Insights From Deep Sequencing of the HBV Genome-Unique, Tiny, and Misunderstood.
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ABSTRACT:
SUBMITTER: McNaughton AL
PROVIDER: S-EPMC6347571 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AIM:Deletions are observed frequently in the preS1/S2 region of hepatitis B virus (HBV) genome, in association with liver disease advancement. However, the most significant preS1/S2 region and its influences on viral markers are unclear. METHODS:The preS1/S2 HBV regions of 90 patients without antiviral therapy were subjected to deep sequencing and deleted regions influencing viral markers were investigated. RESULTS:From the deletion frequency analysis in each patient, deletions were observed most frequently in the preS2 codon 132-141 region. When the patients were divided into three groups (0-0.1%: n = 27, 0.1%-10%: n = 34, 10-100%: n = 29), based on the deletion frequency, FIB-4 (p < 0.01), HBV DNA (p < 0.01), HBcrAg (p < 0.01) and preS1/S2 start codon mutations (p < 0.01, both) were significantly associated with the deletion. When clinical and viral markers were investigated by multivariate analysis for their association with the deletion, FIB-4 (p < 0.05), HBcrAg (p < 0.05), and preS1 start codon mutation (p < 0.01) were extracted as independent variables. When the influence of the preS codon 132-141deletions on HBsAg and HBcrAg, relative to HBV DNA, was investigated, the HBsAg/HBV DNA ratio was lower (0-10% vs. 10%-100%, p<0.05), while the HBcrAg/HBV DNA rati o was higher (0-0.1% vs. 10%-100%, p<0.05) in the presence of the preS codon 132-141deletions. CONCLUSION:The preS codon.132-141 deletions have a significant influence on the clinical characteristics and viral markers, even when present as a minor population. Importantly, the preS codon 132-141 deletions have a clear influence on the viral life cycle and pathogenesis.
| S-EPMC6386350 | biostudies-literature
Project description:Deep whole genome sequencing (WGS) allows for the comprehensive study of genetic landscapes at finer resolution than array based methods. We conducted deep WGS on children with the polyarticular form of juvenile idiopathic arthritis (JIA), using 2 independent cohorts to ascertain the sequencing fidelity. Genome wide SNP density analysis identified 18 SNP hotspots with comparison to the 1000 Genome Projects (1KGP) data. A subset of the genes adjacent to SNP hotspots showed statistically significant enrichment in immunological processes. Genes adjacent to indel hotspots were functionally related to G-protein coupled signaling pathways. Further analyses elucidated significantly more JIA SNPs with regulatory potential compared to 1KGP data. Furthermore, SNPs located within linkage disequibilium (LD) blocks containing previously identified JIA-associated SNPs demonstrated higher regulation potential compared to SNPs outside LD blocks. We also demonstrated enrichment of novel JIA variants in histone modification peaks and DNase hypersensitivity sites in B cells. This study greatly expands the number of genetic variants that may contribute to JIA and give us some clues into what may trigger this disease. To date, this study is the first deep WGS effort on children with JIA and provides useful genetic resources for research communities particularly in understanding JIA etiology.
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Project description:Fluoroquinolone (FQ)-resistant Salmonella spp. were listed by the WHO in 2017 as priority pathogens for which new antibiotics were urgently needed. The overall global burden of Salmonella infections is high, but differs per region. Whereas typhoid fever is most prevalent in South and South-East Asia, non-typhoidal salmonellosis is prevalent across the globe and associated with a mild gastroenteritis. By contrast, invasive non-typhoidal Salmonella cause bloodstream infections associated with high mortality, particularly in sub-Saharan Africa. Most Salmonella strains from clinical sources are resistant to first-line antibiotics, with FQs now being the antibiotic of choice for treatment of invasive Salmonella infections. However, FQ resistance is increasingly being reported in Salmonella, and multiple molecular mechanisms are already described. Whole-genome sequencing (WGS) is becoming more frequently used to analyse bacterial genomes for antibiotic-resistance markers, and to understand the phylogeny of bacteria in relation to their antibiotic-resistance profiles. This mini-review provides an overview of FQ resistance in Salmonella, guided by WGS studies that demonstrate that WGS is a valuable tool for global surveillance.
