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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,506 bioRxiv papers from 264,779 authors.

Most downloaded bioRxiv papers, all time

in category systems biology

1,626 results found. For more information, click each entry to expand.

1: Revised estimates for the number of human and bacteria cells in the body
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Posted to bioRxiv 06 Jan 2016

Revised estimates for the number of human and bacteria cells in the body
31,949 downloads systems biology

Ron Sender, Shai Fuchs, Ron Milo

We critically revisit the ″common knowledge″ that bacteria outnumber human cells by a ratio of at least 10:1 in the human body. We found the total number of bacteria in the ″reference man″ to be 3.9·1013, with an uncertainty (SEM) of 25%, and a variation over the population (CV) of 52%. For human cells we identify the dominant role of the hematopoietic lineage to the total count of body cells (≈90%), and revise past estimates to reach a total of 3.0·1013 human cells in the 70 kg ″reference man″ with 2% uncertainty and 14% CV. Our analysis updates the widely-cited 10:1 ratio, showing that the number of bacteria in our bodies is actually of the same order as the number of human cells. Indeed, the numbers are similar enough that each defecation event may flip the ratio to favor human cells over bacteria.

2: Thanatotranscriptome: genes actively expressed after organismal death
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Posted to bioRxiv 10 Jun 2016

Thanatotranscriptome: genes actively expressed after organismal death
18,887 downloads systems biology

Alexander E Pozhitkov, Rafik Neme, Tomislav Domazet-Loso, Brian Leroux, Shivani Soni, Diethard Tautz, Peter Anthony Noble

A continuing enigma in the study of biological systems is what happens to highly ordered structures, far from equilibrium, when their regulatory systems suddenly become disabled. In life, genetic and epigenetic networks precisely coordinate the expression of genes -- but in death, it is not known if gene expression diminishes gradually or abruptly stops or if specific genes are involved. We investigated the unwinding of the clock by identifying upregulated genes, assessing their functions, and comparing their transcriptional profiles through postmortem time in two species, mouse and zebrafish. We found transcriptional abundance profiles of 1,063 genes were significantly changed after death of healthy adult animals in a time series spanning from life to 48 or 96 h postmortem. Ordination plots revealed non-random patterns in profiles by time. While most thanatotranscriptome (thanatos-, Greek defn. death) transcript levels increased within 0.5 h postmortem, some increased only at 24 and 48 h. Functional characterization of the most abundant transcripts revealed the following categories: stress, immunity, inflammation, apoptosis, transport, development, epigenetic regulation, and cancer. The increase of transcript abundance was presumably due to thermodynamic and kinetic controls encountered such as the activation of epigenetic modification genes responsible for unraveling the nucleosomes, which enabled transcription of previously silenced genes (e.g., development genes). The fact that new molecules were synthesized at 48 to 96 h postmortem suggests sufficient energy and resources to maintain self-organizing processes. A step-wise shutdown occurs in organismal death that is manifested by the apparent upregulation of genes with various abundance maxima and durations. The results are of significance to transplantology and molecular biology.

3: Statistical physics of liquid brains
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Posted to bioRxiv 26 Nov 2018

Statistical physics of liquid brains
11,179 downloads systems biology

Jordi Pinero, Ricard Sole

Liquid neural networks (or ''liquid brains'') are a widespread class of cognitive living networks characterised by a common feature: the agents (ants or immune cells, for example) move in space. Thus, no fixed, long-term agent-agent connections are maintained, in contrast with standard neural systems. How is this class of systems capable of displaying cognitive abilities, from learning to decision-making? In this paper, the collective dynamics, memory and learning properties of liquid brains is explored under the perspective of statistical physics. Using a comparative approach, we review the generic properties of three large classes of systems, namely: standard neural networks (''solid brains''), ant colonies and the immune system. It is shown that, despite their intrinsic physical differences, these systems share key properties with standard neural systems in terms of formal descriptions, but strongly depart in other ways. On one hand, the attractors found in liquid brains are not always based on connection weights but instead on population abundances. However, some liquid systems use fluctuations in ways similar to those found in cortical networks, suggesting a relevant role of criticality as a way of rapidly reacting to external signals.

