Computational biology and bioinformatics

  • Article
    | Open Access

    The design of protein assemblies is a major thrust for biomolecular engineering and nanobiotechnology. Here the authors demonstrate a general mechanism for designing allosteric macromolecular assemblies and showcase a proof of concept for engineered allosteric protein assembly.

    • Luis A. Campos
    • , Rajendra Sharma
    • , Sara Alvira
    • , Federico M. Ruiz
    • , Beatriz Ibarra-Molero
    • , Mourad Sadqi
    • , Carlos Alfonso
    • , Germán Rivas
    • , Jose M. Sanchez-Ruiz
    • , Antonio Romero Garrido
    • , José M. Valpuesta
    •  & Victor Muñoz
  • Article
    | Open Access

    Common Fragile Sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Here the authors use genome-wide and single cell techniques to assess how replication timing and transcriptional activity correlate with genome stability.

    • Olivier Brison
    • , Sami El-Hilali
    • , Dana Azar
    • , Stéphane Koundrioukoff
    • , Mélanie Schmidt
    • , Viola Nähse
    • , Yan Jaszczyszyn
    • , Anne-Marie Lachages
    • , Bernard Dutrillaux
    • , Claude Thermes
    • , Michelle Debatisse
    •  & Chun-Long Chen
  • Article
    | Open Access

    Magnetic resonance imaging (MRI) is widely used to study the rat brain. Here, the authors provide standardized MRI brain templates and descriptive atlases for the rat, incorporating both structural and functional MRI data, along with associated resources.

    • D. A. Barrière
    • , R. Magalhães
    • , A. Novais
    • , P. Marques
    • , E. Selingue
    • , F. Geffroy
    • , F. Marques
    • , J. Cerqueira
    • , J. C. Sousa
    • , F. Boumezbeur
    • , M. Bottlaender
    • , T. M. Jay
    • , A. Cachia
    • , N. Sousa
    •  & S. Mériaux
  • Article
    | Open Access

    Glioblastoma cells are known to be able to adapt easily to different environments. The authors study the dynamic adaptation of glioblastoma cells to the heterogenous brain tumor microenvironment, showing that tumor cells demonstrate varying plasticity of their transcriptomic profiles and an ability to survive new stimuli, in part, by propagating stochastic perturbations over their gene-regulatory network.

    • Orieta Celiku
    • , Mark R. Gilbert
    •  & Orit Lavi
  • Article
    | Open Access

    Single-molecule in vitro assays require dedicated confocal microscopes equipped with fluorescence correlation spectroscopy (FCS) modules. Here the authors present a compact, cheap and open-source 3D-printed confocal microscope for single photon counting and FCS measurements, and use it to detect α-synuclein aggregation.

    • James W. P. Brown
    • , Arnaud Bauer
    • , Mark E Polinkovsky
    • , Akshay Bhumkar
    • , Dominic J. B. Hunter
    • , Katharina Gaus
    • , Emma Sierecki
    •  & Yann Gambin
  • Article
    | Open Access

    While the cellular recycling process autophagy has been linked to aging, the impact of selective autophagy on lifespan remains unclear. Here Kumsta et al. show that the autophagy receptor p62/SQSTM1 is required for hormetic benefits and p62/SQSTM1 overexpression is sufficient to extend C. elegans lifespan and improve proteostasis.

    • Caroline Kumsta
    • , Jessica T. Chang
    • , Reina Lee
    • , Ee Phie Tan
    • , Yongzhi Yang
    • , Rute Loureiro
    • , Elizabeth H. Choy
    • , Shaun H. Y. Lim
    • , Isabel Saez
    • , Alexander Springhorn
    • , Thorsten Hoppe
    • , David Vilchez
    •  & Malene Hansen
  • Article
    | Open Access

    Multiple sequence alignments of proteins carry information about evolution, the protein’s fitness landscape and its stability in the face of mutations. Here, the authors demonstrate the utility of latent space models learned using variational autoencoders to infer these properties from sequences.