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Project description:Because of its size, allohexaploid nature, and high repeat content, the bread wheat genome is a good model to study the impact of the genome structure on gene organization, function, and regulation. However, because of the lack of a reference genome sequence, such studies have long been hampered and our knowledge of the wheat gene space is still limited. The access to the reference sequence of the wheat chromosome 3B provided us with an opportunity to study the wheat transcriptome and its relationships to genome and gene structure at a level that has never been reached before.By combining this sequence with RNA-seq data, we construct a fine transcriptome map of the chromosome 3B. More than 8,800 transcription sites are identified, that are distributed throughout the entire chromosome. Expression level, expression breadth, alternative splicing as well as several structural features of genes, including transcript length, number of exons, and cumulative intron length are investigated. Our analysis reveals a non-monotonic relationship between gene expression and structure and leads to the hypothesis that gene structure is determined by its function, whereas gene expression is subject to energetic cost. Moreover, we observe a recombination-based partitioning at the gene structure and function level.Our analysis provides new insights into the relationships between gene and genome structure and function. It reveals mechanisms conserved with other plant species as well as superimposed evolutionary forces that shaped the wheat gene space, likely participating in wheat adaptation.
| S-EPMC4355351 | biostudies-literature
Project description:Hepatitis B virus (HBV) infection is a common problem in the world, especially in China. More than 60-80% of hepatocellular carcinoma (HCC) cases can be attributed to HBV infection in high HBV prevalent regions. Although traditional Sanger sequencing has been extensively used to investigate HBV sequences, NGS is becoming more commonly used. Further, it is unknown whether word pattern frequencies of HBV reads by Next Generation Sequencing (NGS) can be used to investigate HBV genotypes and predict HCC status. In this study, we used NGS to sequence the pre-S region of the HBV sequence of 94 HCC patients and 45 chronic HBV (CHB) infected individuals. Word pattern frequencies among the sequence data of all individuals were calculated and compared using the Manhattan distance. The individuals were grouped using principal coordinate analysis (PCoA) and hierarchical clustering. Word pattern frequencies were also used to build prediction models for HCC status using both K-nearest neighbors (KNN) and support vector machine (SVM). We showed the extremely high power of analyzing HBV sequences using word patterns. Our key findings include that the first principal coordinate of the PCoA analysis was highly associated with the fraction of genotype B (or C) sequences and the second principal coordinate was significantly associated with the probability of having HCC. Hierarchical clustering first groups the individuals according to their major genotypes followed by their HCC status. Using cross-validation, high area under the receiver operational characteristic curve (AUC) of around 0.88 for KNN and 0.92 for SVM were obtained. In the independent data set of 46 HCC patients and 31 CHB individuals, a good AUC score of 0.77 was obtained using SVM. It was further shown that 3000 reads for each individual can yield stable prediction results for SVM. Thus, another key finding is that word patterns can be used to predict HCC status with high accuracy. Therefore, our study shows clearly that word pattern frequencies of HBV sequences contain much information about the composition of different HBV genotypes and the HCC status of an individual.
| S-EPMC5841821 | biostudies-literature
Project description:South Asia possesses a significant amount of genetic diversity due to considerable intergroup differences in culture and language. There have been numerous reports on the genetic structure of Asian Indians, although these have mostly relied on genotyping microarrays or targeted sequencing of the mitochondria and Y chromosomes. Asian Indians in Singapore are primarily descendants of immigrants from Dravidian-language-speaking states in south India, and 38 individuals from the general population underwent deep whole-genome sequencing with a target coverage of 30X as part of the Singapore Sequencing Indian Project (SSIP). The genetic structure and diversity of these samples were compared against samples from the Singapore Sequencing Malay Project and populations in Phase 1 of the 1,000 Genomes Project (1 KGP). SSIP samples exhibited greater intra-population genetic diversity and possessed higher heterozygous-to-homozygous genotype ratio than other Asian populations. When compared against a panel of well-defined Asian Indians, the genetic makeup of the SSIP samples was closely related to South Indians. However, even though the SSIP samples clustered distinctly from the Europeans in the global population structure analysis with autosomal SNPs, eight samples were assigned to mitochondrial haplogroups that were predominantly present in Europeans and possessed higher European admixture than the remaining samples. An analysis of the relative relatedness between SSIP with two archaic hominins (Denisovan, Neanderthal) identified higher ancient admixture in East Asian populations than in SSIP. The data resource for these samples is publicly available and is expected to serve as a valuable complement to the South Asian samples in Phase 3 of 1 KGP.