4: Deep profiling of mouse splenic architecture with CODEX multiplexed imaging.
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Posted to bioRxiv 20 Oct 2017

Deep profiling of mouse splenic architecture with CODEX multiplexed imaging.
6,416 downloads systems biology

Yury Goltsev, Nikolay Samusik, Julia Kennedy-Darling, Salil Bhate, Matthew Hale, Gustavo Vazquez, Sarah Black, Garry Nolan

A highly multiplexed cytometric imaging approach, termed CO-Detection by indEXing (CODEX), is used here to create multiplexed datasets of normal and lupus (MRL/lpr) murine spleens. CODEX iteratively visualizes antibody binding events using DNA barcodes, fluorescent dNTP analogs, and an in-situ polymerization-based indexing procedure. An algorithmic pipeline for single-cell antigen quantification in tightly packed tissues was developed and used to overlay well-known morphological features with de novo characterization of lymphoid tissue architecture at a single-cell and cellular neighborhood levels. We observed an unexpected, profound impact of the cellular neighborhood on the expression of protein receptors on immune cells. By comparing normal murine spleen to spleens from animals with systemic autoimmune disease (MRL/lpr), extensive and previously uncharacterized splenic cell interaction dynamics in the healthy versus diseased state was observed. The fidelity of multiplexed spatial cytometry demonstrated here allows for quantitative systemic characterization of tissue architecture in normal and clinically aberrant samples.

5: Methods for High-Throughput Drug Combination Screening and Synergy Scoring
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Posted to bioRxiv 05 May 2016

Methods for High-Throughput Drug Combination Screening and Synergy Scoring
5,887 downloads systems biology

Liye He, Evgeny Kulesskiy, Jani Saarela, Laura Turunen, Krister Wennerberg, Tero Aittokallio, Jing Tang

Gene products or pathways that are aberrantly activated in cancer but not in normal tissue hold great promises for being effective and safe anticancer therapeutic targets. Many targeted drugs have entered clinical trials but so far showed limited efficacy mostly due to variability in treatment responses and often rapidly emerging resistance. Towards more effective treatment options, we will critically need multi-targeted drugs or drug combinations, which selectively inhibit the cancer cells and block distinct escape mechanisms for the cells to become resistant. Functional profiling of drug combinations requires careful experimental design and robust data analysis approaches. At the Institute for Molecular Medicine Finland (FIMM), we have developed an experimental-computational pipeline for high-throughput screening of drug combination effects in cancer cells. The integration of automated screening techniques with advanced synergy scoring tools allows for efficient and reliable detection of synergistic drug interactions within a specific window of concentrations, hence accelerating the identification of potential drug combinations for further confirmatory studies.

6: Single-Cell Transcriptomic Analysis of Human Lung Reveals Complex Multicellular Changes During Pulmonary Fibrosis
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Posted to bioRxiv 06 Apr 2018

Single-Cell Transcriptomic Analysis of Human Lung Reveals Complex Multicellular Changes During Pulmonary Fibrosis
5,109 downloads systems biology

Paul A. Reyfman, James M. Walter, Nikita Joshi, Kishore R. Anekalla, Alexandra C. McQuattie-Pimentel, Stephen Chiu, Ramiro Fernandez, Mahzad Akbarpour, Ching-I Chen, Ziyou Ren, Rohan Verma, Hiam Abdala-Valencia, Kiwon Nam, Monica Chi, SeungHye Han, Francisco J. Gonzalez-Gonzalez, Saul Soberanes, Satoshi Watanabe, Kinola J.N. Williams, Annette S. Flozak, Trevor T. Nicholson, Vince K. Morgan, Cara L. Hrusch, Robert D. Guzy, Catherine A. Bonham, Anne I. Sperling, Remzi Bag, Robert B. Hamanaka, Gökhan M. Mutlu, Anjana V. Yeldandi, Stacy A. Marshall, Ali Shilatifard, Luis AN Amaral, Harris Perlman, Jacob I. Sznajder, Deborah R. Winter, Monique Hinchcliff, A. Christine Argento, Colin T. Gillespie, Jane D’Amico Dematte, Manu Jain, Benjamin D. Singer, Karen M. Ridge, Cara J. Gottardi, Anna P. Lam, Ankit Bharat, Sangeeta M. Bhorade, GR Scott Budinger, Alexander V. Misharin

