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29 results on '"631/114"'

1. DrugRepo: a novel approach to repurposing drugs based on chemical and genomic features

Author

Yinyin Wang, Jehad Aldahdooh, Yingying Hu, Hongbin Yang, Markus Vähä-Koskela, Jing Tang, Ziaurrehman Tanoli, Research Program in Systems Oncology, Faculty of Medicine, Institute for Molecular Medicine Finland, Medicum, Department of Biochemistry and Developmental Biology, Department of Mathematics and Statistics, Divisions of Faculty of Pharmacy, Apollo - University of Cambridge Repository, and Aldahdooh, Jehad [0000-0002-9947-4067]

Subjects
Multidisciplinary, 317 Pharmacy, article, Genomics, 631/114, 692/4017
Abstract

The drug development process consumes 9–12 years and approximately one billion US dollars in costs. Due to the high finances and time costs required by the traditional drug discovery paradigm, repurposing old drugs to treat cancer and rare diseases is becoming popular. Computational approaches are mainly data-driven and involve a systematic analysis of different data types leading to the formulation of repurposing hypotheses. This study presents a novel scoring algorithm based on chemical and genomic data to repurpose drugs for 669 diseases from 22 groups, including various cancers, musculoskeletal, infections, cardiovascular, and skin diseases. The data types used to design the scoring algorithm are chemical structures, drug-target interactions (DTI), pathways, and disease-gene associations. The repurposed scoring algorithm is strengthened by integrating the most comprehensive manually curated datasets for each data type. At DrugRepo score ≥ 0.4, we repurposed 516 approved drugs across 545 diseases. Moreover, hundreds of novel predicted compounds can be matched with ongoing studies at clinical trials. Our analysis is supported by a web tool available at: http://drugrepo.org/.

Published
2022

2. Altered subgenomic RNA abundance provides unique insight into SARS-CoV-2 B.1.1.7/Alpha variant infections

Author

Parker, Matthew D, Shaw, Hazel, Shehata, Ola M, Lindsey, Benjamin B, Shah, Dhruv R, Hsu, Sharon, Keeley, Alexander J, Partridge, David G, Leary, Shay, Cope, Alison, State, Amy, Johnson, Katie, Ali, Nasar, Raghei, Rasha, Heffer, Joe, Smith, Nikki, Zhang, Peijun, Gallis, Marta, Louka, Stavroula F, Hornsby, Hailey R, Alamri, Hatoon, Whiteley, Max, Foulkes, Benjamin H, Christou, Stella, Wolverson, Paige, Pohare, Manoj, Hansford, Samantha E, Green, Luke R, Evans, Cariad, Raza, Mohammad, Wang, Dennis, Firth, Andrew, Edgar, James, Gaudieri, Silvana, Mallal, Simon, COVID-19 Genomics UK (COG-UK) Consortium, Collins, Mark O, Peden, Andrew A, De Silva, Thushan I, Parker, Matthew D [0000-0003-2999-3870], Shaw, Hazel [0000-0003-1438-1089], Lindsey, Benjamin B [0000-0003-4227-2592], Shah, Dhruv R [0000-0002-6198-8273], Keeley, Alexander J [0000-0001-9386-1157], Partridge, David G [0000-0002-0417-2016], Heffer, Joe [0000-0001-8733-1117], Louka, Stavroula F [0000-0003-3000-3504], Hornsby, Hailey R [0000-0002-6657-9743], Christou, Stella [0000-0002-8287-788X], Wolverson, Paige [0000-0003-2709-0686], Pohare, Manoj [0000-0003-2272-9946], Hansford, Samantha E [0000-0003-3042-8748], Green, Luke R [0000-0002-2836-2041], Wang, Dennis [0000-0003-0068-1005], Firth, Andrew [0000-0002-7986-9520], Edgar, James [0000-0001-7903-8199], Collins, Mark O [0000-0002-7656-4975], Peden, Andrew A [0000-0003-0144-7712], de Silva, Thushan I [0000-0002-6498-9212], Apollo - University of Cambridge Repository, Stewart, Hazel [0000-0003-1438-1089], and Edgar, James R [0000-0001-7903-8199]

Subjects
SARS-CoV-2, article, COVID-19, Humans, RNA, 45/23, 631/114, 631/326/596/4130, 45/90
Abstract

B.1.1.7 lineage SARS-CoV-2 is more transmissible, leads to greater clinical severity, and results in modest reductions in antibody neutralization. Subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool (periscope) to ARTIC Network Oxford Nanopore Technologies genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA is significantly increased in B.1.1.7 (alpha) infections (n = 879). This increase is seen over the previous dominant lineage in the UK, B.1.177 (n = 943), which is independent of genomic reads, E cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus in vitro. We hypothesise that increased ORF9b in B.1.1.7 is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT > CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3' of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles to evaluate emerging potential variants of concern.

Published
2022
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3. Cell graph neural networks enable the precise prediction of patient survival in gastric cancer

Author

Yanan Wang, Yu Guang Wang, Changyuan Hu, Ming Li, Yanan Fan, Nina Otter, Ikuan Sam, Hongquan Gou, Yiqun Hu, Terry Kwok, John Zalcberg, Alex Boussioutas, Roger J. Daly, Guido Montúfar, Pietro Liò, Dakang Xu, Geoffrey I. Webb, Jiangning Song, Li, Ming [0000-0002-1218-2804], Daly, Roger J [0000-0002-5739-8027], Lio, Pietro [0000-0002-0540-5053], Xu, Dakang [0000-0003-2415-4920], Webb, Geoffrey I [0000-0001-9963-5169], Song, Jiangning [0000-0001-8031-9086], Apollo - University of Cambridge Repository, and Liò, Pietro [0000-0002-0540-5053]

Subjects
Cancer Research, Rare Diseases, Oncology, 692/4028/67/1504/1829, 631/67/2321, article, 32 Biomedical and Clinical Sciences, 3 Good Health and Well Being, 631/114, 3211 Oncology and Carcinogenesis, 692/4028/67/327, Cancer
Abstract

Gastric cancer is one of the deadliest cancers worldwide. An accurate prognosis is essential for effective clinical assessment and treatment. Spatial patterns in the tumor microenvironment (TME) are conceptually indicative of the staging and progression of gastric cancer patients. Using spatial patterns of the TME by integrating and transforming the multiplexed immunohistochemistry (mIHC) images as Cell-Graphs, we propose a graph neural network-based approach, termed Cell−GraphSignatureorCGSignature, powered by artificial intelligence, for the digital staging of TME and precise prediction of patient survival in gastric cancer. In this study, patient survival prediction is formulated as either a binary (short-term and long-term) or ternary (short-term, medium-term, and long-term) classification task. Extensive benchmarking experiments demonstrate that the CGSignature achieves outstanding model performance, with Area Under the Receiver Operating Characteristic curve of 0.960 ± 0.01, and 0.771 ± 0.024 to 0.904 ± 0.012 for the binary- and ternary-classification, respectively. Moreover, Kaplan–Meier survival analysis indicates that the “digital grade” cancer staging produced by CGSignature provides a remarkable capability in discriminating both binary and ternary classes with statistical significance (P value CGSignature improves the assessment of the link between the TME spatial patterns and patient prognosis. Our study suggests the feasibility and benefits of such an artificial intelligence-powered digital staging system in diagnostic pathology and precision oncology.

