Dataset Information

Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver.

ABSTRACT: Interpretation of human genomes is a major challenge. We present the Scripps Genome ADVISER (SG-ADVISER) suite, which aims to fill the gap between data generation and genome interpretation by performing holistic, in-depth, annotations and functional predictions on all variant types and effects. The SG-ADVISER suite includes a de-identification tool, a variant annotation web-server, and a user interface for inheritance and annotation-based filtration. SG-ADVISER allows users with no bioinformatics expertise to manipulate large volumes of variant data with ease--without the need to download large reference databases, install software, or use a command line interface. SG-ADVISER is freely available at genomics.scripps.edu/ADVISER.

SUBMITTER: Pham PH

PROVIDER: S-EPMC4338027 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver.

Pham Phillip H PH Shipman William J WJ Erikson Galina A GA Schork Nicholas J NJ Torkamani Ali A

PloS one 20150223 2

Interpretation of human genomes is a major challenge. We present the Scripps Genome ADVISER (SG-ADVISER) suite, which aims to fill the gap between data generation and genome interpretation by performing holistic, in-depth, annotations and functional predictions on all variant types and effects. The SG-ADVISER suite includes a de-identification tool, a variant annotation web-server, and a user interface for inheritance and annotation-based filtration. SG-ADVISER allows users with no bioinformatic ...[more]

PMID: 25706643

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Project description:BackgroundWhole genome and exome sequencing usually include reads containing mitochondrial DNA (mtDNA). Yet, state-of-the-art pipelines and services for human nuclear genome variant calling and annotation do not handle mitochondrial genome data appropriately. As a consequence, any researcher desiring to add mtDNA variant analysis to their investigations is forced to explore the literature for mtDNA pipelines, evaluate them, and implement their own instance of the desired tool. This task is far from trivial, and can be prohibitive for non-bioinformaticians.ResultsWe have developed SG-ADVISER mtDNA, a web server to facilitate the analysis and interpretation of mtDNA genomic data coming from next generation sequencing (NGS) experiments. The server was built in the context of our SG-ADVISER framework and on top of the MtoolBox platform (Calabrese et al., Bioinformatics 30(21):3115-3117, 2014), and includes most of its functionalities (i.e., assembly of mitochondrial genomes, heteroplasmic fractions, haplogroup assignment, functional and prioritization analysis of mitochondrial variants) as well as a back-end and a front-end interface. The server has been tested with unpublished data from 200 individuals of a healthy aging cohort (Erikson et al., Cell 165(4):1002-1011, 2016) and their data is made publicly available here along with a preliminary analysis of the variants. We observed that individuals over ~90 years old carried low levels of heteroplasmic variants in their genomes.ConclusionsSG-ADVISER mtDNA is a fast and functional tool that allows for variant calling and annotation of human mtDNA data coming from NGS experiments. The server was built with simplicity in mind, and builds on our own experience in interpreting mtDNA variants in the context of sudden death and rare diseases. Our objective is to provide an interface for non-bioinformaticians aiming to acquire (or contrast) mtDNA annotations via MToolBox. SG-ADVISER web server is freely available to all users at https://genomics.scripps.edu/mtdna .

Project description:The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)1, we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.

Dataset Information

Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver.

Publications

Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver.

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