    • Xinqiang Ding
    • , Zhengting Zou
    •  & Charles L. Brooks III
  • Article
    | Open Access

    There are many examples of cell populations exhibiting density-dependent collective oscillatory behaviour. Here, the authors show that sustained collective oscillations emerge when cells anticipate variation in signal and attempt to amplify it, a property that can be linked to adaptation.

    • Shou-Wen Wang
    •  & Lei-Han Tang
  • Article
    | Open Access

    Increasing evidence supports the existence of ordered nanodomains (or rafts) in cholesterol rich cell membranes. Here authors present molecular dynamics simulations and EPR experiments to monitor permeation of oxygen and water through membranes in the liquid ordered and liquid disordered phases.

    • An Ghysels
    • , Andreas Krämer
    • , Richard M. Venable
    • , Walter E. Teague Jr
    • , Edward Lyman
    • , Klaus Gawrisch
    •  & Richard W. Pastor
  • Article
    | Open Access

    Existing computational approaches to predict long-range regulatory interactions do not fully exploit high-resolution Hi-C datasets. Here the authors present a Random Forests regression-based approach to predict high-resolution Hi-C counts using one-dimensional regulatory genomic signals.

    • Shilu Zhang
    • , Deborah Chasman
    • , Sara Knaack
    •  & Sushmita Roy
  • Article
    | Open Access

    Stem-cell-specific genes regulate processes such as maintenance, identity and/or division. Here, the authors show that in the Arabidopsis root TCX2, a gene expressed across different stem cell populations (a stem-cell-ubiquitous gene), controls division and identity by regulating stem-cell-type-specific networks.

    • Natalie M. Clark
    • , Eli Buckner
    • , Adam P. Fisher
    • , Emily C. Nelson
    • , Thomas T. Nguyen
    • , Abigail R. Simmons
    • , Maria A. de Luis Balaguer
    • , Tiara Butler-Smith
    • , Parnell J. Sheldon
    • , Dominique C. Bergmann
    • , Cranos M. Williams
    •  & Rossangela Sozzani
  • Article
    | Open Access

    Intermediate transitions between epithelial and mesenchymal states are associated with tumor progression. Here using mass cytometry, Plevritis and colleagues develop a computational framework to resolve and map these trajectories in lung cancer cells and clinical specimens.

    • Loukia G. Karacosta
    • , Benedict Anchang
    • , Nikolaos Ignatiadis
    • , Samuel C. Kimmey
    • , Jalen A. Benson
    • , Joseph B. Shrager
    • , Robert Tibshirani
    • , Sean C. Bendall
    •  & Sylvia K. Plevritis
  • Article
    | Open Access

    Compared to single nucleotide variants and short indels, structural variants (SVs) are often more challenging to detect using high-throughput sequencing based methods. Here, the authors develop LinkedSV, a computational tool for SV detection using linked-read exome and genome sequencing data.

    • Li Fang
    • , Charlly Kao
    • , Michael V. Gonzalez
    • , Fernanda A. Mafra
    • , Renata Pellegrino da Silva
    • , Mingyao Li
    • , Sören-Sebastian Wenzel
    • , Katharina Wimmer
    • , Hakon Hakonarson
    •  & Kai Wang
  • Article
    | Open Access

    Mechanistic insight into the regulation of transcriptional modules remains scarce. Here, the authors identify statistically independent gene sets by applying independent component analysis to a high-quality E. coli RNA-seq data compendium and find that most gene sets represent the effects of specific transcriptional regulators.

    • Anand V. Sastry
    • , Ye Gao
    • , Richard Szubin
    • , Ying Hefner
    • , Sibei Xu
    • , Donghyuk Kim
    • , Kumari Sonal Choudhary
    • , Laurence Yang
    • , Zachary A. King
    •  & Bernhard O. Palsson
  • Article
    | Open Access

    CRISPR-Cas systems have well characterized, modular structures. Here the authors use that architecture to design a Cas12a library of 560 synthetic chimeras, with altered PAM preferences and specificities.