Pulmonary fibrosis is a devastating disorder that results in the progressive replacement of normal lung tissue with fibrotic scar. Available therapies slow disease progression, but most patients go on to die or require lung transplantation. Single-cell RNA-seq is a powerful tool that can reveal cellular identity via analysis of the transcriptome, but its ability to provide biologically or clinically meaningful insights in a disease context is largely unexplored. Accordingly, we performed single-cell RNA-seq on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and one bronchoscopic cryobiospy sample. Integrated single-cell transcriptomic analysis of donors and patients with pulmonary fibrosis identified the emergence of distinct populations of epithelial cells and macrophages that were common to all patients with lung fibrosis. Analysis of transcripts in the Wnt pathway suggested that within the same cell type, Wnt secretion and response are restricted to distinct non-overlapping cells, which was confirmed using in situ RNA hybridization. Single-cell RNA-seq revealed heterogeneity within alveolar macrophages from individual patients, which was confirmed by immunohistochemistry. These results support the feasibility of discovery-based approaches applying next generation sequencing technologies to clinically obtained samples with a goal of developing personalized therapies.

7: Differential stoichiometry among core ribosomal proteins
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Posted to bioRxiv 26 May 2014

Differential stoichiometry among core ribosomal proteins
4,765 downloads systems biology

Nikolai Slavov, Stefan Semrau, Edoardo Airoldi, Bogdan Budnik, Alexander van Oudenaarden

Understanding the regulation and structure of ribosomes is essential to understanding protein synthesis and its dysregulation in disease. While ribosomes are believed to have a fixed stoichiometry among their core ribosomal proteins (RPs), some experiments suggest a more variable composition. Testing such variability requires direct and precise quantification of RPs. We used mass-spectrometry to directly quantify RPs across monosomes and polysomes of mouse embryonic stem cells (ESC) and budding yeast. Our data show that the stoichiometry among core RPs in wild-type yeast cells and ESC depends both on the growth conditions and on the number of ribosomes bound per mRNA. Furthermore, we find that the fitness of cells with a deleted RP-gene is inversely proportional to the enrichment of the corresponding RP in polysomes. Together, our findings support the existence of ribosomes with distinct protein composition and physiological function.

8: Massively parallel clonal analysis using CRISPR/Cas9 induced genetic scars
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Posted to bioRxiv 01 Jun 2016

Massively parallel clonal analysis using CRISPR/Cas9 induced genetic scars
4,642 downloads systems biology

Jan Philipp Junker, Bastiaan Spanjaard, Josi Peterson-Maduro, Anna Alemany, Bo Hu, Maria Florescu, Alexander van Oudenaarden

A key goal of developmental biology is to understand how a single cell transforms into a full-grown organism consisting of many cells. Although impressive progress has been made in lineage tracing using imaging approaches, analysis of vertebrate lineage trees has mostly been limited to relatively small subsets of cells. Here we present scartrace, a strategy for massively parallel clonal analysis based on Cas9 induced genetic scars in the zebrafish.

9: Evaluation and Design of Genome-wide CRISPR/Cas9 Knockout Screens
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Posted to bioRxiv 16 Mar 2017

Evaluation and Design of Genome-wide CRISPR/Cas9 Knockout Screens
3,908 downloads systems biology

Traver Hart, Amy Tong, Katie Chan, Jolanda van Leeuwen, Ashwin Seetharaman, Michael Aregger, Megha Chandrashekhar, Nicole Hustedt, Sahil Seth, Avery Noonan, Andrea Habsid, Olga Sizova, Lyudmilla Nedyalkova, Ryan Climie, Keith Lawson, Maria Augusta Sartori, Sabriyeh Alibai, David Tieu, Sanna Masud, Patricia Mero, Alexander Weiss, Kevin R. Brown, Matej Ušaj, Maximilian Billmann, Mahfuzur Rahman, Michael Costanzo, Chad L Myers, Brenda Andrews, Charlie Boone, Daniel Durocher, Jason Moffat

