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PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010001
Author(s):  
Ana Cristina Colabardini ◽  
Fang Wang ◽  
Zhengqiang Miao ◽  
Lakhansing Pardeshi ◽  
Clara Valero ◽  
...  

Invasive Pulmonary Aspergillosis, which is caused by the filamentous fungus Aspergillus fumigatus, is a life-threatening infection for immunosuppressed patients. Chromatin structure regulation is important for genome stability maintenance and has the potential to drive genome rearrangements and affect virulence and pathogenesis of pathogens. Here, we performed the first A. fumigatus global chromatin profiling of two histone modifications, H3K4me3 and H3K9me3, focusing on the two most investigated A. fumigatus clinical isolates, Af293 and CEA17. In eukaryotes, H3K4me3 is associated with active transcription, while H3K9me3 often marks silent genes, DNA repeats, and transposons. We found that H3K4me3 deposition is similar between the two isolates, while H3K9me3 is more variable and does not always represent transcriptional silencing. Our work uncovered striking differences in the number, locations, and expression of transposable elements between Af293 and CEA17, and the differences are correlated with H3K9me3 modifications and higher genomic variations among strains of Af293 background. Moreover, we further showed that the Af293 strains from different laboratories actually differ in their genome contents and found a frequently lost region in chromosome VIII. For one such Af293 variant, we identified the chromosomal changes and demonstrated their impacts on its secondary metabolites production, growth and virulence. Overall, our findings not only emphasize the influence of genome heterogeneity on A. fumigatus fitness, but also caution about unnoticed chromosomal variations among common laboratory strains.


Author(s):  
Wangrui Liu ◽  
Chuanyu Li ◽  
Yuhao Wu ◽  
Wenhao Xu ◽  
Shuxian Chen ◽  
...  

Background: As an important epigenetic modification, m6A methylation plays an essential role in post-transcriptional regulation and tumor development. It is urgently needed to comprehensively and rigorously explore the prognostic value of m6A regulators and its association with tumor microenvironment (TME) infiltration characterization of low-grade glioma (LGG).Methods: Based on the expression of 20 m6A regulatory factors, we comprehensively evaluated the m6A modification patterns of LGG after unsupervised clustering. Subsequent analysis of the differences between these groups was performed to obtain m6A-related genes, then consistent clustering was conducted to generate m6AgeneclusterA and m6AgeneclusterB. A Random Forest and machining learning algorithms were used to reduce dimensionality, identify TME characteristics and predict responses for LGG patients receiving immunotherapies.Results: Evident differential m6A regulators were found in mutation, CNV and TME characteristics of LGG. Based on TCGA and CGGA databases, we identified that m6A regulators clusterA could significantly predict better prognosis (p = 0.00016) which enriched in mTOR signaling pathway, basal transcription factors, accompanied by elevated immune cells infiltration, and decreased IDH and TP53 mutations. We also investigated the distribution of differential genes in m6A regulators clusters which was closely associated with tumor immune microenvironment through three independent cohort comparisons. Next, we established m6Ascore based on previous m6A model, which accurately predicts outcomes in 1089 LGG patients (p < 0.0001) from discovering cohort and 497 LGG patients from testing cohort. Significant TME characteristics, including genome heterogeneity, abidance of immune cells, and clinicopathologic parameters have been found between m6Ascore groups. Importantly, LGG patients with high m6Ascore are confronted with significantly decreased responses to chemotherapies, but benefit more from immunotherapies.Conclusion: In conclusion, this study first demonstrates that m6A modification is crucial participant in tumorigenesis and TME infiltration characterization of LGG based on large-scale cohorts. The m6Ascore provides useful and accurately predict of prognosis and clinical responses to chemotherapy, immunotherapy and therapeutic strategy development for LGG patients.


2021 ◽  
Author(s):  
Jose L. Oliver ◽  
Pedro Bernaola-Galvan ◽  
Francisco Perfectti ◽  
Cristina Gomez-Martin ◽  
Miguel Verdu ◽  
...  

