scholarly journals PhenoModifier: a genetic modifier database for elucidating the genetic basis of human phenotypic variation

2019 ◽  
Author(s):  
Hong Sun ◽  
Yangfan Guo ◽  
Xiaoping Lan ◽  
Jia Jia ◽  
Xiaoshu Cai ◽  
...  
Keyword(s):  
Phenotypic Variation ◽  
Large Scale ◽  
Clinical Decision Making ◽  
Genetic Interaction ◽  
Genetic Modifier ◽  
Modifier Genes ◽  
Genetic Modifiers ◽  
Sequencing Data ◽  
Comprehensive Overview ◽  
Full Spectrum

Abstract From clinical observations to large-scale sequencing studies, the phenotypic impact of genetic modifiers is evident. To better understand the full spectrum of the genetic contribution to human disease, concerted efforts are needed to construct a useful modifier resource for interpreting the information from sequencing data. Here, we present the PhenoModifier (https://www.biosino.org/PhenoModifier), a manually curated database that provides a comprehensive overview of human genetic modifiers. By manually curating over ten thousand published articles, 3078 records of modifier information were entered into the current version of PhenoModifier, related to 288 different disorders, 2126 genetic modifier variants and 843 distinct modifier genes. To help users probe further into the mechanism of their interested modifier genes, we extended the yeast genetic interaction data and yeast quantitative trait loci to the human and we also integrated GWAS data into the PhenoModifier to assist users in evaluating all possible phenotypes associated with a modifier allele. As the first comprehensive resource of human genetic modifiers, PhenoModifier provides a more complete spectrum of genetic factors contributing to human phenotypic variation. The portal has a broad scientific and clinical scope, spanning activities relevant to variant interpretation for research purposes as well as clinical decision making.

Genetic Modifiers of Thrombosis in Mice.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
David Ginsburg
Keyword(s):  
Large Scale ◽  
Genetic Factors ◽  
Conflicts Of Interest ◽  
Factor V Leiden ◽  
Mouse Genetics ◽  
Von Willebrand Disease ◽  
Modifier Genes ◽  
Factor V ◽  
Genetic Modifiers ◽  
Von Willebrand

Abstract Abstract SCI-44 The genetic factors responsible for the highly variable clinical course of inherited bleeding disorders including von Willebrand disease and hemophilia are largely unknown. Similar factors are also likely to contribute to the variability of common thrombotic disorders, including factor V Leiden. Studies by our lab over the past 10 years have used the power of mouse genetics to identify genes contributing to this variability (referred to as ‘modifier‘ genes). By performing genetic crosses between inbred strains of mice with elevated plasma levels of von Willebrand Factor (VWF) and other strains with low levels, we have mapped a total of 6 genetic factors contributing to the control of murine plasma VWF levels. Similar studies in ADAMTS13-deficient mice are in progress aimed at characterizing genes modifying susceptibility thrombotic thrombocytopenic purpura. We have also conducted large scale mutagenesis studies in the mouse in an effort to identify larger numbers of genes contributing to thrombosis risk in the setting of Factor V Leiden, and most recently are extending this approach to similar genetic screens in zebrafish. Finally, recent advances in human genetics are expanding the potential opportunities for directly identifying bleeding and thrombosis modifier genes in humans. Disclosures No relevant conflicts of interest to declare.

scholarly journals Multi-platform discovery of haplotype-resolved structural variation in human genomes

2017 ◽  
Author(s):  
Mark J.P. Chaisson ◽  
Ashley D. Sanders ◽  
Xuefang Zhao ◽  
Ankit Malhotra ◽  
David Porubsky ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Structural Variation ◽  
High Throughput Sequencing ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Full Spectrum ◽  
Variant Discovery ◽  
Sequencing Technologies ◽  
Sequencing Studies

ABSTRACTThe incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent–child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per human genome. We also discover 156 inversions per genome—most of which previously escaped detection. Fifty-eight of the inversions we discovered intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The method and the dataset serve as a gold standard for the scientific community and we make specific recommendations for maximizing structural variation sensitivity for future large-scale genome sequencing studies.