The adaptation of CRISPR/Cas9 technology to mammalian cell lines is transforming the study of human functional genomics. Pooled libraries of CRISPR guide RNAs (gRNAs), targeting human protein-coding genes and encoded in viral vectors, have been used to systematically create gene knockouts in a variety of human cancer and immortalized cell lines, in an effort to identify whether these knockouts cause cellular fitness defects. Previous work has shown that CRISPR screens are more sensitive and specific than pooled library shRNA screens in similar assays, but currently there exists significant variability across CRISPR library designs and experimental protocols. In this study, we re-analyze 17 genome-scale knockout screens in human cell lines from three research groups using three different genome-scale gRNA libraries, using the Bayesian Analysis of Gene Essentiality (BAGEL) algorithm to identify essential genes, to refine and expand our previously defined set of human core essential genes, from 360 to 684 genes. We use this expanded set of reference Core Essential Genes (CEG2), plus empirical data from six CRISPR knockout screens, to guide the design of a sequence-optimized gRNA library, the Toronto KnockOut version 3.0 (TKOv3) library. We demonstrate the high effectiveness of the library relative to reference sets of essential and nonessential genes as well as other screens using similar approaches. The optimized TKOv3 library, combined with the CEG2 reference set, provide an efficient, highly optimized platform for performing and assessing gene knockout screens in human cell lines.

10: Lineage tracing on transcriptional landscapes links state to fate during differentiation
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Posted to bioRxiv 11 Nov 2018

Lineage tracing on transcriptional landscapes links state to fate during differentiation
3,860 downloads systems biology

Caleb Weinreb, Alejo E Rodriguez-Fraticelli, Fernando D Camargo, Allon M. Klein

A challenge in stem cell biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Though the development of single cell assays allows for the capture of progenitor cell states in great detail, these assays cannot definitively link those molecular states to their long-term fate. Here, we use expressed DNA barcodes to clonally trace single cell transcriptomes dynamically during differentiation and apply this approach to the study of hematopoiesis. Our analysis identifies functional boundaries of cell potential early in the hematopoietic hierarchy and locates them on a continuous transcriptional landscape. Additionally, we find that the monocyte lineage differentiates through two distinct transcriptional and clonal routes, leaving a persistent imprint on mature cells. Finally, we use our approach to reflect on current methods of dynamics inference from single-cell snapshots. We find that for in vitro hematopoiesis, published fate prediction algorithms do not detect lineage priming in early progenitors, and provide evidence that there are hidden properties that influence cell fate but are not detectable with current single-cell sequencing methods.

11: DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning
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Posted to bioRxiv 11 Aug 2016

DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning
3,697 downloads systems biology

Janine Arloth, Gökcen Eraslan, Till FM Andlauer, Jade Martins, Stella Iurato, Brigitte Kühnel, Melanie Waldenberger, Josef Frank, Ralf Gold, Bernhard Hemmer, Felix Luessi, Sandra Nischwitz, Friedemann Paul, Heinz Wiendl, Christian Gieger, Stefanie Heilmann-Heimbach, Tim Kacprowski, Matthias Laudes, Thomas Meitinger, Annette Peters, Rajesh Rawal, Konstantin Strauch, Susanne Lucae, Bertram Müller-Myhsok, Marcella Rietschel, Fabian J. Theis, Elisabeth B. Binder, Nikola S. Mueller

Genome-wide association studies (GWAS) identify genetic variants associated with quantitative traits or disease. Thus, GWAS never directly link variants to regulatory mechanisms, which, in turn, are typically inferred during post-hoc analyses. In parallel, a recent deep learning-based method allows for prediction of regulatory effects per variant on currently up to 1,000 cell type-specific chromatin features. We here describe "DeepWAS", a new approach that directly integrates predictions of these regulatory effects of single variants into a multivariate GWAS setting. As a result, single variants associated with a trait or disease are, by design, coupled to their impact on a chromatin feature in a cell type. Up to 40,000 regulatory single-nucleotide polymorphisms (SNPs) were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals) to each identify 43-61 regulatory SNPs, called deepSNPs, which are shown to reach at least nominal significance in large GWAS. MS- and height-specific deepSNPs resided in active chromatin and introns, whereas MDD-specific deepSNPs located mostly to intragenic regions and repressive chromatin states. We found deepSNPs to be enriched in public or cohort-matched expression and methylation quantitative trait loci and demonstrate the potential of the DeepWAS method to directly generate testable functional hypotheses based on genotype data alone. DeepWAS is an innovative GWAS approach with the power to identify individual SNPs in non-coding regions with gene regulatory capacity with a joint contribution to disease risk. DeepWAS is available at https://github.com/cellmapslab/DeepWAS.