| S-EPMC4022468 | biostudies-literature
Project description:The emergence of jawed vertebrates (gnathostomes) from jawless vertebrates was accompanied by major morphological and physiological innovations, such as hinged jaws, paired fins and immunoglobulin-based adaptive immunity. Gnathostomes subsequently diverged into two groups, the cartilaginous fishes and the bony vertebrates. Here we report the whole-genome analysis of a cartilaginous fish, the elephant shark (Callorhinchus milii). We find that the C. milii genome is the slowest evolving of all known vertebrates, including the 'living fossil' coelacanth, and features extensive synteny conservation with tetrapod genomes, making it a good model for comparative analyses of gnathostome genomes. Our functional studies suggest that the lack of genes encoding secreted calcium-binding phosphoproteins in cartilaginous fishes explains the absence of bone in their endoskeleton. Furthermore, the adaptive immune system of cartilaginous fishes is unusual: it lacks the canonical CD4 co-receptor and most transcription factors, cytokines and cytokine receptors related to the CD4 lineage, despite the presence of polymorphic major histocompatibility complex class II molecules. It thus presents a new model for understanding the origin of adaptive immunity.
| S-EPMC3964593 | biostudies-literature
Project description:Chromatin immunoprecipitation followed by high-throughput (HTP) sequencing (ChIP-seq) is a powerful tool to establish protein-DNA interactions genome-wide. The primary limitation of its broad application at present is the often-limited access to sequencers. Here we report a protocol, Mab-seq, that generates genome-scale quality evaluations for nucleic acid libraries intended for deep-sequencing. We show how commercially available genomic microarrays can be used to maximize the efficiency of library creation and quickly generate reliable preliminary data on a chromosomal scale in advance of deep sequencing. We also exploit this technique to compare enriched regions identified using microarrays with those identified by sequencing, demonstrating that they agree on a core set of clearly identified enriched regions, while characterizing the additional enriched regions identifiable using HTP sequencing.
| S-EPMC2577887 | biostudies-literature
Project description:Fully characterising the exchange of volatile elements between the Earth's interior and surface layers has been a longstanding challenge. Volatiles scavenged from seawater by hydrothermally altered oceanic crust have been transferred to the upper mantle during subduction of the oceanic crust, but whether these volatiles are carried deeper into the lower mantle is poorly understood. Here we present evidence of the deep-mantle Cl cycle recorded in melt inclusions in olivine crystals in ocean island basalts sourced from the lower mantle. We show that Cl-rich melt inclusions are associated with radiogenic Pb isotopes, indicating ancient subducted oceanic crust in basalt sources, together with lithophile elements characteristic of melts from a carbonated source. These signatures collectively indicate that seawater-altered and carbonated oceanic crust conveyed surface Cl downward to the lower mantle, forming a Cl-rich reservoir that accounts for 13-26% or an even greater proportion of the total Cl in the mantle.
| S-EPMC6320363 | biostudies-literature
Project description:BackgroundViral genotype shift in chronic hepatitis B (CHB) patients during antiviral therapy has been reported, but the underlying mechanism remains elusive.Methods38 CHB patients treated with ADV for one year were selected for studying genotype shift by both deep sequencing and Sanger sequencing method.ResultsSanger sequencing method found that 7.9% patients showed mixed genotype before ADV therapy. In contrast, all 38 patients showed mixed genotype before ADV treatment by deep sequencing. 95.5% mixed genotype rate was also obtained from additional 200 treatment-naïve CHB patients. Of the 13 patients with genotype shift, the fraction of the minor genotype in 5 patients (38%) increased gradually during the course of ADV treatment. Furthermore, responses to ADV and HBeAg seroconversion were associated with the high rate of genotype shift, suggesting drug and immune pressure may be key factors to induce genotype shift. Interestingly, patients with genotype C had a significantly higher rate of genotype shift than genotype B. In genotype shift group, ADV treatment induced a marked enhancement of genotype B ratio accompanied by a reduction of genotype C ratio, suggesting genotype C may be more sensitive to ADV than genotype B. Moreover, patients with dominant genotype C may have a better therapeutic effect. Finally, genotype shifts was correlated with clinical improvement in terms of ALT.ConclusionsOur findings provided a rational explanation for genotype shift among ADV-treated CHB patients. The genotype and genotype shift might be associated with antiviral efficiency.
| S-EPMC4482366 | biostudies-literature