Abstract 41: Dnajb6b Is A Novel Genetic Modifier For Cardiomyopathy That Regulates ER Stress Response

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yonghe Ding ◽  
Weibin Liu ◽  
Beninio Gore ◽  
Stephen C Ekker ◽  
Xiaolei Xu
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Insertional Mutagenesis ◽  
Genetic Modifier ◽  
Phenotypic Expression ◽  
Modifier Genes ◽  
Genetic Modifiers ◽  
Loss Of Function ◽  
Adult Zebrafish ◽  
Er Stress Response

Background: Cardiomyopathy and heart failure affect millions of people worldwide. Because genetic modifiers contribute in large part to the highly variable phenotypic expression of cardiomyopathy in patients even with identical disease-causing mutations, the identification of modifier genes for this disease will greatly improve risk stratification, prognostic test development, and personalized therapy. However, only a rather limited number of modifier genes for cardiomyopathy have been identified sporadically. Objective: To identify genetic modifiers for cardiomyopathy using a novel insertional mutagenesis screening approach in adult zebrafish. Methods and Results: We screened 476 gene break-transposon (GBT) lines and isolated 44 zebrafish insertional cardiac (ZIC) mutants. Employing doxorubicin (DOX) stress to these ZIC mutants, we identified four candidate GBT lines that modified the progression of DOX-induced cardiomyopathy. Here, we report the detailed study of the GBT0411 mutant that exacerbated DOX-induced cardiomyopathy. GBT0411 mutant was tagged to the dnajb6b gene. Mutations in the short (sarcomeric) isoform of its human homologue gene DNAJB6 was recently reported to cause limb-girdle muscular dystrophy type 1D. Interestingly, our data showed that long (nuclei) isoform (dnajb6b[L]) was the major isoform expressed in the heart, and loss-of-function of which deteriorated the progression of DOX-induced cardiomyopathy. We further found that a cardiomyocyte-specific dnajb6b(L) transgene reverted the deleterious modifying effect of GBT0411 mutant, and exerted a cardioprotective function on chronic anemia induced cardiomyopathy. Mechanistically, Dnajb6b(L) could partially localize to endoplasmic reticulum (ER) upon ER stress, and function as an ER stress suppressor. Indeed, inhibition of ER stress by using a chemical chaperon mimics the cardioprotective effect of dnajb6b(L) transgene. Conclusions: By conducting an unbiased mutagenesis screening in adult zebrafish, we identified dnajb6b as a novel genetic modifier for cardiomyopathy. A cardioprotective function was identified by overexpressing its long isoform in cardiomyocytes, which might be conveyed by inhibition of ER stress response.

scholarly journals Translating Genomics to the Clinic: Implications of Cancer Heterogeneity

2013 ◽  
Vol 59 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Nardin Samuel ◽  
Thomas J Hudson
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Clinical Decision Making ◽  
Cancer Genomics ◽  
Clinical Decision ◽  
Sequencing Analysis ◽  
Breast Cancers ◽  
Sequencing Data ◽  
Cancer Heterogeneity ◽  
Cancer Genomes

BACKGROUND Sequencing of cancer genomes has become a pivotal method for uncovering and understanding the deregulated cellular processes driving tumor initiation and progression. Whole-genome sequencing is evolving toward becoming less costly and more feasible on a large scale; consequently, thousands of tumors are being analyzed with these technologies. Interpreting these data in the context of tumor complexity poses a challenge for cancer genomics. CONTENT The sequencing of large numbers of tumors has revealed novel insights into oncogenic mechanisms. In particular, we highlight the remarkable insight into the pathogenesis of breast cancers that has been gained through comprehensive and integrated sequencing analysis. The analysis and interpretation of sequencing data, however, must be considered in the context of heterogeneity within and among tumor samples. Only by adequately accounting for the underlying complexity of cancer genomes will the potential of genome sequencing be understood and subsequently translated into improved management of patients. SUMMARY The paradigm of personalized medicine holds promise if patient tumors are thoroughly studied as unique and heterogeneous entities and clinical decisions are made accordingly. Associated challenges will be ameliorated by continued collaborative efforts among research centers that coordinate the sharing of mutation, intervention, and outcomes data to assist in the interpretation of genomic data and to support clinical decision-making.

scholarly journals Verification of Arabidopsis stock collections using SNPmatch - an algorithm for genotyping high-plexed samples

2017 ◽  
Author(s):  
Rahul Pisupati ◽  
Ilka Reichardt ◽  
Ümit Seren ◽  
Pamela Korte ◽  
Viktoria Nizhynska ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Genetic Variation ◽  
Phenotypic Variation ◽  
Large Scale ◽  
Command Line ◽  
Web Interface ◽  
Sequencing Data ◽  
Link Type ◽  
Gregor Mendel ◽  
Low Coverage

AbstractLarge-scale studies such as the ​Arabidopsis thaliana 1001 Genomes Project aim to understand genetic variation in populations and link it to phenotypic variation. Such studies require routine genotyping of stocks to avoid sample contamination and mix-ups. To genotype samples efficiently and economically, sequencing must be inexpensive a​nd data processing simple. Here we present SNPmatch, a tool which identifies the most likely strain (inbred line, or “accession”) from a SNP database. We tested the tool by performing low-coverage sequencing of over 2000 strains. SNPmatch could readily genotype samples correctly from 1-fold coverage sequencing data, and could also identify the parents of F1 or F2 individuals. SNPmatch can be run either on the command line or through AraGeno (https://arageno.gmi.oeaw.ac.at), a web interface that permits sample genotyping from a user-uploaded VCF or BED file.Availability and implementation: https://github.com/Gregor-Mendel-Institute/SNPmatch.git

scholarly journals Prioritization of COPD protein biomarkers, based on a systematic study of the literature