    • R. M. Liu
    • , L. L. Liang
    • , E. Freed
    • , H. Chang
    • , E. Oh
    • , Z. Y. Liu
    • , A. Garst
    • , C. A. Eckert
    •  & R. T. Gill
  • Article
    | Open Access

    Many approaches exist to process data from individual imaging modalities, but integrating them is challenging. The authors develop an automated resource that enables co-registered network- and tract-level analysis of macroscopic in-vivo imaging and microscopic imaging of cleared tissue.

    • Maged Goubran
    • , Christoph Leuze
    • , Brian Hsueh
    • , Markus Aswendt
    • , Li Ye
    • , Qiyuan Tian
    • , Michelle Y. Cheng
    • , Ailey Crow
    • , Gary K. Steinberg
    • , Jennifer A. McNab
    • , Karl Deisseroth
    •  & Michael Zeineh
  • Article
    | Open Access

    Sequencing cancer genomes reveals low frequency novel somatic variants without known function. Here, the authors leverage statistical methodology from the fields of computational linguistics and ecology to highlight the potentially important signals harboured by these novel variants that are often dismissed.

    • Saptarshi Chakraborty
    • , Arshi Arora
    • , Colin B. Begg
    •  & Ronglai Shen
  • Article
    | Open Access

    Disease heritability and genetic correlations between traits depend on genetics, the environment and their interaction. Here, Jia et al. compute disease prevalence curves and disease embeddings from electronic health records and impute heritability for hundreds of diseases and genetic correlations for thousands of disease pairs.

    • Gengjie Jia
    • , Yu Li
    • , Hanxin Zhang
    • , Ishanu Chattopadhyay
    • , Anders Boeck Jensen
    • , David R. Blair
    • , Lea Davis
    • , Peter N. Robinson
    • , Torsten Dahlén
    • , Søren Brunak
    • , Mikael Benson
    • , Gustaf Edgren
    • , Nancy J. Cox
    • , Xin Gao
    •  & Andrey Rzhetsky
  • Article
    | Open Access

    One of the underlying causes of aging is the accumulation of senescent cells, but their turnover rates and dynamics during ageing are unknown. Here the authors measure and model senescent cell production and removal and explore implications for mortality.

    • Omer Karin
    • , Amit Agrawal
    • , Ziv Porat
    • , Valery Krizhanovsky
    •  & Uri Alon
  • Article
    | Open Access

    Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.

    • Chiara Ghezzi
    • , Alicia Wong
    • , Bao Ying Chen
    • , Bernard Ribalet
    • , Robert Damoiseaux
    •  & Peter M. Clark
  • Article
    | Open Access

    Viral genomic DNA is often modified to evade the host bacterial restriction system. Here the authors identified 2′-deoxy-7-deazaguanine modifications on phage DNA by comparative genomics and experimental validation, showing their role in genome protection.

    • Geoffrey Hutinet
    • , Witold Kot
    • , Liang Cui
    • , Roman Hillebrand
    • , Seetharamsingh Balamkundu
    • , Shanmugavel Gnanakalai
    • , Ramesh Neelakandan
    • , Alexander B. Carstens
    • , Chuan Fa Lui
    • , Denise Tremblay
    • , Deborah Jacobs-Sera
    • , Mandana Sassanfar
    • , Yan-Jiun Lee
    • , Peter Weigele
    • , Sylvain Moineau
    • , Graham F. Hatfull
    • , Peter C. Dedon
    • , Lars H. Hansen
    •  & Valérie de Crécy-Lagard
  • Article
    | Open Access

    How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.

    • Ayshwarya Subramanian
    • , Eriene-Heidi Sidhom
    • , Maheswarareddy Emani
    • , Katherine Vernon
    • , Nareh Sahakian
    • , Yiming Zhou
    • , Maria Kost-Alimova
    • , Michal Slyper
    • , Julia Waldman
    • , Danielle Dionne
    • , Lan T. Nguyen
    • , Astrid Weins
    • , Jamie L. Marshall
    • , Orit Rosenblatt-Rosen
    • , Aviv Regev
    •  & Anna Greka
  • Article
    | Open Access

    One measurement of tuberculosis vaccine efficacy in clinical trials is prevention of disease, but different mechanisms can underlie disease prevention. Here, the authors develop a mathematical model that allows to identify mechanisms of action of a vaccine preventing TB disease.