12: A reference map of the human protein interactome
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Posted to bioRxiv 10 Apr 2019

A reference map of the human protein interactome
3,623 downloads systems biology

Katja Luck, Dae-Kyum Kim, Luke Lambourne, Kerstin Spirohn, Bridget E Begg, Wenting Bian, Ruth Brignall, Tiziana Cafarelli, Francisco J Campos-Laborie, Benoit Charloteaux, Dongsic Choi, Atina G. Cote, Meaghan Daley, Steven Deimling, Alice Desbuleux, Amelie Dricot, Marinella Gebbia, Madeleine F Hardy, Nishka Kishore, Jennifer J Knapp, Istvan A Kovacs, Irma Lemmens, Miles W Mee, Joseph C. Mellor, Carl Pollis, Carles Pons, Aaron D Richardson, Sadie Schlabach, Bridget Teeking, Anupama Yadav, Mariana Babor, Dawit Balcha, Omar Basha, Christian Bowman-Colin, Suet-Feung Chin, Soon Gang Choi, Claudia Colabella, Georges Coppin, Cassandra D'Amata, David De Ridder, Steffi De Rouck, Miquel Duran-Frigola, Hanane Ennajdaoui, Florian Goebels, Liana Goehring, Anjali Gopal, Ghazal Haddad, Elodie Hatchi, Mohamed Helmy, Yves Jacob, Yoseph Kassa, Serena Landini, Roujia Li, Natascha van Lieshout, Andrew MacWilliams, Dylan Markey, Joseph N Paulson, Sudharshan Rangarajan, John Rasla, Ashyad Rayhan, Thomas Rolland, Adriana San-Miguel, Yun Shen, Dayag Sheykhkarimli, Gloria M. Sheynkman, Eyal Simonovsky, Murat Taşan, Alexander Tejeda, Jean-Claude Twizere, Yang Wang, Robert J. Weatheritt, Jochen Weile, Yu Xia, Xinping Yang, Esti Yeger-Lotem, Quan Zhong, Patrick Aloy, Gary D. Bader, Javier De Las Rivas, Suzanne Gaudet, Tong Hao, Janusz Rak, Jan Tavernier, Vincent Tropepe, David E. Hill, Marc Vidal, Frederick P Roth, Michael A. Calderwood

Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here we present the first human "all-by-all" binary reference interactome map, or "HuRI". With ~53,000 high-quality protein-protein interactions (PPIs), HuRI is approximately four times larger than the information curated from small-scale studies available in the literature. Integrating HuRI with genome, transcriptome and proteome data enables the study of cellular function within essentially any physiological or pathological cellular context. We demonstrate the use of HuRI in identifying specific subcellular roles of PPIs and protein function modulation via splicing during brain development. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms underlying tissue-specific phenotypes of Mendelian diseases. HuRI thus represents an unprecedented, systematic reference linking genomic variation to phenotypic outcomes.

13: Ordinary Differential Equations in Cancer Biology
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Posted to bioRxiv 23 Aug 2016

Ordinary Differential Equations in Cancer Biology
3,485 downloads systems biology

Margaret P Chapman, Claire J. Tomlin

Ordinary differential equations (ODEs) provide a classical framework to model the dynamics of biological systems, given temporal experimental data. Qualitative analysis of the ODE model can lead to further biological insight and deeper understanding compared to traditional experiments alone. Simulation of the model under various perturbations can generate novel hypotheses and motivate the design of new experiments. This short paper will provide an overview of the ODE modeling framework, and present examples of how ODEs can be used to address problems in cancer biology.

