Power and Pitfalls of Computational Methods to Identify New Genes Responsible for Acute Liver Failure of Indeterminate Etiology in Adults.
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SUBMITTER: Heddar A
PROVIDER: S-EPMC7447419 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Power and Pitfalls of Computational Methods to Identify New Genes Responsible for Acute Liver Failure of Indeterminate Etiology in Adults.
Heddar Abdelkader A Misrahi Micheline M
Clinical and translational gastroenterology 20200801 8
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Project description:In clinical virome research, whole-genome/transcriptome amplification is required when starting material is limited. An improved method, named "template-dependent multiple displacement amplification" (tdMDA), has recently been developed in our lab (Wang et al. in BioTechniques 63:21-25. https://doi.org/10.2144/000114566, 2017). In combination with Illumina sequencing and bioinformatics pipelines, its application in virome sequencing was explored using a serum sample from a patient with chronic hepatitis C virus (HCV) infection. In comparison to an amplification-free procedure, virome sequencing via tdMDA showed a 9.47-fold enrichment for HCV-mapped reads and, accordingly, an increase in HCV genome coverage from 28.5% to 70.1%. Eight serum samples from acute patients liver failure (ALF) with or without known etiology were then used for virome sequencing with an average depth at 94,913x. Both similarity-based (mapping, NCBI BLASTn, BLASTp, and profile hidden Markov model analysis) and similarity-independent methods (machine-learning algorithms) identified viruses from multiple families, including Herpesviridae, Picornaviridae, Myoviridae, and Anelloviridae. However, their commensal nature and cross-detection ruled out an etiological interpretation. Together with a lack of detection of novel viruses in a comprehensive analysis at a resolution of single reads, these data indicate that viral agents might be rare in ALF cases with indeterminate etiology.
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Project description:Background and Aims: Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury, however the precise inflammatory pathways have not been well defined. We have thus characterized the hepatic cytokine and transcriptional signatures of PALF patients. Approach and Results: Retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n=17) or other diagnoses (DX-PALF; n=6) with available archived liver tissue. Specimens were stained for CD8 T-cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA-sequencing (RNA-seq) were performed on whole liver tissue. Immune analyte data was analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene set enrichment analysis. Most IND-PALF patients (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including TNFα, IFNγ, IL-1β, IL-12, CXCL9, and CXCL12. Transcriptional analyses identified 2 transcriptional PALF phenotypes. Most patients in Group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell-subset specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 also expressed significantly higher levels of gene signatures for T-regulatory cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T-cells, and activated dendritic cells (p-adj <0.05). In contrast, patients in Group 2 exhibited increased expression for genes involved in metabolic processes. Conclusions: IND-PALF patients have evidence of a Th1 mediated inflammatory response driven by IFNγ. Transcriptional analyses suggest a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide novel insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.
2021-06-01 | GSE164397 | GEO
Project description:Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury; however, the precise inflammatory pathways are not well defined. We have characterized the hepatic cytokine and transcriptional signatures of patients with PALF. A retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n = 17) or other known diagnoses (DX-PALF; n = 6) with available archived liver tissue. Specimens were stained for clusters of differentiation 8 (CD8) T cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA sequencing (RNA-seq) was performed on whole-liver tissue. Immune analyte data were analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene-set enrichment analysis. Most patients with IND-PALF (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including tumor necrosis factor α, interferon γ (IFN-γ), interleukin (IL) 1β, IL-12, C-X-C motif chemokine ligand (CXCL) 9, and CXCL12. Transcriptional analyses identified two transcriptional PALF phenotypes. Most patients in group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell subset-specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 expressed significantly higher levels of gene signatures for regulatory T cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T cells, and activated dendritic cells (adjusted P < 0.05). In contrast, patients in group 2 exhibited increased expression for genes involved in metabolic processes. Conclusion: Patients with IND-PALF have evidence of a Th1-mediated inflammatory response driven by IFN-γ. Transcriptional analyses suggest that a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.
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Project description:Until recently, the search for genes contributing to Alzheimer's disease (AD) had been slow and disappointing, with the notable exception of the APOE ε4 allele, which increases risk and reduces the age at onset of AD in a dose-dependent fashion. Findings from genome-wide association studies (GWAS) made up of fewer than several thousand cases and controls each have not been replicated. Efforts of several consortia--each assembling much larger datasets with sufficient power to detect loci conferring small changes in AD risk--have resulted in robust associations with many novel genes involved in multiple biological pathways. Complex data mining strategies are being used to identify additional members of these pathways and gene-gene interactions contributing to AD risk. Guided by GWAS results, next-generation sequencing and functional studies are under way with the hope of helping us better understand AD pathology and providing new drug targets.
