Browsing by Author "Blankenberg, Daniel"
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Publication CNV-ClinViewer: enhancing the clinical interpretation oflarge copy-number variants online(2023) Macnee, Marie; Pérez Palma, Eduardo; Brünger, Tobias; Klöckner, Chiara; Platzer, Konrad; Stefansk, Arthur; Montanucci, Ludovica; Bayat, Allan; Radtke, Maximilian; Collins, Ryan; Talkowski, Michael; Blankenberg, Daniel; Møller, Rikke; Lemke, Johannes; Nothnagel, Michael; May, Patrick; Lal, DennisMotivation: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Results: Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators' patient care and for basic scientists' translational genomic research.Item Controlling for contamination in re-sequencing studies with a reproducible web-based phylogenetic approach(2014) Dickins, Benjamin; Rebolledo-Jaramillo, Boris; Su, Marcia Shu-Wei; Paul, Ian M.; Blankenberg, Daniel; Stoler, Nicholas; Makova, Kateryna D.; Nekrutenko, AntonPolymorphism discovery is a routine application of next-generation sequencing technology where multiple samples are sent to a service provider for library preparation, subsequent sequencing, and bioinformatic analyses. The decreasing cost and advances in multiplexing approaches have made it possible to analyze hundreds of samples at a reasonable cost. However, because of the manual steps involved in the initial processing of samples and handling of sequencing equipment, cross-contamination remains a significant challenge. It is especially problematic in cases where polymorphism frequencies do not adhere to diploid expectation, for example, heterogeneous tumor samples, organellar genomes, as well as during bacterial and viral sequencing. In these instances, low levels of contamination may be readily mistaken for polymorphisms, leading to false results. Here we describe practical steps designed to reliably detect contamination and uncover its origin, and also provide new, Galaxy-based, readily accessible computational tools and workflows for quality control. All results described in this report can be reproduced interactively on the web as described at http://usegalaxy.org/contamination.Item Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA(2014) Rebolledo-Jaramillo, Boris; Su, Marcia Shu-Wei; Stoler, Nicholas; McElhoe, Jennifer A; Dickins, Benjamín; Blankenberg, Daniel; Korneliussen, Thorfinn S.; Chiaromonte, Francesca; Nielsen, Rasmus; Holland, Mitchell M.The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at similar to 20,000x per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease- associated heteroplasmy, with minor allele frequency >= 1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germline mtDNA bottleneck at only similar to 30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 x 10(-8) (interquartile range from 4.2 x 10(-9) to 4.1 x 10(-8)) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.Item SimText: a text mining framework for interactive analysis and visualization of similarities among biomedical entities(2021) Macnee, Marie; Pérez Palma, Eduardo; Schumacher-Bass, Sarah; Dalton, Jarrod; Leu, Costin; Blankenberg, Daniel; Lal, DennisLiterature exploration in PubMed on a large number of biomedical entities (e.g. genes, diseases or experiments) can be time-consuming and challenging, especially when assessing associations between entities. Here, we describe SimText, a user-friendly toolset that provides customizable and systematic workflows for the analysis of similarities among a set of entities based on text. SimText can be used for (i) text collection from PubMed and extraction of words with different text mining approaches, and (ii) interactive analysis and visualization of data using unsupervised learning techniques in an interactive app.