Published
2022

4. A quantitative model of cellular decision making in direct neuronal reprogramming

Author

Viktor Drugge, Victor Olariu, Emilie M. Legault, Adriaan Merlevede, Janelle Drouin-Ouellet, Roger A. Barker, Apollo - University of Cambridge Repository, and Barker, Roger [0000-0001-8843-7730]

Subjects
Computer science, Cell, Gene Expression, 631/553/2701, Gene expression, 631/114/2114, Numerical simulations, Interaction dynamics, Cellular Reprogramming Techniques, Gene Regulatory Networks, 631/553/2709, Stochastic modelling, Neurons, Transdifferentiation, Gene knockdown, Multidisciplinary, article, Middle Aged, Cellular Reprogramming, 631/532/2128, medicine.anatomical_structure, Medicine, Female, Systems biology, Reprogramming, Polypyrimidine Tract-Binding Protein, Time series, Science, Primary Cell Culture, Nerve Tissue Proteins, Computational biology, 631/553/2696, Gene interaction, medicine, Humans, Gene, Aged, Stochastic Processes, Computational Biology, Fibroblasts, Models, Theoretical, Quantitative model, Computational biology and bioinformatics, 631/553/2699, Gene Expression Regulation, Nonlinear dynamics, 631/553, 631/114, 631/136/2128, Transcription Factors
Abstract

Funder: Fonds du Québec en Recherche, Santé (FRQS), Funder: Parkinson Quebec., Funder: Lund University, The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put forward a quantitative model of the governing gene regulatory system, supported by measurements of mRNA expression. We found that nPTB needs to feed back into the direct neural conversion network most likely via PTB in order to accurately capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This was experimentally validated by nPTB knockdown leading to successful neural conversion. We also proposed a novel analytical technique to dissect system behaviour and reveal the influence of individual factors on resulting gene expression. Overall, we demonstrate that computational analysis is a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming, paving the way for future models that can help improve cell conversion strategies.

Published
2021

5. De novo metatranscriptomic exploration of gene function in the millipede holobiont

Author

Puspendu Sardar, Vladimír Šustr, Alica Chroňáková, František Lorenc, Lucie Faktorová, Apollo - University of Cambridge Repository, Sardar, Puspendu [0000-0001-8011-2915], and Lorenc, František [0000-0002-4986-3160]

Subjects
631/326/2565, Multidisciplinary, Bacteroidetes, article, 631/114/2403, 631/114/2404, Fatty Acids, Volatile, Gastrointestinal Microbiome, 631/114/1386, 631/114/2410, Animals, Amino Acids, Essential, 631/114, Arthropods, 631/114/2184
Abstract

Invertebrate–microbial associations are widespread in the biosphere and are often related to the function of novel genes, fitness advantages, and even speciation events. Despite ~ 13,000 species of millipedes identified across the world, millipedes and their gut microbiota are markedly understudied compared to other arthropods. Exploring the contribution of individual host-associated microbes is often challenging as many are uncultivable. In this study, we conducted metatranscriptomic profiling of different body segments of a millipede at the holobiont level. This is the first reported transcriptome assembly of a tropical millipede Telodeinopus aoutii (Demange, 1971), as well as the first study on any Myriapoda holobiont. High-throughput RNA sequencing revealed that Telodeinopus aoutii contained > 90% of the core Arthropoda genes. Proteobacteria, Bacteroidetes, Firmicutes, and Euryarchaeota represented dominant and functionally active phyla in the millipede gut, among which 97% of Bacteroidetes and 98% of Firmicutes were present exclusively in the hindgut. A total of 37,831 predicted protein-coding genes of millipede holobiont belonged to six enzyme classes. Around 35% of these proteins were produced by microbiota in the hindgut and 21% by the host in the midgut. Our results indicated that although major metabolic pathways operate at the holobiont level, the involvement of some host and microbial genes are mutually exclusive and microbes predominantly contribute to essential amino acid biosynthesis, short-chain fatty acid metabolism, and fermentation.

Published
2022

6. Kinetic interplay between droplet maturation and coalescence modulates shape of aged protein condensates

Author

Jorge R. Espinosa, Rosana Collepardo-Guevara, Jerelle A. Joseph, Adiran Garaizar, Apollo - University of Cambridge Repository, Joseph, Jerelle [0000-0003-4525-180X], and Espinosa, Jorge R [0000-0001-9530-2658]

Subjects
Coalescence (physics), Work (thermodynamics), Quantitative Biology::Biomolecules, Multidisciplinary, Chemistry, Nucleation, article, Interaction strength, Proteins, Kinetic energy, Biophysical Phenomena, Kinetics, Chemical physics, Thermodynamics, 631/114, Peptides, 631/57/2269, 631/57/2266
Abstract

Biomolecular condensates formed by the process of liquid–liquid phase separation (LLPS) play diverse roles inside cells, from spatiotemporal compartmentalisation to speeding up chemical reactions. Upon maturation, the liquid-like properties of condensates, which underpin their functions, are gradually lost, eventually giving rise to solid-like states with potential pathological implications. Enhancement of inter-protein interactions is one of the main mechanisms suggested to trigger the formation of solid-like condensates. To gain a molecular-level understanding of how the accumulation of stronger interactions among proteins inside condensates affect the kinetic and thermodynamic properties of biomolecular condensates, and their shapes over time, we develop a tailored coarse-grained model of proteins that transition from establishing weak to stronger inter-protein interactions inside condensates. Our simulations reveal that the fast accumulation of strongly binding proteins during the nucleation and growth stages of condensate formation results in aspherical solid-like condensates. In contrast, when strong inter-protein interactions appear only after the equilibrium condensate has been formed, or when they accumulate slowly over time, with respect to the time needed for droplets to fuse and grow, spherical solid-like droplets emerge. By conducting atomistic potential-of-mean-force simulations of NUP-98 peptides—prone to forming inter-protein β -sheets—we observe that formation of inter-peptide β -sheets increases the strength of the interactions consistently with the loss of liquid-like condensate properties we observe at the coarse-grained level. Overall, our work aids in elucidating fundamental molecular, kinetic, and thermodynamic mechanisms linking the rate of change in protein interaction strength to condensate shape and maturation during ageing., Adiran Garaizar is funded by the EPRSC Doctoral Programme Training number EP/N509620/.

Published
2022

7. Computer-aided synthesis of dapsone-phytochemical conjugates against dapsone-resistant Mycobacterium leprae

Author

Rabindra N. Padhy, Shasank S. Swain, Madhusmita Das, Sudhir Kumar Paidesetty, Sundeep Chaitanya Vedithi, Budheswar Dehury, Apollo - University of Cambridge Repository, and Vedithi, Sundeep Chaitanya [0000-0003-3474-4705]

Subjects
Bacilli, Phytochemicals, lcsh:Medicine, Leprostatic Agents, 101/58, Dapsone, Pharmacology, SDG 3 - Good Health and Well-being, Oral administration, In vivo, Leprosy, 38/23, medicine, 38/22, Humans, Drug discovery and development, Computer Simulation, 631/154/309/2144, lcsh:Science, Multidisciplinary, biology, business.industry, Drug discovery, lcsh:R, 631/154, article, 45/77, medicine.disease, biology.organism_classification, In vitro, Computational biology and bioinformatics, Mycobacterium leprae, Phytochemical, Toxicity, 14/63, 64/60, lcsh:Q, 631/114, business, medicine.drug
Abstract

Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the ‘mouse-foot-pad propagation method’, with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.