    • Mario Tovar
    • , Sergio Arregui
    • , Dessislava Marinova
    • , Carlos Martín
    • , Joaquín Sanz
    •  & Yamir Moreno
  • Article
    | Open Access

    Visualisation tools that use dimensionality reduction, such as t-SNE, provide poor visualisation on large data sets of millions of observations. Here the authors present opt-SNE, that automatically finds data set-tailored parameters for t-SNE to optimise visualisation and improve analysis.

    • Anna C. Belkina
    • , Christopher O. Ciccolella
    • , Rina Anno
    • , Richard Halpert
    • , Josef Spidlen
    •  & Jennifer E. Snyder-Cappione
  • Article
    | Open Access

    Haplotype information inferred by phasing is useful in genetic and genomic analysis. Here, the authors develop SHAPEIT4, a phasing method that exhibits sub-linear running time, provides accurate haplotypes and enables integration of external phasing information.

    • Olivier Delaneau
    • , Jean-François Zagury
    • , Matthew R. Robinson
    • , Jonathan L. Marchini
    •  & Emmanouil T. Dermitzakis
  • Article
    | Open Access

    Identification of clinically relevant gene expression signatures for cancer stratification remains challenging. Here, the authors introduce a flexible nonlinear signal superposition model that enables dissection of large gene expression data sets into signatures and extraction of gene interactions.

    • Michael Grau
    • , Georg Lenz
    •  & Peter Lenz
  • Article
    | Open Access

    The limited availability of high-resolution 3D RNA structures for model training limits RNA secondary structure prediction. Here, the authors overcome this challenge by pre-training a DNN on a large set of predicted RNA structures and using transfer learning with high-resolution structures.

    • Jaswinder Singh
    • , Jack Hanson
    • , Kuldip Paliwal
    •  & Yaoqi Zhou
  • Article
    | Open Access

    Structural variants may be omitted in sequence analysis despite their importance in genome variation and phenotypic impact. Here the authors present GraphTyper2, which uses pangenome graphs to genotype structural variants using short-reads and can be applied in large-scale sequencing studies.

    • Hannes P. Eggertsson
    • , Snaedis Kristmundsdottir
    • , Doruk Beyter
    • , Hakon Jonsson
    • , Astros Skuladottir
    • , Marteinn T. Hardarson
    • , Daniel F. Gudbjartsson
    • , Kari Stefansson
    • , Bjarni V. Halldorsson
    •  & Pall Melsted
  • Article
    | Open Access

    Machine learning algorithms can be trained to estimate age from brain structural MRI. Here, the authors introduce a new deep-learning-based age prediction approach, and then carry out a GWAS of the difference between predicted and chronological age, revealing two associated variants.

    • B. A. Jonsson
    • , G. Bjornsdottir
    • , T. E. Thorgeirsson
    • , L. M. Ellingsen
    • , G. Bragi Walters
    • , D. F. Gudbjartsson
    • , H. Stefansson
    • , K. Stefansson
    •  & M. O. Ulfarsson
  • Article
    | Open Access

    There is disproportionally high cancer prevalence in males. Here, the authors analyse the tumour suppressor p53 in sporadic cancers, highlighting a higher incidence of its mutation in males. Males are further disadvantaged by a failure to shield against the expression of damaged X-linked genes in p53-networks. These factors likely contribute to sex-disparity.

    • Sue Haupt
    • , Franco Caramia
    • , Alan Herschtal
    • , Thierry Soussi
    • , Guillermina Lozano
    • , Hu Chen
    • , Han Liang
    • , Terence P. Speed
    •  & Ygal Haupt
  • Article
    | Open Access

    In vivo laser ablation of dendrites in single L2/3 pyramidal neurons reveals that neuronal orientation tuning in V1 is robust to loss of dendritic input. Orientation tuning functions remain unchanged following apical dendrite ablation and change only slightly upon loss of two primary basal dendrites.

