390 research outputs found

    Next-generation human genetics

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    Genome interrupted: sequencing of prostate cancer reveals the importance of chromosomal rearrangements

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    A recent study involving whole genome sequencing of seven prostate cancers has provided the first comprehensive assessment of genomic changes that underlie this common malignancy. Point mutations were found to be infrequent but changes in chromosome structure were common. Rearrangements were linked to chromatin organization and associated with regions involved in transcription factor binding. Novel candidate prostate cancer genes were also identified, highlighting the importance of genome sequencing to identify oncogenic changes that are otherwise invisible to detection

    CADD-Splice—improving genome-wide variant effect prediction using deep learning-derived splice scores

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    Background: Splicing of genomic exons into mRNAs is a critical prerequisite for the accurate synthesis of human proteins. Genetic variants impacting splicing underlie a substantial proportion of genetic disease, but are challenging to identify beyond those occurring at donor and acceptor dinucleotides. To address this, various methods aim to predict variant effects on splicing. Recently, deep neural networks (DNNs) have been shown to achieve better results in predicting splice variants than other strategies. Methods: It has been unclear how best to integrate such process-specific scores into genome-wide variant effect predictors. Here, we use a recently published experimental data set to compare several machine learning methods that score variant effects on splicing. We integrate the best of those approaches into general variant effect prediction models and observe the effect on classification of known pathogenic variants. Results: We integrate two specialized splicing scores into CADD (Combined Annotation Dependent Depletion; cadd.gs.washington.edu), a widely used tool for genome-wide variant effect prediction that we previously developed to weight and integrate diverse collections of genomic annotations. With this new model, CADD-Splice, we show that inclusion of splicing DNN effect scores substantially improves predictions across multiple variant categories, without compromising overall performance. Conclusions: While splice effect scores show superior performance on splice variants, specialized predictors cannot compete with other variant scores in general variant interpretation, as the latter account for nonsense and missense effects that do not alter splicing. Although only shown here for splice scores, we believe that the applied approach will generalize to other specific molecular processes, providing a path for the further improvement of genome-wide variant effect prediction

    Smash and DASH with Cas9

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