In the brief time since the outbreak of the COVID 19 pandemic, and despite its proofreading mechanism, the SARS-CoV-2 coronavirus has accumulated a significant amount of genetic variability through recombination and mutation events. To test evolutionary trends that could inform us on the adaptive process of the virus to its human host, we summarize all this variability in the Sequence Compositional Complexity (SCC), a measure of genome heterogeneity that captures the mutational and recombinational changes accumulated by a nucleotide sequence along time. Despite the brief time elapsed, we detected many differences in the number and length of compositional domains, as well as in their nucleotide frequencies, in more than 12,000 high-quality coronavirus genomes from across the globe. These differences in SCC are phylogenetically structured, as revealed by significant phylogenetic signal. Phylogenetic ridge regression shows that SCC followed a generalized decreasing trend along the ongoing process of pathogen evolution. In contrast, SCC evolutionary rate increased with time, showing that it accelerates toward the present. In addition, a low rate set of genomes was detected in all the genome groups, suggesting the existence of a stepwise distribution of rates, a strong indication of selection in favor of different dominant strains. Coronavirus variants reveal an exacerbation of this trend: non-significant SCC regression, low phylogenetic signal and, concomitantly, a threefold increase in the evolutionary rate. Altogether, these results show an accelerated decline of genome heterogeneity along with the SARS CoV 2 pandemic expansion, a process that might be related to viral adaptation to the human host, perhaps paralleling the transformation of the current pandemic to epidemic.


PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0250915
Author(s):  
Zachary Stephens ◽  
Daniel O’Brien ◽  
Mrunal Dehankar ◽  
Lewis R. Roberts ◽  
Ravishankar K. Iyer ◽  
...  

The integration of viruses into the human genome is known to be associated with tumorigenesis in many cancers, but the accurate detection of integration breakpoints from short read sequencing data is made difficult by human-viral homologies, viral genome heterogeneity, coverage limitations, and other factors. To address this, we present Exogene, a sensitive and efficient workflow for detecting viral integrations from paired-end next generation sequencing data. Exogene’s read filtering and breakpoint detection strategies yield integration coordinates that are highly concordant with long read validation. We demonstrate this concordance across 6 TCGA Hepatocellular carcinoma (HCC) tumor samples, identifying integrations of hepatitis B virus that are also supported by long reads. Additionally, we applied Exogene to targeted capture data from 426 previously studied HCC samples, achieving 98.9% concordance with existing methods and identifying 238 high-confidence integrations that were not previously reported. Exogene is applicable to multiple types of paired-end sequence data, including genome, exome, RNA-Seq and targeted capture.


2021 ◽  
Author(s):  
Jean-Pierre Kocher ◽  
Zachary Stephens ◽  
Daniel O'Brien ◽  
Mrunal Dehankar ◽  
Lewis Roberts ◽  
...  

The integration of viruses into the human genome is known to be associated with tumorigenesis in many cancers, but the accurate detection of integration breakpoints from short read sequencing data is made difficult by human-viral homologies, viral genome heterogeneity, coverage limitations, and other factors. To address this, we present Exogene, a sensitive and efficient workflow for detecting viral integrations from paired-end next generation sequencing data. Exogene's read filtering and breakpoint detection strategies yield integration coordinates that are highly concordant with those found in long read validation sets. We demonstrate this concordance across 6 TCGA Hepatocellular carcinoma (HCC) tumor samples, identifying integrations of hepatitis B virus that are validated by long reads. Additionally, we applied Exogene to targeted capture data from 426 previously studied HCC samples, achieving 98.9% concordance with existing methods and identifying 238 high-confidence integrations that were not previously reported. Exogene is applicable to multiple types of paired-end sequence data, including genome, exome, RNA-Seq or targeted capture.


Author(s):  
Misako Yajima ◽  
Risako Kakuta ◽  
Yutaro Saito ◽  
Shiori Kitaya ◽  
Atsushi Toyoda ◽  
...  

Epstein–Barr virus (EBV) establishes lifelong latent infection in the majority of healthy individuals, while it is a causative agent for various diseases, including some malignancies. Recent high-throughput sequencing results indicate that there are substantial levels of viral genome heterogeneity among different EBV strains. However, the extent of EBV strain variation among asymptomatically infected individuals remains elusive. Here, we present a streamlined experimental strategy to clone and sequence EBV genomes derived from human tonsillar tissues, which are the reservoirs of asymptomatic EBV infection. Complete EBV genome sequences, including those of repetitive regions, were determined for seven tonsil-derived EBV strains. Phylogenetic analyses based on the whole viral genome sequences of worldwide non-tumour-derived EBV strains revealed that Asian EBV strains could be divided into several distinct subgroups. EBV strains derived from nasopharyngeal carcinoma-endemic areas constitute different subgroups from a subgroup of EBV strains from non-endemic areas, including Japan. The results could be consistent with biased regional distribution of EBV-associated diseases depending on the different EBV strains colonizing different regions in Asian countries.


