Computational biology and bioinformatics articles within Nature Communications

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  • Article
    | Open Access

    Large-scale metabolic models of organisms from microbes to mammals can provide great insight into cellular function, but their analysis remains challenging. Here, the authors provide an approximate analytic method to estimate the feasible solution space for the flux vectors of metabolic networks, enabling more accurate analysis under a wide range of conditions of interest.

    • Alfredo Braunstein
    • , Anna Paola Muntoni
    •  & Andrea Pagnani

  • Article
    | Open Access

    While rare cell subpopulations frequently make the difference between health and disease, their detection remains a challenge. Here, the authors devise CellCnn, a representation learning approach to detecting such rare cell populations from high-dimensional single cell data, and, among other examples, demonstrate its capacity for detecting rare leukaemic blasts in minimal residual disease.

    • Eirini Arvaniti
    •  & Manfred Claassen

  • Article
    | Open Access

    Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.

    • Kuan-lin Huang
    • , Shunqiang Li
    •  & Li Ding

  • Article
    | Open Access

    The gene-battery model posits transposable elements (TEs) may becis-regulatory elements to control gene expression. Here, mouse-specific TEs are shown as binding sites for multiple collaborating transcription factors in embryonic stem cells, and act as cis-regulatory modules in synergistic fashion.

    • Vasavi Sundaram
    • , Mayank N. K. Choudhary
    •  & Ting Wang

  • Article
    | Open Access

    The three-dimensional architecture of genome-reduced bacteria is poorly understood. Here the authors combine Hi-C with super-resolution microscopy inMycoplasma pneumoniaeand provide evidence of how supercoiling and local organization influences gene regulation.

    • Marie Trussart
    • , Eva Yus
    •  & Luís Serrano

  • Article
    | Open Access

    The TIM barrel fold is an evolutionarily conserved motif found in proteins with a variety of enzymatic functions. Here the authors explore the fitness landscape of the TIM barrel protein IGPS and uncover evolutionary constraints on both sequence and structure, accompanied by long range allosteric interactions.

    • Yvonne H. Chan
    • , Sergey V. Venev
    •  & C. Robert Matthews

  • Article
    | Open Access

    Assembling genomes using currently available computational methods can be time consuming. Here, Coin and colleagues describe a bioinformatics tool named npScarf that can scaffold and complete an existing short read assembly in real-time using nanopore sequencing.

    • Minh Duc Cao
    • , Son Hoang Nguyen
    •  & Lachlan J. M. Coin

  • Article
    | Open Access

    Long noncoding-RNAs have been linked to hepatocellular carcinoma (HCC) and some can be used as prognostic markers. Here the authors, by analysing RNA-seq in 60 clinical samples from 20 patients, provide a resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis.

    • Yang Yang
    • , Lei Chen
    •  & Zhi John Lu

  • Article
    | Open Access

    Sequencing initiatives have detected multiple types of mutations in cancer. Here the authors, analysing enhancer-targeting sequence data, show that small insertions in transcriptional enhancers are frequently found near oncogenes, and demonstrate how one mutation deregulates expression of LMO2 in leukemia cells.

    • Brian J. Abraham
    • , Denes Hnisz
    •  & Richard A. Young

  • Article
    | Open Access

    Single-cell RNA sequencing has enabled great advances in understanding developmental biology but reconstructing cellular lineages from this data remains challenging. Here the authors develop an algorithm,dpath, which models the lineage relationships of underlying single cells based on single cell RNA seq data and apply it to study lineage progression of Etv2 expressing progenitors.

    • Wuming Gong
    • , Tara L. Rasmussen
    •  & Daniel J. Garry

  • Article
    | Open Access

    The rat is a widely-used model for human biology, but we must be aware of metabolic differences. Here, the authors reconstruct the genome-scale metabolic network of the rat, and after reconciling it with an improved human metabolic model, demonstrate the power of the models to integrate toxicogenomics data, providing species-specific biomarker predictions in response to a panel of drugs.

    • Edik M. Blais
    • , Kristopher D. Rawls
    •  & Jason A. Papin

  • Article
    | Open Access

    Translocation of the tRNA on the ribosome is associated with large-scale molecular movements of the ribosomal L1 stalk. Here the authors identify the key determinants that allow these dramatic movements, and suggest they represent general strategies used to enable large-scale motions in functional RNAs.

    • Srividya Mohan
    •  & Harry F Noller

  • Article
    | Open Access

    Genetic data has led to great advances in our understanding of human evolution and dispersal, but information on more recent events is limited. Here, the authors analyse genotypes from 770,000 US individuals to map the fine-scale population structure of North America after European settlement.