    • Jiyoung Park
    • , Athanasia Papoutsi
    • , Ryan T. Ash
    • , Miguel A. Marin
    • , Panayiota Poirazi
    •  & Stelios M. Smirnakis
  • Article
    | Open Access

    Reconstructing system dynamics on complex high-dimensional energy landscapes from static experimental snapshots remains challenging. Here, the authors introduce a framework to infer the essential dynamics of physical and biological systems without need for time-dependent measurements.

    • Philip Pearce
    • , Francis G. Woodhouse
    • , Aden Forrow
    • , Ashley Kelly
    • , Halim Kusumaatmaja
    •  & Jörn Dunkel
  • Article
    | Open Access

    In Drosophila, dosage compensation involves a twofold transcriptional upregulation of the single male chromosome X. Here the authors show that global conformational differences are specifically present in the male X chromosome and detectable using Hi-C data, indicating that dosage compensation affects global chromosome structure.

    • Koustav Pal
    • , Mattia Forcato
    • , Daniel Jost
    • , Thomas Sexton
    • , Cédric Vaillant
    • , Elisa Salviato
    • , Emilia Maria Cristina Mazza
    • , Enrico Lugli
    • , Giacomo Cavalli
    •  & Francesco Ferrari
  • Article
    | Open Access

    Interference from overlapping memories can cause forgetting. Here, the authors show using fMRI decoding approaches that spontaneous reactivation of older memories during new encoding leads to integration, and less interference, between overlapping items.

    • Avi J. H. Chanales
    • , Nicole M. Dudukovic
    • , Franziska R. Richter
    •  & Brice A. Kuhl
  • Article
    | Open Access

    The endoplasmic reticulum (ER) is an intracellular network characterized by highly dynamic behavior whose control mechanisms are unclear. Here, the authors show that the ER-membrane protein Reticulon (Rtnl1) can constrict ER bilayers and lead to ER fission.

    • Javier Espadas
    • , Diana Pendin
    • , Rebeca Bocanegra
    • , Artur Escalada
    • , Giulia Misticoni
    • , Tatiana Trevisan
    • , Ariana Velasco del Olmo
    • , Aldo Montagna
    • , Sergio Bova
    • , Borja Ibarra
    • , Peter I. Kuzmin
    • , Pavel V. Bashkirov
    • , Anna V. Shnyrova
    • , Vadim A. Frolov
    •  & Andrea Daga
  • Article
    | Open Access

    Genome sequencing is being widely adopted for diagnosis of genetic diseases, but identifying the causal variants remains challenging. Here, the authors introduce a tool that incorporates tissue-specific gene expression data into predicting variant pathogenicity, improving accuracy.

    • Denise Anderson
    • , Gareth Baynam
    • , Jenefer M. Blackwell
    •  & Timo Lassmann
  • Article
    | Open Access

    Whole genome sequencing (WGS) holds promise to solve a subset of Mendelian disease cases for which exome sequencing did not provide a genetic diagnosis. Here, Wells et al. report a supervised machine learning model trained on functional, mutational and structural features for rank-scoring and interpreting variants in non-coding regions from WGS.

    • Alex Wells
    • , David Heckerman
    • , Ali Torkamani
    • , Li Yin
    • , Jonathan Sebat
    • , Bing Ren
    • , Amalio Telenti
    •  & Julia di Iulio
  • Article
    | Open Access

    Transcription initiation involves the coordinated assembly and activity of large multimeric complexes. Here the authors report on the chaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes in fission yeast, providing insight into the de novo assembly of transcriptional complexes and the contribution of dedicated chaperones to this process.

    • Alberto Elías-Villalobos
    • , Damien Toullec
    • , Céline Faux
    • , Martial Séveno
    •  & Dominique Helmlinger
  • Article
    | Open Access

    Drug target identification is a crucial step in drug development. Here, the authors introduce a Bayesian machine learning framework that integrates multiple data types to predict the targets of small molecules, enabling identification of a new set of microtubule inhibitors and the target of the anti-cancer molecule ONC201.