Published
2020

8. Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts

Author

Sophie Momen, Martin Hemberg, Ilias Georgakopoulos-Soares, Josef Jiricny, Gene Koh, Serena Nik-Zainal, Koh, Gene [0000-0002-3840-4954], Hemberg, Martin [0000-0001-8895-5239], Nik-Zainal, Serena [0000-0001-5054-1727], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, DNA Repair, Transcription, Genetic, Amino Acid Motifs, DNA Mutational Analysis, General Physics and Astronomy, Genome, chemistry.chemical_compound, 0302 clinical medicine, INDEL Mutation, Transcription (biology), Neoplasms, Cancer genomics, DNA Breaks, Double-Stranded, lcsh:Science, Cancer, Multidisciplinary, article, food and beverages, Genomics, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, DNA mismatch repair, DNA Replication, 631/67, DNA repair, Science, Polynucleotides, Computational biology, 631/67/69, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Humans, Repetitive Sequences, Nucleic Acid, 45, Genome, Human, Sequence Analysis, RNA, Computational Biology, Genetic Variation, General Chemistry, Computational biology and bioinformatics, 030104 developmental biology, chemistry, Mutagenesis, Human genome, lcsh:Q, 631/114, 119, DNA, Gene Deletion, Nucleotide excision repair
Abstract

The mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. Here, we introduce a method to evaluate indels, orientating them relative to gene transcription. In so doing, we reveal a number of surprising findings: First, there is a transcriptional strand asymmetry in the distribution of mononucleotide repeat tracts in the reference human genome. Second, there is a strong transcriptional strand asymmetry of indels across 2,575 whole genome sequenced human cancers. We suggest that this is due to the activity of transcription-coupled nucleotide excision repair (TC-NER). Furthermore, TC-NER interacts with mismatch repair (MMR) under physiological conditions to produce strand bias. Finally, we show how insertions and deletions differ in their dependencies on these repair pathways. Our analytical approach reveals insights into the contribution of DNA repair towards indel mutagenesis in human cells., Nature Communications, 11 (1), ISSN:2041-1723

Published
2020

9. Predicting genes associated with RNA methylation pathways using machine learning

Author

Tsagkogeorga, Georgia, Santos-Rosa, Helena, Alendar, Andrej, Leggate, Dan, Rausch, Oliver, Kouzarides, Tony, Weisser, Hendrik, Han, Namshik, Tsagkogeorga, Georgia [0000-0002-9657-453X], Weisser, Hendrik [0000-0001-9723-7503], Han, Namshik [0000-0002-7741-6384], and Apollo - University of Cambridge Repository

Subjects
Machine Learning, Proteomics, 45, 631/337/176, article, Medicine (miscellaneous), Humans, RNA, Supervised Machine Learning, 631/114, General Agricultural and Biological Sciences, Methylation, General Biochemistry, Genetics and Molecular Biology
Abstract

RNA methylation plays an important role in functional regulation of RNAs, and has thus attracted an increasing interest in biology and drug discovery. Here, we collected and collated transcriptomic, proteomic, structural and physical interaction data from the Harmonizome database, and applied supervised machine learning to predict novel genes associated with RNA methylation pathways in human. We selected five types of classifiers, which we trained and evaluated using cross-validation on multiple training sets. The best models reached 88% accuracy based on cross-validation, and an average 91% accuracy on the test set. Using protein-protein interaction data, we propose six molecular sub-networks linking model predictions to previously known RNA methylation genes, with roles in mRNA methylation, tRNA processing, rRNA processing, but also protein and chromatin modifications. Our study exemplifies how access to large omics datasets joined by machine learning methods can be used to predict gene function.

Published
2022

10. Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Author

Hima Anbunathan, Anne M. Bowcock, Yu Zhi Zhang, William O.C.M. Cookson, Miriam F. Moffatt, Tatyana Chernova, S. Gennatas, Anne E. Willis, Mark Lathrop, I. Alex Bowman, Eric Lim, A. Mandal, Marion MacFarlane, Anthony Newman Taylor, Sanjay Popat, Tim Benepal, A. Nastase, Matthew S. Edwards, Deborah J. Morris-Rosendahl, Robert C. Rintoul, Andrew G. Nicholson, Xiao-Ming Sun, Shir Kiong Lu, Guys & St Thomas NHS Foundation Trust, Department of Health, Rintoul, Robert [0000-0003-3875-3780], Willis, Anne [0000-0002-1470-8531], Apollo - University of Cambridge Repository, Mandal, Amit [0000-0002-2530-8103], and Willis, Anne E [0000-0002-1470-8531]

Subjects
Male, Molecular biology, medicine.medical_treatment, Biopsy, Aurora kinase, CDKN2A, Medicine, Mesothelioma, Cancer, YAP1, Aged, 80 and over, Multidisciplinary, 631/250, article, Genomics, Middle Aged, Gene Expression Regulation, Neoplastic, Oncology, Pleura, Female, 631/337, medicine.drug, 631/67, DNA Copy Number Variations, Science, Pleural Neoplasms, Immunology, 692/308, Primary Cell Culture, Antineoplastic Agents, Malignancy, 692/4028, Medical research, 692/53, Biomarkers, Tumor, Humans, Hippo Signaling Pathway, Hedgehog, Aged, Whole Genome Sequencing, business.industry, Gene Expression Profiling, Mesothelioma, Malignant, Immunotherapy, medicine.disease, Computational biology and bioinformatics, Mutation, Cancer research, 631/114, business, Biomarkers, Interferon type I
Abstract

Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation, Funder: UK Medical Research Council, Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Published
2021
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11. Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy

Author

Chin Yang Shapland, Ditte Demontis, Stephen Burgess, Ellen Verhoef, Anders D. Børglum, Dheeraj Rai, Beate St Pourcain, Jakob Grove, Verhoef, Ellen [0000-0002-8315-1095], Grove, Jakob [0000-0003-2284-5744], Shapland, Chin Yang [0000-0002-5797-1241], Demontis, Ditte [0000-0001-9124-2766], Burgess, Stephen [0000-0001-5365-8760], Børglum, Anders D. [0000-0001-8627-7219], St Pourcain, Beate [0000-0002-4680-3517], Apollo - University of Cambridge Repository, and Børglum, Anders D [0000-0001-8627-7219]

Subjects
Male, Population genetics, Autism Spectrum Disorder, Science, General Physics and Astronomy, 631/208/1515, Biology, 631/208/457, Polymorphism, Single Nucleotide, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Correlation, Pleiotropy, Genetic variation, 631/208/366, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Allele, 692/699/476, Genetics, Multidisciplinary, Neurodevelopmental disorders, article, General Chemistry, medicine.disease, Educational attainment, Computational biology and bioinformatics, Autism spectrum disorder, Attention Deficit Disorder with Hyperactivity, Behavioural genetics, Regression Analysis, Female, 631/114, Psychiatric disorders, Genome-Wide Association Study
Abstract

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610–766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions., Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder are co-occurring neurodevelopmental conditions displaying strong, discordant polygenic associations with educational attainment. Here, the authors study genetic mechanisms underlying genome-wide correlation patterns across these traits.

Published
2021

12. Immunological and hematological outcomes following protracted low dose/low dose rate ionizing radiation and simulated microgravity

Author

Eliah G. Overbey, Nathaniel Szewczyk, Nina C. Nishiyama, Willian A. da Silveira, Michael J. Pecaut, Xiao Wen Mao, Sulekha Anand, Jonathan M. Galazka, and Amber M. Paul

Subjects
Science, Immunology, 631/250/2502, Spleen, Inflammation, Biology, Spaceflight, Article, Gene regulatory networks, law.invention, Transcriptome, Andrology, Mice, Immune system, 692/53, SDG 3 - Good Health and Well-being, law, 631/114/2114, medicine, Animals, B cell, Whole blood, Multidisciplinary, 631/250, article, Dose-Response Relationship, Radiation, Hematopoiesis, Computational biology and bioinformatics, Gene regulation in immune cells, Red blood cell, medicine.anatomical_structure, Hindlimb Suspension, Gamma Rays, Medicine, Female, 631/114, medicine.symptom, Biomarkers, Signal Transduction
Abstract

Using a ground-based model to simulate spaceflight [21-days of single-housed, hindlimb unloading (HLU) combined with continuous low-dose gamma irradiation (LDR, total dose of 0.04 Gy)], an in-depth survey of the immune and hematological systems of mice at 7-days post-exposure was performed. Collected blood was profiled with a hematology analyzer and spleens were analyzed by whole transcriptome shotgun sequencing (RNA-sequencing). The results revealed negligible differences in immune differentials. However, hematological system analyses of whole blood indicated large disparities in red blood cell differentials and morphology, suggestive of anemia. Murine Reactome networks indicated majority of spleen cells displayed differentially expressed genes (DEG) involved in signal transduction, metabolism, cell cycle, chromatin organization, and DNA repair. Although immune differentials were not changed, DEG analysis of the spleen revealed expression profiles associated with inflammation and dysregulated immune function persist to 1-week post-simulated spaceflight. Additionally, specific regulation pathways associated with human blood disease gene orthologs, such as blood pressure regulation, transforming growth factor-β receptor signaling, and B cell differentiation were noted. Collectively, this study revealed differential immune and hematological outcomes 1-week post-simulated spaceflight conditions, suggesting recovery from spaceflight is an unremitting process.