    • Eunjung Han
    • , Peter Carbonetto
    •  & Catherine A. Ball

  • Article
    | Open Access

    Tumours frequently metastasize to multiple anatomical sites and understanding how these different metastases evolve may be important for therapy. Here, the authors develop a method—Treeomics—that can construct phylogenies from multiple metastases from next-generation sequencing data.

    • Johannes G. Reiter
    • , Alvin P. Makohon-Moore
    •  & Martin A. Nowak

  • Article
    | Open Access

    Fission yeastSchizosaccharomyces pombe has diverse traits. Jeffares et al. characterize large copy number variations (CNVs) and rearrangements in S. pombe, and show that CNVs are transient with effects on quantitative traits and gene expression, whereas rearrangements influence intrinsic reproductive isolation.

    • Daniel C. Jeffares
    • , Clemency Jolly
    •  & Fritz J. Sedlazeck

  • Article
    | Open Access

    Embryonic development is a complex process where genetic and biochemical information direct morphogenesis. Here the authors describe MecaGen, an agent-based model and simulation platform of multicellular development designed to allow a quantitative comparison between simulations and real biological data.

    • Julien Delile
    • , Matthieu Herrmann
    •  & René Doursat

  • Article
    | Open Access

    Currently available metagenomic data analysis relies on reference genomes. Here, the authors describe a newde novometagenomic assembly method, metaSort, that constructs bacterial genomes from metagenomic samples to reduce microbial community complexity while increasing genome recovery and assembly.

    • Peifeng Ji
    • , Yanming Zhang
    •  & Fangqing Zhao

  • Article
    | Open Access

    Experience constantly shapes perception, but the neural mechanisms of this rapid plasticity are unclear. Here, Holdgraf et al. record neural activity in the human auditory cortex and show that listening to normal speech elicits rapid plasticity that increases the neural gain for features of sound that are key for speech intelligibility.

    • Christopher R. Holdgraf
    • , Wendy de Heer
    •  & Frédéric E. Theunissen

  • Article
    | Open Access

    Altered DNA methylation is a feature of cancer and between-patient variability is prevalent. Here, the authors integrate data on thousands of human tumours, and find that expression levels of methionine metabolism genes are predictive of methylation features, and that the breakdown of this relationship is a negative prognostic marker.

    • Mahya Mehrmohamadi
    • , Lucas K. Mentch
    •  & Jason W. Locasale

  • Article
    | Open Access

    Formation and reinforcement of E-cadherin-mediated adhesion depends on intracellular trafficking and interactions with the actin cytoskeleton, but how these are coordinated is not known. Here the authors conduct a focused phenotypic screen to identify new pathways regulating cell–cell junction homeostasis.

    • J. C. Erasmus
    • , S. Bruche
    •  & V. M. M. Braga

  • Article
    | Open Access

    Experimenter scoring of cellular imaging data can be biased. This study describes an automated and unbiased multidimensional phenotyping method that relies on machine learning and complex feature computation of imaging data, and identifies weak alleles affecting synapse morphology in live C. elegans.

    • Adriana San-Miguel
    • , Peri T. Kurshan
    •  & Hang Lu

  • Article
    | Open Access

    mTORC1 is known to mediate the signalling activity of amino acids. Here, the authors combine modelling with experiments and find that amino acids acutely stimulate mTORC2, IRS/PI3K and AMPK, independently of mTORC1. AMPK activation through CaMKKβ sustains autophagy under non-starvation conditions.

    • Piero Dalle Pezze
    • , Stefanie Ruf
    •  & Kathrin Thedieck

  • Article
    | Open Access

    Identification of the function of proteins is difficult when there are no structurally or biochemically characterized homologs. Here, the authors present an approach that allows the prediction of nucleic-acid binding proteins based on sequence alone, and they are able to experimentally validate their method.

    • Sapir Peled
    • , Olga Leiderman
    •  & Yanay Ofran

  • Article
    | Open Access

    Early embryonic cell fate and lineage specification is tightly regulated in the preimplantation mammalian embryo. Here, the authors quantitatively examine the ratio of epiblast to primitive endoderm lineages in the blastocyst and show composition of the inner cell mass is conserved, independent of its size.

    • Néstor Saiz
    • , Kiah M. Williams
    •  & Anna-Katerina Hadjantonakis

  • Article
    | Open Access

    Protein repeats may be considered a paradox, being evolutionarily conserved yet also hotspots of protein evolution associated with innovation. Here, the authors use a novel method to show that new repeats undergo rapid divergence within species, but are then fixed and conserved between species.

    • Erez Persi
    • , Yuri I. Wolf
    •  & Eugene V Koonin

  • Article
    | Open Access

    Pathway analysis aids interpretation of large-scale gene expression data, but existing algorithms fall short of providing robust pathway identification. The method introduced here includes coexpression analysis and gene importance estimation to robustly identify relevant pathways and biomarkers for patient stratification.

