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      Using deep learning to model the hierarchical structure and function of a cell

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          Abstract

          Although artificial neural networks simulate a variety of human functions, their internal structures are hard to interpret. In the life sciences, extensive knowledge of cell biology provides an opportunity to design visible neural networks (VNNs) which couple the model’s inner workings to those of real systems. Here we develop DCell, a VNN embedded in the hierarchical structure of 2526 subsystems comprising a eukaryotic cell ( http://d-cell.ucsd.edu/). Trained on several million genotypes, DCell simulates cellular growth nearly as accurately as laboratory observations. During simulation, genotypes induce patterns of subsystem activities, enabling in-silico investigations of the molecular mechanisms underlying genotype-phenotype associations. These mechanisms can be validated and many are unexpected; some are governed by Boolean logic. Cumulatively, 80% of the importance for growth prediction is captured by 484 subsystems (21%), reflecting the emergence of a complex phenotype. DCell provides a foundation for decoding the genetics of disease, drug resistance, and synthetic life.

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          Most cited references31

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          The genetic landscape of a cell.

          A genome-scale genetic interaction map was constructed by examining 5.4 million gene-gene pairs for synthetic genetic interactions, generating quantitative genetic interaction profiles for approximately 75% of all genes in the budding yeast, Saccharomyces cerevisiae. A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function. The global network identifies functional cross-connections between all bioprocesses, mapping a cellular wiring diagram of pleiotropy. Genetic interaction degree correlated with a number of different gene attributes, which may be informative about genetic network hubs in other organisms. We also demonstrate that extensive and unbiased mapping of the genetic landscape provides a key for interpretation of chemical-genetic interactions and drug target identification.
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            Learning hierarchical features for scene labeling.

            Scene labeling consists of labeling each pixel in an image with the category of the object it belongs to. We propose a method that uses a multiscale convolutional network trained from raw pixels to extract dense feature vectors that encode regions of multiple sizes centered on each pixel. The method alleviates the need for engineered features, and produces a powerful representation that captures texture, shape, and contextual information. We report results using multiple postprocessing methods to produce the final labeling. Among those, we propose a technique to automatically retrieve, from a pool of segmentation components, an optimal set of components that best explain the scene; these components are arbitrary, for example, they can be taken from a segmentation tree or from any family of oversegmentations. The system yields record accuracies on the SIFT Flow dataset (33 classes) and the Barcelona dataset (170 classes) and near-record accuracy on Stanford background dataset (eight classes), while being an order of magnitude faster than competing approaches, producing a $(320\times 240)$ image labeling in less than a second, including feature extraction.
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              A global genetic interaction network maps a wiring diagram of cellular function.

              We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.
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                Author and article information

                Journal
                101215604
                32338
                Nat Methods
                Nat. Methods
                Nature methods
                1548-7091
                1548-7105
                8 February 2018
                05 March 2018
                April 2018
                05 September 2018
                : 15
                : 4
                : 290-298
                Affiliations
                [1 ]Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
                [2 ]Program in Bioinformatics, University of California San Diego, La Jolla CA 92093, USA
                [3 ]Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
                [4 ]Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
                Author notes
                [* ]Correspondence to Trey Ideker at tideker@ 123456ucsd.edu
                [†]

                These authors contributed equally to this manuscript

                Article
                NIHMS941151
                10.1038/nmeth.4627
                5882547
                29505029
                d2491830-f63d-421e-8f8e-646932fd1e14

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                Life sciences
                Life sciences

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