Published
2021

13. Chromosomal copy number heterogeneity predicts survival rates across cancers

Author

Lisanne E. Nijman, Cornelis J A Punt, Khalid El Makrini, Erik van Dijk, Bauke Ylstra, Louis Vermeulen, Rebecca C. Fitzgerald, Daniël M. Miedema, Jurriaan B. Tuynman, Tom van den Bosch, Jan Paul Medema, Geert J. P. L. Kops, Hendrik F. van Essen, Michiel Boekhout, Joris H. Hageman, Kristiaan J. Lenos, Hugo J. Snippert, Nico Lansu, van den Bosch, Tom [0000-0002-5266-8446], Lenos, Kristiaan J [0000-0003-1165-8732], Hageman, Joris H [0000-0002-1386-054X], Fitzgerald, Rebecca C [0000-0002-3434-3568], Snippert, Hugo J G [0000-0002-4189-5213], Kops, Geert J P L [0000-0003-3555-5295], Ylstra, Bauke [0000-0001-9479-3010], Vermeulen, Louis [0000-0002-6066-789X], Miedema, Daniël M [0000-0002-0729-3753], Apollo - University of Cambridge Repository, Center of Experimental and Molecular Medicine, Graduate School, CCA - Cancer biology and immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Oncology, Radiotherapy, Hubrecht Institute for Developmental Biology and Stem Cell Research, Lenos, Kristiaan J. [0000-0003-1165-8732], Hageman, Joris H. [0000-0002-1386-054X], Fitzgerald, Rebecca C. [0000-0002-3434-3568], Snippert, Hugo J. G. [0000-0002-4189-5213], Kops, Geert J. P. L. [0000-0003-3555-5295], Miedema, Daniël M. [0000-0002-0729-3753], Snippert, Hugo JG [0000-0002-4189-5213], Kops, Geert JPL [0000-0003-3555-5295], Internal medicine, Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, and Pathology

Subjects
0301 basic medicine, Oncology, Male, Tumor Microenvironment/genetics, General Physics and Astronomy, Datasets as Topic, Disease, 0302 clinical medicine, Models, Chromosome instability, Neoplasms, 80 and over, Cancer genomics, Tumor Microenvironment, Child, Aged, 80 and over, Multidisciplinary, Genomics, Middle Aged, Prognosis, Neoplasms/genetics, Progression-Free Survival, 3. Good health, Survival Rate, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Science, Tumour heterogeneity, 45/23, 631/67/69, Biology, 631/67/2329, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetic Heterogeneity, Young Adult, Genetic, Internal medicine, medicine, Humans, Computer Simulation, Progression-free survival, Risk Assessment/methods, Survival rate, Aged, Neoplastic, Models, Genetic, Genetic heterogeneity, Gene Expression Profiling, Cancer, General Chemistry, medicine.disease, Computational biology and bioinformatics, Gene expression profiling, 030104 developmental biology, Gene Expression Regulation, 14/63, Mutation, 631/114
Abstract

Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types., Intratumour heterogeneity (ITH) is associated with worse prognosis in cancer, and efficient frameworks to measure it are needed. Here the authors develop a method to estimate copy number heterogeneity, and propose that it is driven by chromosomal instability and can predict pan-cancer survival.

Published
2021

14. Multilayer modelling of the human transcriptome and biological mechanisms of complex diseases and traits

Author

Tiago Azevedo, Giovanna Maria Dimitri, Eric R. Gamazon, Pietro Liò, Azevedo, Tiago [0000-0002-2052-3832], Gamazon, Eric R. [0000-0003-4204-8734], Apollo - University of Cambridge Repository, and Gamazon, Eric R [0000-0003-4204-8734]

Subjects
QH301-705.5, Data_MISCELLANEOUS, Computational biology, Biology, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, 631/208, 03 medical and health sciences, 0302 clinical medicine, Cancer genome, Drug Discovery, Gene expression, medicine, Genetics, Humans, Gene Regulatory Networks, Biology (General), Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Applied Mathematics, Cancer, Genomics, medicine.disease, Biobank, Systematic testing, Computer Science Applications, Biomarker (cell), Computational biology and bioinformatics, Phenotype, Organ Specificity, Modeling and Simulation, 631/114, 030217 neurology & neurosurgery
Abstract

Funder: W. D. Armstrong Trust Fund, University of Cambridge, UK, Here, we performed a comprehensive intra-tissue and inter-tissue multilayer network analysis of the human transcriptome. We generated an atlas of communities in gene co-expression networks in 49 tissues (GTEx v8), evaluated their tissue specificity, and investigated their methodological implications. UMAP embeddings of gene expression from the communities (representing nearly 18% of all genes) robustly identified biologically-meaningful clusters. Notably, new gene expression data can be embedded into our algorithmically derived models to accelerate discoveries in high-dimensional molecular datasets and downstream diagnostic or prognostic applications. We demonstrate the generalisability of our approach through systematic testing in external genomic and transcriptomic datasets. Methodologically, prioritisation of the communities in a transcriptome-wide association study of the biomarker C-reactive protein (CRP) in 361,194 individuals in the UK Biobank identified genetically-determined expression changes associated with CRP and led to considerably improved performance. Furthermore, a deep learning framework applied to the communities in nearly 11,000 tumors profiled by The Cancer Genome Atlas across 33 different cancer types learned biologically-meaningful latent spaces, representing metastasis (p < 2.2 × 10−16) and stemness (p < 2.2 × 10−16). Our study provides a rich genomic resource to catalyse research into inter-tissue regulatory mechanisms, and their downstream consequences on human disease.

Published
2021

15. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Author

Xi, Ruibin, Jain, Dhawal, Jung, Youngsook L., Yang, Lixing, Gordenin, Dmitry, Pellman, David S., Akdemir, Kadir C., Alvarez, Eva G., Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Brors, Benedikt, Burns, Kathleen H., Campbell, Peter J., Chan, Kin, Chen, Ken, Cortés-Ciriano, Isidro, Dueso-Barroso, Ana, Dunford, Andrew J., Edwards, Paul A., Estivill, Xavier, Etemadmoghadam, Dariush, Feuerbach, Lars, Fink, J. Lynn, Frenkel-Morgenstern, Milana, Garsed, Dale W., Gerstein, Mark, Gordenin, Dmitry A., Haan, David, Haber, James E., Hess, Julian M., Hutter, Barbara, Imielinski, Marcin, Jones, David T. W., Ju, Young Seok, Kazanov, Marat D., Klimczak, Leszek J., Koh, Youngil, Korbel, Jan O., Kumar, Kiran, Lee, Eunjung Alice, Lee, Jake June-Koo, Li, Yilong, Lynch, Andy G., Macintyre, Geoff, Markowetz, Florian, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Miyano, Satoru, Nakagawa, Hidewaki, Navarro, Fabio C. P., Ossowski, Stephan, Park, Peter J., Pearson, John V., Puiggròs, Montserrat, Rippe, Karsten, Roberts, Nicola D., Roberts, Steven A., Rodriguez-Martin, Bernardo, Schumacher, Steven E., Scully, Ralph, Shackleton, Mark, Sidiropoulos, Nikos, Sieverling, Lina, Stewart, Chip, Torrents, David, Tubio, Jose M. C., Villasante, Izar, Waddell, Nicola, Wala, Jeremiah A., Weischenfeldt, Joachim, Yao, Xiaotong, Yoon, Sung-Soo, Zamora, Jorge, Zhang, Cheng-Zhong, Cortés-Ciriano, Isidro [0000-0002-2036-494X], Lee, Jake June-Koo [0000-0003-1348-4094], Xi, Ruibin [0000-0001-7545-7361], Gordenin, Dmitry [0000-0002-8399-1836], Klimczak, Leszek J. [0000-0003-3048-2576], Zhang, Cheng-Zhong [0000-0001-8825-7158], Park, Peter J. [0000-0001-9378-960X], and Apollo - University of Cambridge Repository