    • Neel S. Madhukar
    • , Prashant K. Khade
    • , Linda Huang
    • , Kaitlyn Gayvert
    • , Giuseppe Galletti
    • , Martin Stogniew
    • , Joshua E. Allen
    • , Paraskevi Giannakakou
    •  & Olivier Elemento
  • Article
    | Open Access

    People are able to mentally time travel to distant memories and reflect on the consequences of those past events. Here, the authors show how a mechanism that connects learning from delayed rewards with memory retrieval can enable AI agents to discover links between past events to help decide better courses of action in the future.

    • Chia-Chun Hung
    • , Timothy Lillicrap
    • , Josh Abramson
    • , Yan Wu
    • , Mehdi Mirza
    • , Federico Carnevale
    • , Arun Ahuja
    •  & Greg Wayne
  • Article
    | Open Access

    Metabolic syndrome is characterized by complex phenotypes that increases the risk of cardiovascular disease and type 2 diabetes. Here the authors’ integrative network analysis suggests BTK inhibitor ibrutinib to be a promising treatment through its obesity-associated inflammation lowering effect.

    • Karla Misselbeck
    • , Silvia Parolo
    • , Francesca Lorenzini
    • , Valeria Savoca
    • , Lorena Leonardelli
    • , Pranami Bora
    • , Melissa J. Morine
    • , Maria Caterina Mione
    • , Enrico Domenici
    •  & Corrado Priami
  • Article
    | Open Access

    Imaging heart development is challenging due to constant tissue movement and changing physical landmarks. Here the authors present an algorithm capable of maintaining phase-locked imaging throughout a 24 hour timespan, enabling long term timelapse imaging studies of zebrafish heart development, repair and regeneration.

    • Jonathan M. Taylor
    • , Carl J. Nelson
    • , Finnius A. Bruton
    • , Aryan K. Baghbadrani
    • , Charlotte Buckley
    • , Carl S. Tucker
    • , Adriano G. Rossi
    • , John J. Mullins
    •  & Martin A. Denvir
  • Article
    | Open Access

    Allele-specific expression at single-cell resolution can reveal stochastic and dynamic features of gene expression in greater detail. The authors propose scBASE, a soft zero-and-one inflated model that improves estimation of cellular allelic proportions by pooling information across cells.

    • Kwangbom Choi
    • , Narayanan Raghupathy
    •  & Gary A. Churchill
  • Article
    | Open Access

    Our understanding of the mechanisms of drug interactions remains limited. Here the authors introduce a framework to study how complex cellular perturbations induced by different drugs affect each other in morphological feature space.

    • Michael Caldera
    • , Felix Müller
    • , Isabel Kaltenbrunner
    • , Marco P. Licciardello
    • , Charles-Hugues Lardeau
    • , Stefan Kubicek
    •  & Jörg Menche
  • Article
    | Open Access

    The clonal origins of metastases and the timing of dissemination remains an open question for most cancer types. Using primary and metastatic samples taken from one colorectal cancer patient, Alves et al. use Bayesian phylogenetics to reconstruct the history of metastasis.

    • Joao M. Alves
    • , Sonia Prado-López
    • , José Manuel Cameselle-Teijeiro
    •  & David Posada
  • Article
    | Open Access

    N1-methyladenosine (m1A) was recently reported as a new mRNA modification but its prevalence has been controversial. Here the authors showed that m1A, if present in mRNA, is at very low stoichiometry, with the notable exception of MT-ND5. Further, they show that the previously reported enrichment of m1A near the start of transcripts are false-positive identifications due to cross-reactivity of the commonly used m1A antibody with mRNA caps.

    • Anya V. Grozhik
    • , Anthony O. Olarerin-George
    • , Miriam Sindelar
    • , Xing Li
    • , Steven S. Gross
    •  & Samie R. Jaffrey