2021 ◽  
Vol 60 ◽  
pp. 13-20
Author(s):  
Piotr Solarczyk

Cyclospora is an intracellular, gastrointestinal parasite found in birds and mammals worldwide. Limited accessibility of the protozoan for experimental use, scarcity, genome heterogeneity of the isolates and narrow panel of molecular markers hamper zoonotic investigations. One of the significant limitation in zoonotic studies is the lack of precise molecular tools that would be useful in linking animal vectors as a source of human infection. Strong and convincing evidence of zoonotic features will be achieved through proper typing of Cyclospora spp. taxonomic units (e.g. species or genotypes) in animal reservoirs. The most promising method that can be employ for zoonotic surveys is next-generation sequencing.


2021 ◽  
Vol 17 ◽  
pp. 117693432110141
Author(s):  
Sean P Ryder ◽  
Brittany R Morgan ◽  
Peren Coskun ◽  
Katianna Antkowiak ◽  
Francesca Massi

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has motivated a widespread effort to understand its epidemiology and pathogenic mechanisms. Modern high-throughput sequencing technology has led to the deposition of vast numbers of SARS-CoV-2 genome sequences in curated repositories, which have been useful in mapping the spread of the virus around the globe. They also provide a unique opportunity to observe virus evolution in real time. Here, we evaluate two sets of SARS-CoV-2 genomic sequences to identify emerging variants within structured cis-regulatory elements of the SARS-CoV-2 genome. Overall, 20 variants are present at a minor allele frequency of at least 0.5%. Several enhance the stability of Stem Loop 1 in the 5ʹ untranslated region (UTR), including a group of co-occurring variants that extend its length. One appears to modulate the stability of the frameshifting pseudoknot between ORF1a and ORF1b, and another perturbs a bi-ss molecular switch in the 3ʹUTR. Finally, 5 variants destabilize structured elements within the 3ʹUTR hypervariable region, including the S2M (stem loop 2 m) selfish genetic element, raising questions as to the functional relevance of these structures in viral replication. Two of the most abundant variants appear to be caused by RNA editing, suggesting host-viral defense contributes to SARS-CoV-2 genome heterogeneity. Our analysis has implications for the development of therapeutics that target viral cis-regulatory RNA structures or sequences.


2020 ◽  
Vol 8 (12) ◽  
pp. 1970
Author(s):  
Bin Liu ◽  
Denny Popp ◽  
Nicolai Müller ◽  
Heike Sträuber ◽  
Hauke Harms ◽  
...  

The platform chemicals n-caproate and iso-butyrate can be produced by anaerobic fermentation from agro-industrial residues in a process known as microbial chain elongation. Few lactate-consuming chain-elongating species have been isolated and knowledge on their shared genetic features is still limited. Recently we isolated three novel clostridial strains (BL-3, BL-4, and BL-6) that convert lactate to n-caproate and iso-butyrate. Here, we analyzed the genetic background of lactate-based chain elongation in these isolates and other chain-elongating species by comparative genomics. The three strains produced n-caproate, n-butyrate, iso-butyrate, and acetate from lactate, with the highest proportions of n-caproate (18%) for BL-6 and of iso-butyrate (23%) for BL-4 in batch cultivation at pH 5.5. They show high genomic heterogeneity and a relatively small core-genome size. The genomes contain highly conserved genes involved in lactate oxidation, reverse β-oxidation, hydrogen formation and either of two types of energy conservation systems (Rnf and Ech). Including genomes of another eleven experimentally validated chain-elongating strains, we found that the chain elongation-specific core-genome encodes the pathways for reverse β-oxidation, hydrogen formation and energy conservation, while displaying substantial genome heterogeneity. Metabolic features of these isolates are important for biotechnological applications in n-caproate and iso-butyrate production.


2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Mattia Miotto ◽  
Lorenzo Monacelli
Keyword(s):  

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