfhydryl groups.

scholarly journals Extensive genomic rearrangements mediated by repetitive sequences in plastomes of Medicago and its relatives

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuang Wu ◽  
Jinyuan Chen ◽  
Ying Li ◽  
Ai Liu ◽  
Ao Li ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Genome Instability ◽  
Repetitive Sequences ◽  
Genomic Analysis ◽  
Genomic Rearrangements ◽  
Comparative Genomic ◽  
Length Variation ◽  
Substitution Rates ◽  
Repeat Content ◽  
Plastome Evolution

Abstract Background Although plastomes are highly conserved with respect to gene content and order in most photosynthetic angiosperms, extensive genomic rearrangements have been reported in Fabaceae, particularly within the inverted repeat lacking clade (IRLC) of Papilionoideae. Two hypotheses, i.e., the absence of the IR and the increased repeat content, have been proposed to affect the stability of plastomes. However, this is still unclear for the IRLC species. Here, we aimed to investigate the relationships between repeat content and the degree of genomic rearrangements in plastomes of Medicago and its relatives Trigonella and Melilotus, which are nested firmly within the IRLC. Results We detected abundant repetitive elements and extensive genomic rearrangements in the 75 newly assembled plastomes of 20 species, including gene loss, intron loss and gain, pseudogenization, tRNA duplication, inversion, and a second independent IR gain (IR ~ 15 kb in Melilotus dentata) in addition to the previous first reported cases in Medicago minima. We also conducted comparative genomic analysis to evaluate plastome evolution. Our results indicated that the overall repeat content is positively correlated with the degree of genomic rearrangements. Some of the genomic rearrangements were found to be directly linked with repetitive sequences. Tandem repeated sequences have been detected in the three genes with accelerated substitution rates (i.e., accD, clpP, and ycf1) and their length variation could be explained by the insertions of tandem repeats. The repeat contents of the three localized hypermutation regions around these three genes with accelerated substitution rates are also significantly higher than that of the remaining plastome sequences. Conclusions Our results suggest that IR reemergence in the IRLC species does not ensure their plastome stability. Instead, repeat-mediated illegitimate recombination is the major mechanism leading to genome instability, a pattern in agreement with recent findings in other angiosperm lineages. The plastome data generated herein provide valuable genomic resources for further investigating the plastome evolution in legumes.

Mathematical models of gene amplification with applications to cellular drug resistance and tumorigenicity.

Genetics ◽  
1990 ◽  
Vol 125 (3) ◽  
pp. 633-644
Author(s):  
M Kimmel ◽  
D E Axelrod
Keyword(s):  
Mathematical Models ◽  
Cell Lines ◽  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Published Data ◽  
Reductase Gene ◽  
Double Minute ◽  
Double Minute Chromosomes

Abstract An increased number of copies of specific genes may offer an advantage to cells when they grow in restrictive conditions such as in the presence of toxic drugs, or in a tumor. Three mathematical models of gene amplification and deamplification are proposed to describe the kinetics of unstable phenotypes of cells with amplified genes. The models differ in details but all assume probabilistic mechanisms of increase and decrease in gene copy number per cell (gene amplification/deamplification). Analysis of the models indicates that a stable distribution of numbers of copies of genes per cell, observed experimentally, exists only if the probability of deamplification exceeds the probability of amplification. The models are fitted to published data on the loss of methotrexate resistance in cultured cell lines, due to the loss of amplified dihydrofolate reductase gene. For two mouse cell lines unstably resistant to methotrexate the probabilities of amplification and deamplification of the dihydrofolate reductase gene on double minute chromosomes are estimated to be approximately 2% and 10%, respectively. These probabilities are much higher than widely presumed. The models explain the gradual disappearance of the resistant phenotype when selective pressure is withdrawn, by postulating that the rate of deamplification exceeds the rate of amplification. Thus it is not necessary to invoke a growth advantage of nonresistant cells which has been the standard explanation. For another analogous process, the loss of double minute chromosomes containing the myc oncogene from SEWA tumor cells, the growth advantage model does seem to be superior to the amplification and deamplification model. In a more theoretical section of the paper, it is demonstrated that gene amplification/deamplification can result in reduction to homozygosity, such as is observed in some tumors. Other applications are discussed.

Sign in / Sign up

Export Citation Format

Share Document