Subjects
631/67, 45, analysis, 631/208/212, 45/23, 631/114
Abstract

Funder: Ludwig Center at Harvard, Funder: National Cancer Institute: K22CA193848, Funder: US National Institutes of Health Intramural Research Program Project Z1AES103266, Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

Published
2021
Full Text
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16. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

Author

D Simone, Mirjana Efremova, Arthur G. Pratt, Ash Maroof, Hussein Al-Mossawi, Paul Bowness, Matthew D. Young, Lira Mamanova, Andrew Filer, Andrew L. Croxford, Charlotte Guzzo, LN Nwosu, F Penkava, Suzanne Cole, Nicole Yager, Chrysothemis C. Brown, John D. Isaacs, Sarah A. Teichmann, Alicia Lledo Lara, Martin Del Castillo Velasco-Herrera, Sam Behjati, Penkava, Frank [0000-0001-9163-8576], Velasco-Herrera, Martin Del Castillo [0000-0001-5956-0211], Nwosu, Lilian N [0000-0001-8938-8678], Guzzo, Charlotte [0000-0003-3742-5961], Filer, Andrew [0000-0001-8164-6249], Teichmann, Sarah [0000-0002-6294-6366], Bowness, Paul [0000-0003-4597-0484], Hussein Al-Mossawi, M [0000-0002-2312-3754], Apollo - University of Cambridge Repository, Nwosu, Lilian N. [0000-0001-8938-8678], and Hussein Al-Mossawi, M. [0000-0002-2312-3754]

Subjects
0301 basic medicine, Inflammatory arthritis, Receptors, Antigen, T-Cell, alpha-beta, General Physics and Astronomy, Arthritis, Autoimmunity, CD8-Positive T-Lymphocytes, urologic and male genital diseases, CXCR3, 631/250/38, 0302 clinical medicine, Synovial Fluid, Cytotoxic T cell, lcsh:Science, Clonal Selection, Antigen-Mediated, Multidisciplinary, Synovial Membrane, article, Chronic inflammation, humanities, medicine.anatomical_structure, Receptors, Chemokine, Single-Cell Analysis, Science, T cell, Adaptive immunity, Receptors, Lymphocyte Homing, Biology, General Biochemistry, Genetics and Molecular Biology, 38/91, 631/250/2152, 03 medical and health sciences, Psoriatic arthritis, medicine, Synovial fluid, CXCL10, Humans, 030203 arthritis & rheumatology, 82/58, Gene Expression Profiling, Arthritis, Psoriatic, General Chemistry, medicine.disease, Computational biology and bioinformatics, 030104 developmental biology, 631/250/256/2515, Cancer research, lcsh:Q, 631/114, Immunologic Memory
Abstract

Funder: Kennedy Trust studentship, Funder: Oxford-UCB Prize Fellowship, Funder: National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University and Versus Arthritis Research into Inflammatory Arthritis Centre; ref. 22072)., Funder: NIHR Birmingham BRC at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Funder: St Baldrick’s Foundation, Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

Published
2020

17. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Author

Manuel Mayhaus, Sandro Sorbi, Peter R. Schofield, A. Rollin, A. Karydas, Alessandro Padovani, Gilles Gasparoni, Peter St George-Hyslop, Carol Dobson-Stone, Stefano F. Cappa, D. S. Knopman, John Hardy, John R. Hodges, Graziella Milan, Florence Pasquier, Christopher Morris, Edward D. Huey, Marc Cruts, Y.A.L. Pijnenburg, R. C. Petersen, Elisa Rubino, P. Scheltens, Vincent Deramecourt, Neil Graff-Radford, Elio Scarpini, Ting Wang, Panagiotis Alexopoulos, Peter Heutink, Lena E. Hjermind, AB Singleton, Jordan Grafman, Elizabeth Thompson, Adrian Danek, Pietro Pietrini, Raffaele Ferrari, Innocenzo Rainero, C. Van Broeckhoven, Rosa Capozzo, Adaikalavan Ramasamy, J. van der Zee, Eric M. Wassermann, Karin Nilsson, Ging-Yuek Robin Hsiung, J. C. van Swieten, Ping Zeng, Rosa Rademakers, Siro Bagnoli, Amalia C. Bruni, Anna Richardson, Dimitrios Kapogiannis, Ian R. A. Mackenzie, Martin N. Rossor, Bruce L. Miller, Roberta Ghidoni, Raffaele Maletta, Massimo Franceschi, Rafael Blesa, Vivianna M. Van Deerlin, Christer Nilsson, Glenda M. Halliday, Jordi Clarimón, John Q. Trojanowski, Michael Tierney, Valeria Novelli, Agustín Ruiz, Didier Hannequin, Giorgio Giaccone, Elise G.P. Dopper, Nicoletta Smirne, F Tagliavini, I. Leber, Julie S. Snowden, Sara Rollinson, Alexis Brice, Ian G. McKeith, John E. Nielsen, Paolo Sorrentino, Véronique Golfier, Maura Gallo, Lauren Bartley, B. F. Boeve, Giancarlo Logroscino, Elena Alonso, Lorenzo Pinessi, Matt Baker, Nigel J. Cairns, Matthias Riemenschneider, William S. Brooks, Alexander Gerhard, Mark Kristiansen, Eric Haan, Israel Hernandez, Ekaterina Rogaeva, Jason D. Warren, Thibaud Lebouvier, Nick C. Fox, Stuart Pickering-Brown, Giacomina Rossi, Carlos Cruchaga, G. Binetti, Maria Landqvist Waldö, William W. Seeley, Jonathan D. Rohrer, Keith A. Josephs, Diego Albani, Wei Gu, Huei-Hsin Chiang, Luigi Ferrucci, H. Zhao, Howie Rosen, Pau Pastor, Alfredo Postiglione, Evelyn Jaros, Livia Bernardi, Dena G. Hernandez, Alberto Lleó, James B. Rowe, Parastoo Momeni, Maria Serpente, Huw R. Morris, Timothy D. Griffiths, Maria Grazia Spillantini, Alan J. Thomas, Maria Elena Conidi, M. Anfossi, Sabrina Pichler, Martine Vercelletto, Murray Grossman, Johannes C. M. Schlachetzki, Gianluigi Forloni, Dennis W. Dickson, Chiara Fenoglio, Olivier Piguet, John B.J. Kwok, Benedetta Nacmias, Harro Seelaar, Robert Perneczky, A. Baborie, Patrizia Rizzu, Y. Gao, Simon Mead, Janine Diehl-Schmid, Sara Ortega-Cubero, Mike A. Nalls, Daniela Galimberti, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Johannes Attems, Luisa Benussi, Chiara Cupidi, Irene Piaceri, Xinghao Yu, Joseph E. Parisi, Alexander Kurz, John Collinge, James Uphill, Barbara Borroni, Francesca Frangipane, Caroline Graff, Bernd Ibach, D. M. A. Mann, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Neurology, Apollo - University of Cambridge Repository, and Int FTD-Genomics Consortium IFGC