14: Mechanistic modelling and Bayesian inference elucidates the variable dynamics of double-strand break repair
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Posted to bioRxiv 04 Sep 2015

Mechanistic modelling and Bayesian inference elucidates the variable dynamics of double-strand break repair
3,477 downloads systems biology

Mae Woods, Chris P Barnes

DNA double-strand breaks are lesions that form during metabolism, DNA replication and exposure to mutagens. When a double-strand break occurs one of a number of repair mechanisms is recruited, all of which have differing propensities for mutational events. Despite DNA repair being of crucial importance, the relative contribution of these mechanisms and their regulatory interactions remain to be fully elucidated. Understanding these mutational processes will have a profound impact on our knowledge of genomic instability, with implications across health, disease and evolution. Here we present a new method to model the combined activation of non-homologous end joining, single strand annealing and alternative end joining, following exposure to ionizing radiation. We use Bayesian statistics to integrate eight biological data sets of double-strand break repair curves under varying genetic knockouts and confirm that our model is predictive by re-simulating and comparing to additional data. Analysis of the model suggests that there are at least three disjoint modes of repair, which we assign as fast, slow and intermediate. Our results show that when multiple data sets are combined, the rate for intermediate repair is variable amongst genetic knockouts. Further analysis suggests that the ratio between slow and intermediate repair depends on the presence or absence of DNA-PKcs and Ku70, which implies that non-homologous end joining and alternative end joining are not independent. Finally, we consider the proportion of double-strand breaks within each mechanism as a time series and predict activity as a function of repair rate. We outline how our insights can be directly tested using imaging and sequencing techniques and conclude that there is evidence of variable dynamics in alternative repair pathways. Our approach is an important step towards providing a unifying theoretical framework for the dynamics of DNA repair processes.

15: Transcriptional burst initiation and polymerase pause release are key control points of transcriptional regulation
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Posted to bioRxiv 02 Mar 2018

Transcriptional burst initiation and polymerase pause release are key control points of transcriptional regulation
3,448 downloads systems biology

Caroline Bartman, Cheryl A Keller, Belinda Giardine, Ross C Hardison, Gerd A Blobel, Arjun Raj

Transcriptional regulation occurs via changes to the rates of various biochemical processes. Sequencing based approaches that average together many cells have suggested that polymerase binding and polymerase release from promoter proximal pausing are two key regulated steps in the transcriptional process. However, single cell studies have revealed that transcription occurs in short, discontinuous bursts, suggesting that transcriptional burst initiation and termination might also be regulated steps. Here, we develop and apply a quantitative framework to connect changes in both Pol II ChIP sequencing and single cell transcriptional measurements to changes in the rates of specific steps of transcription. Using a number of global and targeted transcriptional regulatory perturbations, we show that burst initiation rate is indeed a key regulated step, demonstrating that transcriptional activity can be frequency modulated. Polymerase pause release is a second key regulated step, but the rate of polymerase binding is not changed by any of the biological perturbations we examined. Our results establish an important role for transcriptional burst regulation in the control of gene expression.

16: Charting a tissue from single-cell transcriptomes
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Posted to bioRxiv 30 Oct 2018

Charting a tissue from single-cell transcriptomes
3,335 downloads systems biology

Mor Nitzan, Nikos Karaiskos, Nir Friedman, Nikolaus Rajewsky

Massively multiplexed sequencing of RNA in individual cells is transforming basic and clinical life sciences. However, in standard experiments, tissues must first be dissociated. Thus, after sequencing, information about the spatial relationships between cells is lost although this knowledge is crucial for understanding cellular and tissue-level function. Recent attempts to overcome this fundamental challenge rely on employing additional in situ gene expression imaging data which can guide spatial mapping of sequenced cells. Here we present a conceptually different approach that allows to reconstruct spatial positions of cells in a variety of tissues without using reference imaging data. We first show for several complex biological systems that distances of single cells in expression space monotonically increase with their physical distances across tissues. We therefore seek to map cells to tissue space such that this principle is optimally preserved, while matching existing imaging data when available. We show that this optimization problem can be cast as a generalized optimal transport problem and solved efficiently. We apply our approach successfully to reconstruct the mammalian liver and intestinal epithelium as well as fly and zebrafish embryos. Our results demonstrate a simple spatial expression organization principle and that this principle (or future refined principles) can be used to infer, for individual cells, meaningful spatial position probabilities from the sequencing data alone.