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Project description:The molecular causes by which the epidermal growth factor receptor tyrosine kinase induces malignant transformation are largely unknown. To better understand EGFs' transforming capacity whole genome scans were applied to a transgenic mouse model of liver cancer and subjected to advanced methods of computational analysis to construct de novo gene regulatory networks based on a combination of sequence analysis and entrained graph-topological algorithms. Here we identified transcription factors, processes, key nodes and molecules to connect as yet unknown interacting partners at the level of protein-DNA interaction. Many of those could be confirmed by electromobility band shift assay at recognition sites of gene specific promoters and by western blotting of nuclear proteins. A novel cellular regulatory circuitry could therefore be proposed that connects cell cycle regulated genes with components of the EGF signaling pathway. Promoter analysis of differentially expressed genes suggested the majority of regulated transcription factors to display specificity to either the pre-tumor or the tumor state. Subsequent search for signal transduction key nodes upstream of the identified transcription factors and their targets suggested the insulin-like growth factor pathway to render the tumor cells independent of EGF receptor activity. Notably, expression of IGF2 in addition to many components of this pathway was highly upregulated in tumors. Together, we propose a switch in autocrine signaling to foster tumor growth that was initially triggered by EGF and demonstrate the knowledge gain form promoter analysis combined with upstream key node identification.
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Project description:In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology.Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months.Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations.Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.
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Project description:IntroductionThe etiology of acute liver failure (ALF) remains an important prognostic factor. The Acute Liver Failure Study Group recently reported that 150 of 2,718 adult patients with ALF (5.5%) had an indeterminate etiology. Our aim was to use whole exome sequencing to identify genetic variants associated with phenotypic, biochemical, and histologic features among patients with indeterminate ALF.MethodsThis effort has defined a cohort of well-pedigreed patients with indeterminate ALF; DNA samples extracted from whole blood samples were obtained from 26 respective patients with indeterminate ALF. These samples were kept at the Acute Liver Failure Study Group repository at the NIDDK, Bethesda. Whole exome sequencing and bioinformatics analysis were performed at the Mayo Clinic Center of Individualized Medicine in Rochester, MN.ResultsOf the 26 patients, 8 survived spontaneously, 6 died, and 12 underwent a liver transplantation; all those transplanted were alive at 21 days after enrollment in the study. Twenty-two of the 26 patients presented as ALF. We found 12 variants associated with 11 genes. The most common variant was rs4940595 in the SERPINB11 gene which was found in 23 of the 26 patients. This variant had a stop codon; no reports of disorders have been associated with this variant. The next most commonly found variant was rs1135840 in the CYP2D6 gene; this mutation is a missense_variant and has been reported to be associated with hepatotoxicity of antituberculous therapy. None of our patients were receiving this therapy. We also found a significant asymmetric distribution of rs1800754 of the CYP2D7 gene and rs1135840 of the CYP2D6 gene between patients who survived spontaneously (75%) and those who died or underwent liver transplantation (30.5% and 25%, respectively).DiscussionWe found 12 variants of 11 genes significantly associated with ALF among adults with indeterminate etiology. We also found a significant asymmetric distribution of 2 variants belonging to the CYP2D7 and CYP2D6 genes, respectively, between those who survived spontaneously and those who died or underwent liver transplantation. The 2 most common variants, rs4940595 and rs1135840, of the SERPINB11 and CYP2D6 genes, respectively, found in our patients with ALF have been described as potentially important in the adaptive response combating the emergence of infectious diseases and associated with hepatotoxicity of antituberculous therapy, respectively. Our findings need to be expanded to include more patients with indeterminate ALF as well as viral, drug toxicity, and autoimmune etiologies to determine whether our findings are associated with the specific etiology, indeterminate, or with the overall ALF syndrome itself.
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Project description:Spatially resolved transcriptomics offers unprecedented insight by enabling the profiling of gene expression within the intact spatial context of cells, effectively adding a new and essential dimension to data interpretation. To efficiently detect spatial structure of interest, an essential step in analyzing such data involves identifying spatially variable genes. Despite researchers having developed several computational methods to accomplish this task, the lack of a comprehensive benchmark evaluating their performance remains a considerable gap in the field. Here, we present a systematic evaluation of 14 methods using 60 simulated datasets generated by four different simulation strategies, 12 real-world transcriptomics, and three spatial ATAC-seq datasets. We find that spatialDE2 consistently outperforms the other benchmarked methods, and Moran's I achieves competitive performance in different experimental settings. Moreover, our results reveal that more specialized algorithms are needed to identify spatially variable peaks.
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Project description:Adenovirus, adeno-associated virus, and severe acute respiratory syndrome-coronavirus-2 (SARS-COV2) have been recently implicated as probable causative agents of severe acute hepatitis of unknown etiology reported from most of Europe. High mortality and liver transplantation (LT) rates have been observed in those presenting with acute liver failure (ALF). Such cases have not been reported from the Indian subcontinent. We analyzed the etiologies, clinical course, and in-hospital outcomes of cases of severe acute hepatitis with ALF presenting to us between May and October 2022. A total of 178 children presented with severe acute hepatitis of known/unknown etiology including 28 presenting as ALF. Eight of them fulfilled the definition of severe acute hepatitis of unknown etiology presenting as ALF. Adenovirus was not associated with cases of ALF in these children. SARS-COV2 antibodies were detected in 6 (75%) of them. Children with severe acute hepatitis of unknown etiology presenting as ALF were young (median age 4 years), had hyper-acute presentation with a predominance of gastrointestinal symptoms, and a fulminant course with worse outcomes (native liver survival 25%). Expedited evaluation of these children for LT would be the key to management.
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