Subjects
0301 basic medicine, Oncology, lcsh:Medicine, Genome-wide association study, Neurodegenerative, 631/208, 0302 clinical medicine, Leukocytes, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, Amyotrophic lateral sclerosis, lcsh:Science, Telomerase, Telomere Shortening, education.field_of_study, Multidisciplinary, 692/617, article, Mendelian Randomization Analysis, Amyotrophic Lateral Sclerosis, Asian Continental Ancestry Group, Cholesterol, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, LDL, Polymorphism, Single Nucleotide, Proportional Hazards Models, Telomere, Frontotemporal Dementia, Single Nucleotide, Neurology, Engineering sciences. Technology, 692/499, medicine.medical_specialty, Lipoproteins, 692/308, Population, White People, LDL, Mendelian randomization (MR) , leukocyte telomere length (LTL) , amyotrophic lateral sclerosis (ALS), 03 medical and health sciences, Medical research, Rare Diseases, Asian People, Internal medicine, Mendelian randomization, Genetics, medicine, Polymorphism, education, Genetic association, business.industry, Proportional hazards model, International FTD-Genomics Consortium, lcsh:R, Neurosciences, Odds ratio, medicine.disease, Computational biology and bioinformatics, Brain Disorders, 030104 developmental biology, Risk factors, lcsh:Q, 631/114, ALS, business, ddc:600, 030217 neurology & neurosurgery
Abstract

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Published
2020

18. Tracking the Near Eastern origins and European dispersal of the western house mouse

Author

Yannis Hamilakis, Fanis Mavridis, Melinda A. Zeder, François Raymond Valla, François Bonhomme, Régis Debruyne, Fereidoun Biglari, Greger Larson, Emma Jenkins, Cameron A. Petrie, Antoine Zazzo, Adrian Bălășescu, Alireza Sardari, Jean-Christophe Auffray, Roohollah Siahsarvi, Marjan Mashkour, Christiane Denys, Jean-Denis Vigne, Jamshid Darvish, Thomas Cucchi, Alan H. Simmons, Katerina Papayianni, Lloyd Weeks, Sophie Cersoy, Sepideh Maziar, Rémi Berthon, Laetitia Aznar-Cormano, David Orton, Jeremy B. Searle, Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Wiener Laboratory, American School of Classical Studies at Athens, Centre de Recherche sur la Conservation (CRC ), Muséum national d'Histoire naturelle (MNHN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Paléontologie - Paris (CR2P), Muséum national d'Histoire naturelle (MNHN)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Direction générale déléguée à la Recherche, à l’Expertise, à la Valorisation et à l’Enseignement-Formation (DGD.REVE), Muséum national d'Histoire naturelle (MNHN), Institute of Archaeology Vasile Parvan, Desert Research Institute (DRI), Archéologies et Sciences de l'Antiquité (ArScAn), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Brown University, Ephorate of Palaeoanthropology–Speleology, Hellenic Ministry of Culture and Sports (YPPO), Ferdowsi University of Mashhad, Center for Paleolithic Research, National Museum of Iran, Department of Archaeology and Anthropology, University of Cambridge, Cambridge, UK, School of Humanities, Arts and Social Sciences, University of New England, Armidale, New South Wales, Australia, Research Institute of Cultural Heritage and Tourism (RICHT), Iranian Center for Archaeological Research (ICAR), Tehran, Iran, Goethe-Universität Frankfurt am Main, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Departments of Archaeology [York] (BioArch), University of York [York, UK], Bournemouth University [Poole] (BU), Smithsonian Institution, National Museum of Natural History, Cornell University [New York], University of Oxford [Oxford], Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-LABX-0003,BCDiv,Biological and Cultural Diversities : Origins, Evolution, Interactions, Future(2010), Petrie, Cameron [0000-0002-2926-7230], Apollo - University of Cambridge Repository, Université Panthéon-Sorbonne (UP1)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226, Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Institut national de recherches archéologiques préventives (Inrap)-Centre National de la Recherche Scientifique (CNRS), Ferdowsi University of Mashhad (FUM), University of Oxford, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, 631/45, Molecular biology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Introduced species, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, 01 natural sciences, Biochemistry, House mouse, law.invention, [SHS]Humanities and Social Sciences, Mice, law, Radiocarbon dating, Europe, Eastern, lcsh:Science, 631/601, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Middle East, biology, Ecology, article, Mitochondria, Geography, Archaeology, [SDE]Environmental Sciences, 631/337, 010506 paleontology, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, DNA, Mitochondrial, 03 medical and health sciences, Human settlement, Asia, Western, Animals, Humans, Domestication, 0105 earth and related environmental sciences, lcsh:R, Radiometric Dating, Sequence Analysis, DNA, biology.organism_classification, Computational biology and bioinformatics, 030104 developmental biology, Cyprus, Biological dispersal, lcsh:Q, House mice, 631/114, 631/158, Introduced Species, Zoology
Abstract

The house mouse (Mus musculus) represents the extreme of globalization of invasive mammals. However, the timing and basis of its origin and early phases of dispersal remain poorly documented. To track its synanthropisation and subsequent invasive spread during the develoment of complex human societies, we analyzed 829 Mus specimens from 43 archaeological contexts in Southwestern Asia and Southeastern Europe, between 40,000 and 3,000 cal. BP, combining geometric morphometrics numerical taxonomy, ancient mitochondrial DNA and direct radiocarbon dating. We found that large late hunter-gatherer sedentary settlements in the Levant, c. 14,500 cal. BP, promoted the commensal behaviour of the house mouse, which probably led the commensal pathway to cat domestication. House mouse invasive spread was then fostered through the emergence of agriculture throughout the Near East 12,000 years ago. Stowaway transport of house mice to Cyprus can be inferred as early as 10,800 years ago. However, the house mouse invasion of Europe did not happen until the development of proto urbanism and exchange networks — 6,500 years ago in Eastern Europe and 4000 years ago in Southern Europe — which in turn may have driven the first human mediated dispersal of cats in Europe.

Published
2020

19. Inferring structural variant cancer cell fraction

Author

Cmero, Marek, Yuan, Ke, Ong, Cheng Soon, Schröder, Jan, Corcoran, Niall M., Papenfuss, Tony, Hovens, Christopher M., Markowetz, Florian, Macintyre, Geoff, Adams, David J., Anur, Pavana, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Campbell, Peter J., Cao, Shaolong, Christie, Elizabeth L., Cun, Yupeng, Dawson, Kevin J., Demeulemeester, Jonas, Dentro, Stefan C., Deshwar, Amit G., Donmez, Nilgun, Drews, Ruben M., Eils, Roland, Fan, Yu, Fittall, Matthew W., Garsed, Dale W., Gerstung, Moritz, Getz, Gad, Gonzalez, Santiago, Ha, Gavin, Haase, Kerstin, Imielinski, Marcin, Jerman, Lara, Ji, Yuan, Jolly, Clemency, Kleinheinz, Kortine, Lee, Juhee, Lee-Six, Henry, Leshchiner, Ignaty, Livitz, Dimitri, Malikic, Salem, Martincorena, Iñigo, Mitchell, Thomas J., Morris, Quaid D., Mustonen, Ville, Oesper, Layla, Peifer, Martin, Peto, Myron, Raphael, Benjamin J., Rosebrock, Daniel, Rubanova, Yulia, Sahinalp, S. Cenk, Salcedo, Adriana, Schlesner, Matthias, Schumacher, Steven E., Sengupta, Subhajit, Shi, Ruian, Shin, Seung Jun, Spellman, Paul T., Spiro, Oliver, Stein, Lincoln D., Tarabichi, Maxime, Van Loo, Peter, Vembu, Shankar, Vázquez-García, Ignacio, Wang, Wenyi, Wedge, David C., Wheeler, David A., Wintersinger, Jeffrey A., Yang, Tsun-Po, Yao, Xiaotong, Yu, Kaixian, Zhu, Hongtu, Cmero, Marek [0000-0001-7783-5530], Yuan, Ke [0000-0002-2318-1460], Ong, Cheng Soon [0000-0002-2302-9733], Papenfuss, Tony [0000-0002-1102-8506], Markowetz, Florian [0000-0002-2784-5308], Macintyre, Geoff [0000-0003-3906-467X], Apollo - University of Cambridge Repository, Dentro, SC, Wedge, DC, Yang, T-P, Organismal and Evolutionary Biology Research Programme, Institute of Biotechnology, Bioinformatics, and Department of Computer Science

