Interpreting variants, especially noncoding ones, in the increasing
number of personal genomes is challenging. We used patterns of polymorphisms in
functionally annotated regions in 1092 humans to identify deleterious variants;
then we experimentally validated candidates. We analyzed both coding and
noncoding regions, with the former corroborating the latter. We found regions
particularly sensitive to mutations (“ultrasensitive”) and
variants that are disruptive because of mechanistic effects on
transcription-factor binding (that is, “motif-breakers”). We also
found variants in regions with higher network centrality tend to be deleterious.
Insertions and deletions followed a similar pattern to single-nucleotide
variants, with some notable exceptions (e.g., certain deletions and enhancers).
On the basis of these patterns, we developed a computational tool (FunSeq),
whose application to ~90 cancer genomes reveals nearly a hundred
candidate noncoding drivers.
Visualizations of biomolecular networks assist in systems-level data exploration in many cellular processes. Data generated from high-throughput experiments increasingly inform these networks, yet current tools do not adequately scale with concomitant increase in their size and complexity. We present an open source software platform, interactome-CAVE (iCAVE), for visualizing large and complex biomolecular interaction networks in 3D. Users can explore networks (i) in 3D using a desktop, (ii) in stereoscopic 3D using 3D-vision glasses and a desktop, or (iii) in immersive 3D within a CAVE environment. iCAVE introduces 3D extensions of known 2D network layout, clustering, and edge-bundling algorithms, as well as new 3D network layout algorithms. Furthermore, users can simultaneously query several built-in databases within iCAVE for network generation or visualize their own networks (e.g., disease, drug, protein, metabolite). iCAVE has modular structure that allows rapid development by addition of algorithms, datasets, or features without affecting other parts of the code. Overall, iCAVE is the first freely available open source tool that enables 3D (optionally stereoscopic or immersive) visualizations of complex, dense, or multi-layered biomolecular networks. While primarily designed for researchers utilizing biomolecular networks, iCAVE can assist researchers in any field.
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