17: A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
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Posted to bioRxiv 27 Jun 2018

A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
3,297 downloads systems biology

Dongxue Wang, Basak Eraslan, Thomas Wieland, Björn Hallström, Thomas Hopf, Daniel Paul Zolg, Jana Zecha, Anna Asplund, Li-hua Li, Chen Meng, Martin Frejno, Tobias Schmidt, Karsten Schnatbaum, Mathias Wilhelm, Frederik Ponten, Mathias Uhlen, Julien Gagneur, Hannes Hahne, Bernhard Kuster

Genome-, transcriptome- and proteome-wide measurements provide valuable insights into how biological systems are regulated. However, even fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we have generated a systematic, quantitative and deep proteome and transcriptome abundance atlas from 29 paired healthy human tissues from the Human Protein Atlas Project and representing human genes by 17,615 transcripts and 13,664 proteins. The analysis revealed that few proteins show truly tissue-specific expression, that vast differences between mRNA and protein quantities within and across tissues exist and that the expression levels of proteins are often more stable across tissues than those of transcripts. In addition, only ~2% of all exome and ~7% of all mRNA variants could be confidently detected at the protein level showing that proteogenomics remains challenging, requires rigorous validation using synthetic peptides and needs more sophisticated computational methods. Many uses of this resource can be envisaged ranging from the study of gene/protein expression regulation to protein biomarker specificity evaluation to name a few.

18: A compound that directly and selectively stalls PCSK9 translation
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Posted to bioRxiv 25 Oct 2016

A compound that directly and selectively stalls PCSK9 translation
3,184 downloads systems biology

Nathanael G. Lintner, Kim F. McClure, Donna Petersen, Allyn T. Londregan, David W. Piotrowski, Liuqing Wei, Jun Xiao, Michael Bolt, Paula M. Loria, Bruce Maguire, Kieran F. Geoghegan, Austin Huang, Tim Rolph, Spiros Liras, Jennifer A Doudna, Robert G. Dullea, Jamie H.D. Cate

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome, which allows small molecules to specifically block translation of individual transcripts.

19: Determining protein structures using genetics
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Posted to bioRxiv 20 Apr 2018

Determining protein structures using genetics
3,143 downloads systems biology

Joern Schmiedel, Ben Lehner

Determining the three dimensional structures of macromolecules is a major goal of biological research because of the close relationship between structure and function. Structure determination usually relies on physical techniques including x-ray crystallography, NMR spectroscopy and cryo-electron microscopy. Here we present a method that allows the high-resolution three-dimensional structure of a biological macromolecule to be determined only from measurements of the activity of mutant variants of the molecule. This genetic approach to structure determination relies on the quantification of genetic interactions (epistasis) between mutations and the discrimination of direct from indirect interactions. This provides a new experimental strategy for structure determination, with the potential to reveal functional and in vivo structural conformations at low cost and high throughput.

20: Composite measurements and molecular compressed sensing for highly efficient transcriptomics
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Posted to bioRxiv 02 Jan 2017

Composite measurements and molecular compressed sensing for highly efficient transcriptomics
3,045 downloads systems biology

Brian Cleary, Le Cong, Eric S Lander, Aviv Regev

RNA profiling is an excellent phenotype of cellular responses and tissue states, but can be costly to generate at the massive scale required for studies of regulatory circuits, genetic states or perturbation screens. Here, we draw on a series of advances over the last decade in the field of mathematics to establish a rigorous link between biological structure, data compressibility, and efficient data acquisition. We propose that very few random composite measurements - in which gene abundances are combined in a random linear combination - are needed to approximate the high-dimensional similarity between any pair of gene abundance profiles. We then show how finding latent, sparse representations of gene expression data would enable us to 'decompress' a small number of random composite measurements and recover high-dimensional gene expression levels that were not measured (unobserved). We present a new algorithm for finding sparse, modular structure, which improves the ability to interpret samples in terms of small numbers of active modules, and show that the modular structure we find is sufficient to recover gene expression profiles from composite measurements (with ~100-fold fewer composite measurements than genes). Moreover, the knowledge that sparse, modular structures exist allows us to recover expression profiles from composite measurements, even without access to any training data. Finally, we present a proof-of-concept experiment for making composite measurements in the laboratory, involving the measurement of linear combinations of RNA abundances. Altogether, our results suggest new compressive modalities in experimental biology that can form a foundation for massive scaling in high-throughput measurements, while also offering new insights into the interpretation of high-dimensional data. A recorded seminar presentation of this work is available at: https://www.youtube.com/watch?v=2dBZEOXqKHs

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