Subjects
Male, 0301 basic medicine, Medizin, General Physics and Astronomy, Somatic evolution in cancer, Genome, 0302 clinical medicine, Gene Frequency, Neoplasms, 129, lcsh:Science, Cancer, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Manchester Cancer Research Centre, Prostatic Neoplasms/genetics, Liver Neoplasms, 1184 Genetics, developmental biology, physiology, Neoplasms/genetics, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Ovarian Cancer, 3. Good health, 030220 oncology & carcinogenesis, 1181 Ecology, evolutionary biology, 139, Female, Algorithms, Human, 631/67, DNA Copy Number Variations, Science, In silico, Computational biology, Biology, Sensitivity and Specificity, Article, General Biochemistry, Genetics and Molecular Biology, Ovarian Neoplasms/genetics, 03 medical and health sciences, Rare Diseases, Machine learning, Genetics, PCAWG Evolution and Heterogeneity Working Group, medicine, Humans, Computer Simulation, ddc:610, Liver Neoplasms/genetics, Allele frequency, Whole genome sequencing, 45, Whole Genome Sequencing, Genome, Human, ResearchInstitutes_Networks_Beacons/mcrc, Human Genome, Breakpoint, Computational Biology, Prostatic Neoplasms, PCAWG Consortium, General Chemistry, Computational Biology/methods, 631/114/1305, 113 Computer and information sciences, Pancreatic Neoplasms/genetics, medicine.disease, Computational biology and bioinformatics, Pancreatic Neoplasms, 030104 developmental biology, lcsh:Q, Human genome, 631/114, 119, Digestive Diseases
Abstract

We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity., The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Published
2020

20. Genomic footprints of activated telomere maintenance mechanisms in cancer

Author

Hong, Chen, Koser, Sandra D., Ginsbach, Philip, Kleinheinz, Kortine, Braun, Delia M., Xi, Ruibin, Kabbe, Rolf, Eils, Roland, Schlesner, Matthias, Brors, Benedikt, Jones, David T. W., Akdemir, Kadir C., Alvarez, Eva G., Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Burns, Kathleen H., Campbell, Peter J., Chan, Kin, Chen, Ken, Cortés-Ciriano, Isidro, Dueso-Barroso, Ana, Dunford, Andrew J., Edwards, Paul A., Estivill, Xavier, Etemadmoghadam, Dariush, Feuerbach, Lars, Fink, J. Lynn, Frenkel-Morgenstern, Milana, Garsed, Dale W., Gerstein, Mark, Gordenin, Dmitry A., Haan, David, Haber, James E., Hess, Julian M., Hutter, Barbara, Imielinski, Marcin, Ju, Young Seok, Kazanov, Marat D., Klimczak, Leszek J., Koh, Youngil, Korbel, Jan O., Kumar, Kiran, Lee, Eunjung Alice, Lee, Jake June-Koo, Li, Yilong, Lynch, Andy G., Macintyre, Geoff, Markowetz, Florian, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Meyerson, Matthew, Miyano, Satoru, Nakagawa, Hidewaki, Navarro, Fabio C. P., Ossowski, Stephan, Park, Peter J., Pearson, John V., Puiggròs, Montserrat, Rippe, Karsten, Roberts, Nicola D., Roberts, Steven A., Rodriguez-Martin, Bernardo, Schumacher, Steven E., Scully, Ralph, Shackleton, Mark, Sidiropoulos, Nikos, Sieverling, Lina, Stewart, Chip, Torrents, David, Tubio, Jose M. C., Villasante, Izar, Waddell, Nicola, Wala, Jeremiah A., Weischenfeldt, Joachim, Yang, Lixing, Yao, Xiaotong, Yoon, Sung-Soo, Zamora, Jorge, Zhang, Cheng-Zhong, Sieverling, Lina [0000-0002-0595-4976], Hong, Chen [0000-0003-1244-3506], Hutter, Barbara [0000-0002-9034-0329], Braun, Delia M. [0000-0002-6059-7588], Cortés-Ciriano, Isidro [0000-0002-2036-494X], Xi, Ruibin [0000-0001-7545-7361], Park, Peter J. [0000-0001-9378-960X], Schlesner, Matthias [0000-0002-5896-4086], Rippe, Karsten [0000-0001-9951-9395], and Apollo - University of Cambridge Repository

Subjects
45, article, 631/67/69, 631/114, 692/4028/67
Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

Published
2020

21. SciPy 1.0: fundamental algorithms for scientific computing in Python: 24 February 2020 : An amendment to this paper has been published and can be accessed via a link at the top of the paper

Author

Virtanen, P., Gommers, R., Oliphant, T.E., Haberland, M., Reddy, T., Cournapeau, D., Burovski, E., Peterson, P., Weckesser, W., Bright, J., Walt, S.J., Brett, M., Wilson, J., Millman, K.J., Mayorov, N., Nelson, A.R.J., Jones, E., Kern, R., Larson, E., Carey, C.J., Polat, I., Feng, Y., Moore, E.W., VanderPlas, J., Laxalde, D., Perktold, J., Cimrman, R., Henriksen, I., Quintero, E.A., Harris, C.R., Archibald, A.M., Ribeiro, A.H., Pedregosa, F., Mulbregt, P., Vijaykumar, A., Bardelli, A.P., Rothberg, A., Hilboll, A., Kloeckner, A., Scopatz, A., Lee, A., Rokem, A., Woods, C.N., Fulton, C., Masson, C., Häggström, C., Fitzgerald, C., Nicholson, D.A., Hagen, D.R., Pasechnik, D.V., Olivetti, E., Martin, E., Wieser, E., Lenders, F., Silva, Fabrice, Wilhelm, F., Young, G., Price, G.A., Ingold, G.-L., Allen, G.E., Lee, G.R., Audren, H., Probst, Irvin, Dietrich, J.P., Silterra, J., Webber, J.T., Slavič, J., Nothman, J., Buchner, J., Kulick, J., Schönberger, J.L., Miranda Cardoso, J.V., Reimer, J., Harrington, J., Rodríguez, J.L.C., Nunez-Iglesias, J., Kuczynski, J., Tritz, K., Thoma, M., Newville, M., Kümmerer, M., Bolingbroke, M., Tartre, M., Pak, M., Smith, N.J., Nowaczyk, N., Shebanov, N., Pavlyk, O., Brodtkorb, P.A., Lee, P., McGibbon, R.T., Feldbauer, R., Lewis, S., Tygier, S., Sievert, S., Vigna, S., Peterson, S., More, S., Pudlik, T., Oshima, T., Pingel, T.J., Robitaille, T.P., Spura, T., Jones, T.R., Cera, T., Leslie, T., Zito, T., Krauss, T., Upadhyay, U., Halchenko, Y.O., Vázquez-Baeza, Y., SciPy 1.0, Contributors, Low Temperature Laboratory, TKK Helsinki University of Technology (TKK), Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Tribologie et Dynamique des Systèmes (LTDS), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Ecole Nationale d'Ingénieurs de Saint Etienne-Centre National de la Recherche Scientifique (CNRS), SNECMA Villaroche [Moissy-Cramayel], Safran Group, New Technologies Research Centre [Plzeň] (NTC), University of West Bohemia [Plzeň ], Institute of Environmental Physics [Bremen] (IUP), University of Bremen, Istituto Nazionale di Ricerca Metrologica (INRiM), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Mécanique et d'Acoustique [Marseille] (LMA ), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Sons, Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), European Synchrotron Radiation Facility (ESRF), Lab-STICC_ENSTAB_CID_PRASYS, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT), Max Planck Institute for Solar System Research (MPS), Max-Planck-Gesellschaft, University of Chicago, Consortium of Advanced Radiation Sciences, Advanced Photon Source, GSECARS, University of Chicago, Laboratoire de physique des gaz et des plasmas (LPGP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), The Open University [Milton Keynes] (OU), Nobeyama Radio Observatory, Gommers, Ralf [0000-0002-0300-3333], Haberland, Matt [0000-0003-4806-3601], Reddy, Tyler [0000-0003-2364-6157], van der Walt, Stéfan J. [0000-0001-9276-1891], Millman, K. Jarrod [0000-0002-5263-5070], Nelson, Andrew R. J. [0000-0002-4548-3558], Laxalde, Denis [0000-0002-5540-4825], Ribeiro, Antônio H. [0000-0003-3632-8529], van Mulbregt, Paul [0000-0002-2382-8308], Apollo - University of Cambridge Repository, van der Walt, Stéfan J [0000-0001-9276-1891], Millman, K Jarrod [0000-0002-5263-5070], Nelson, Andrew RJ [0000-0002-4548-3558], Ribeiro, Antônio H [0000-0003-3632-8529], Quansight LLC, California Polytechnic State University [San Luis Obispo] (CAL POLY), Los Alamos National Laboratory (LANL), AUTRES, National Research University Higher School of Economics [St. Petersburg], Tallinn Technical University, University of California [Berkeley] (UC Berkeley), University of California (UC), University of Birmingham [Birmingham], Skolkovo Innovation Center, Australian Nuclear Science and Technology Organisation [Australie] (ANSTO), Enthought Inc, University of Washington [Seattle], University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Bruker BioSpin Corporation, Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Ecole Nationale d'Ingénieurs de Saint Etienne (ENISE)-Centre National de la Recherche Scientifique (CNRS), University of Texas at Austin [Austin], Astronomical Institute Anton Pannekoek (AI PANNEKOEK), University of Amsterdam [Amsterdam] (UvA), Universidade Federal de Minas Gerais [Belo Horizonte] (UFMG), Google LLC, Laboratoire Chrono-environnement (UMR 6249) (LCE), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL)-IMT Atlantique (IMT Atlantique), and Max-Planck-Institut für Sonnensystemforschung = Max Planck Institute for Solar System Research (MPS)