    • Ivan V. Ozerov
    • , Ksenia V. Lezhnina
    •  & Alex Zhavoronkov

  • Article
    | Open Access

    Currently available methods for phenotype to genetic markers association need to account for population structure. Here, Klasen et al. devise a statistical method called Quantitative Trait Cluster Association Test (QTCAT) that overcomes the need for population structure correction.

    • Jonas R. Klasen
    • , Elke Barbez
    •  & Korbinian Schneeberger

  • Article
    | Open Access

    Knockout collections provide a valuable tool to explore gene function, yet are expensive and technically challenging to produce at a genome-wide scale. Here Baym et al. devise a cost-effective transposon-based method to quickly develop a knockout collection for the electroactive microbe Shewanella oneidensis.

    • Michael Baym
    • , Lev Shaket
    •  & Buz Barstow

  • Article
    | Open Access

    MHCII proteins bind and present both foreign and self-antigens to potentially activate CD4+ T cells via cognate T cell receptors (TCRs) during the adaptive immune response. Here, the authors combine NMR-detected H/D exchange with Markov modelling analysis to shed light on the dynamics of MHCII peptide exchange.

    • Marek Wieczorek
    • , Jana Sticht
    •  & Christian Freund

  • Article
    | Open Access

    Multi-layered neural architectures that implement learning require elaborate mechanisms for symmetric backpropagation of errors that are biologically implausible. Here the authors propose a simple resolution to this problem of blame assignment that works even with feedback using random synaptic weights.

    • Timothy P. Lillicrap
    • , Daniel Cownden
    •  & Colin J. Akerman

  • Article
    | Open Access

    Accurate estimations of the frequency distribution of rare variants are needed to quantify the discovery power and guide large-scale human sequencing projects. This study describes an algorithm called UnseenEst to estimate the distribution of genetic variations using tens of thousands of exomes.

    • James Zou
    • , Gregory Valiant
    •  & Daniel G. MacArthur

  • Article
    | Open Access

    Early vestibular pathways are thought to code sensory inputs regarding self-motion via changes in firing rate. Here, the authors record from both regular and irregular afferents in macaques, and find both irregular afferents and central neurons also represent self-motion via temporally precise spike timing.

    • Mohsen Jamali
    • , Maurice J. Chacron
    •  & Kathleen E. Cullen

  • Article
    | Open Access

    Absolute concentration robustness (ACR), independence of the steady-state concentration of a molecule from the environment, is difficult to predict. Here, the authors derive a network structure-based necessary condition for ACR, and suggest that metabolites satisfying the condition are prevalent.

    • Jeanne M. O. Eloundou-Mbebi
    • , Anika Küken
    •  & Zoran Nikoloski

  • Article
    | Open Access

    Cancer cells reprogramme their metabolism with unclear clinical implications. Here, the authors analyse the expression of metabolic genes across 20 types of solid cancers and find that clinical aggressiveness, poor survival and metastasis are associated with the deregulation of mitochondrial metabolism.

    • Edoardo Gaude
    •  & Christian Frezza

  • Article
    | Open Access

    Expression of TEM β-lactamase is a predominant mechanism underlying antibiotic resistance in pathogenic Gram-negative bacteria. Here, the authors use Markov state models to reveal and experimentally confirm hidden conformations that determine TEM substrate specificity.

    • Kathryn M. Hart
    • , Chris M. W. Ho
    •  & Gregory R. Bowman

  • Article
    | Open Access

    Retinitis pigmentosa is often caused by mutations that affect the activity or transport of rhodopsin, but some mutations cause disease even though an apparently functional protein is produced. Here the authors show that three such enigmatic mutants retain scramblase activity but are unable to dimerize.

    • Birgit Ploier
    • , Lydia N. Caro
    •  & Anant K. Menon

  • Article
    | Open Access

    Many drugs are small molecule inhibitors of cell signalling. Through single cell analysis and mathematical modelling here the authors show that cell-to-cell variability diversifies inhibition response into digital and analogue, and that the two translate into distinct long-term functional responses.

    • Robert M. Vogel
    • , Amir Erez
    •  & Grégoire Altan-Bonnet

  • Article
    | Open Access

    Building multi-component enzymatic processes in one pot is challenged by the inherent complexity of each biochemical system. Here, the authors use online mass spectroscopy and engineering systems theory to achieve forward design of a ten-membered reaction cascade.

    • Christoph Hold
    • , Sonja Billerbeck
    •  & Sven Panke

  • Article
    | Open Access

    A wealth of gene expression data is publicly available, yet is little use without additional human curation. Ma’ayan and colleagues report a crowdsourcing project involving over 70 participants to annotate and analyse thousands of human disease-related gene expression datasets.

    • Zichen Wang
    • , Caroline D. Monteiro
    •  & Avi Ma’ayan

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