2016 ◽  
Vol 1 (1) ◽  
pp. 4 ◽  
Author(s):  
Sara Ongay ◽  
Frank Klont ◽  
Peter Horvatovich ◽  
Rainer Bischoff ◽  
Nick HT Ten Hacken
Keyword(s):  
Large Scale ◽  
Complex Disease ◽  
Clinical Decision Making ◽  
Early Stage ◽  
Clinical Decision ◽  
Chronic Obstructive ◽  
Protein Biomarkers ◽  
Lung Function Decline ◽  
Comprehensive Overview ◽  
Wide Range

Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease mostly due to smoking and until now diagnosed by spirometry (post bronchodilator FEV1/FVC <70%). However, in spite of the usefulness of FEV1 as diagnostic and prognostic tool, it has proven to be a weak indicator of future exacerbations, unable to predict lung function decline within COPD patients, as well as unable to identify the smokers “susceptible” to developing COPD at an early stage. Thus, there is an urgent need for biomarkers that address these questions and support clinical decision making in the diagnosis and treatment of (early) COPD. In this respect, considerable efforts have been devoted to identifying protein biomarkers that enable a better understanding of this complex disease and leading to better diagnostic and prognostic tools. However, in spite of the wide range of candidates that have been suggested as potentially useful COPD biomarkers, most remained at the level of the initial discovery, and only fibrinogen has been approved by the Food and Drug Administration (FDA) as predictor for all-cause mortality and COPD exacerbations. There is thus a need for future investigations of these biomarkers in large-scale and well characterized studies in order to prove their usefulness as surrogate endpoints. Based on this, the aim of the present review is to advance COPD biomarker development by providing a comprehensive overview of protein biomarker candidates which have been evaluated in clinical studies and prioritize them according to their potential of becoming valid, clinically useful COPD biomarkers.

Genetic Modifier Screens in Drosophila Demonstrate a Role for Rho1 Signaling in Ecdysone-Triggered Imaginal Disc Morphogenesis

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1397-1415 ◽  
Author(s):  
Robert E Ward ◽  
Janelle Evans ◽  
Carl S Thummel
Keyword(s):  
Imaginal Disc ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Genetic Interaction ◽  
Genetic Modifier ◽  
Early Gene ◽  
Genetic Screens ◽  
Major Transitions ◽  
Candidate Mutation ◽  
Ideal Model System

Abstract Drosophila adult leg development provides an ideal model system for characterizing the molecular mechanisms of hormone-triggered morphogenesis. A pulse of the steroid hormone ecdysone at the onset of metamorphosis triggers the rapid transformation of a flat leg imaginal disc into an immature adult leg, largely through coordinated changes in cell shape. In an effort to identify links between the ecdysone signal and the cytoskeletal changes required for leg morphogenesis, we performed two large-scale genetic screens for dominant enhancers of the malformed leg phenotype associated with a mutation in the ecdysoneinducible broad early gene (br1). From a screen of &gt;750 independent deficiency and candidate mutation stocks, we identified 17 loci on the autosomes that interact strongly with br1. In a complementary screen of ∼112,000 F1 progeny of EMS-treated br1 animals, we recovered 26 mutations that enhance the br1 leg phenotype [E(br) mutations]. Rho1, stubbloid, blistered (DSRF), and cytoplasmic Tropomyosin were identified from these screens as br1-interacting genes. Our findings suggest that ecdysone exerts its effects on leg morphogenesis through a Rho1 signaling cascade, a proposal that is supported by genetic interaction studies between the E(br) mutations and mutations in the Rho1 signaling pathway. In addition, several E(br) mutations produce unexpected defects in midembryonic morphogenetic movements. Coupled with recent evidence implicating ecdysone signaling in these embryonic morphogenetic events, our results suggest that a common ecdysone-dependent, Rho1-mediated regulatory pathway controls morphogenesis during the two major transitions in the life cycle, embryogenesis and metamorphosis.

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 141-157 ◽  
Author(s):  
Dubravka S. Strac ◽  
Marcela Konjevod ◽  
Matea N. Perkovic ◽  
Lucija Tudor ◽  
Gordana N. Erjavec ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Comprehensive Overview ◽  
Brain Functions ◽  
Specific Effects ◽  
And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

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