Subjects
FOS: Computer and information sciences, Computer science, 01 natural sciences, Biochemistry, Computer Science - Software Engineering, 631/45/56, Data Structures and Algorithms (cs.DS), 010303 astronomy & astrophysics, computer.programming_language, 0303 health sciences, Signal processing, Signal Processing, Computer-Assisted, Computational Physics (physics.comp-ph), ddc, Linear algebra, Perspective, Minification, Physics - Computational Physics, Algorithm, Algorithms, Biotechnology, De facto standard, FOS: Physical sciences, Image processing, History, 21st Century, Models, Biological, 706/703/559, Python (Computer program language), Computational science, 03 medical and health sciences, Computer Science - Data Structures and Algorithms, 0103 physical sciences, Computer Simulation, [INFO]Computer Science [cs], ddc:530, Cluster analysis, Molecular Biology, Scientific computing, 030304 developmental biology, Sparse matrix, software, Computational Biology, Cell Biology, Python (programming language), History, 20th Century, [INFO.INFO-NA]Computer Science [cs]/Numerical Analysis [cs.NA], Software Engineering (cs.SE), Nonlinear Dynamics, Linear Models, Computer Science - Mathematical Software, Programming Languages, 631/114, computer, Mathematical Software (cs.MS), Python
Abstract

SciPy is an open source scientific computing library for the Python programming language. SciPy 1.0 was released in late 2017, about 16 years after the original version 0.1 release. SciPy has become a de facto standard for leveraging scientific algorithms in the Python programming language, with more than 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories, and millions of downloads per year. This includes usage of SciPy in almost half of all machine learning projects on GitHub, and usage by high profile projects including LIGO gravitational wave analysis and creation of the first-ever image of a black hole (M87). The library includes functionality spanning clustering, Fourier transforms, integration, interpolation, file I/O, linear algebra, image processing, orthogonal distance regression, minimization algorithms, signal processing, sparse matrix handling, computational geometry, and statistics. In this work, we provide an overview of the capabilities and development practices of the SciPy library and highlight some recent technical developments., Comment: Article source data is available here: https://github.com/scipy/scipy-articles

Published
2020

22. Biotin proximity tagging favours unfolded proteins and enables the study of intrinsically disordered regions

Author

Minde, David-Paul, Ramakrishna, Manasa, Lilley, Kathryn S, Minde, David-Paul [0000-0002-2985-622X], Ramakrishna, Manasa [0000-0002-5736-8311], Lilley, Kathryn S. [0000-0003-0594-6543], Apollo - University of Cambridge Repository, and Lilley, Kathryn S [0000-0003-0594-6543]

Subjects
Models, Molecular, Proteomics, 631/45, Protein Conformation, Medicine (miscellaneous), medicine.disease_cause, Ribosome, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Biotin, 631/92, lcsh:QH301-705.5, 0303 health sciences, article, 101/47, Chemical biology, humanities, Cell biology, Protein Transport, Biotinylation, General Agricultural and Biological Sciences, Structural biology, 631/535, Protein Binding, 101, 101/58, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Structure-Activity Relationship, In vivo, medicine, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, 101/1, Escherichia coli, Cellular compartment, 030304 developmental biology, Protein Unfolding, 82, Lysine, Computational biology and bioinformatics, Intrinsically Disordered Proteins, chemistry, lcsh:Biology (General), Time course, Tyrosine, 631/80, 631/114, Protein Processing, Post-Translational, Ribosomes, 030217 neurology & neurosurgery
Abstract

Intrinsically Disordered Regions (IDRs) are enriched in disease-linked proteins known to have multiple post-translational modifications, but there is limited in vivo information about how locally unfolded protein regions contribute to biological functions. We reasoned that IDRs should be more accessible to targeted in vivo biotinylation than ordered protein regions, if they retain their flexibility in human cells. Indeed, we observed increased biotinylation density in predicted IDRs in several cellular compartments >20,000 biotin sites from four proximity proteomics studies. We show that in a biotin ‘painting’ time course experiment, biotinylation events in Escherichia coli ribosomes progress from unfolded and exposed regions at 10 s, to structured and less accessible regions after five minutes. We conclude that biotin proximity tagging favours sites of local disorder in proteins and suggest the possibility of using biotin painting as a method to gain unique insights into in vivo condition-dependent subcellular plasticity of proteins., David-Paul Minde, Manasa Ramakrishna et al. look at intrinsically disordered regions of disease-linked proteins in vivo by biotinylation. They show that biotin “painting” could be used as a method to examine the condition-dependent plasticity of proteins in vivo.

Published
2020

23. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author

Escala-Garcia, Maria, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Ashworth, Alan, Auer, Paul L, Auvinen, Päivi, Beckmann, Matthias W, Beesley, Jonathan, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Dwek, Miriam, Earl, Helena M, Eccles, Diana M, Eliassen, A Heather, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Guo, Qi, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Harrington, Patricia A, Hiller, Louise, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Chiun-Sheng, Huang, Guanmengqian, Hunter, David J, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Kitahara, Cari M, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orr, Nick, Peterlongo, Paolo, Petridis, Christos, Prentice, Ross L, Presneau, Nadege, Punie, Kevin, Ramachandran, Dhanya, Rennert, Gad, Romero, Atocha, Sachchithananthan, Mythily, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schwentner, Lukas, Scott, Christopher, Simard, Jacques, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Terry, Mary Beth, Thorne, Heather, Tollenaar, Rob A E M, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Turnbull, Clare, Vachon, Celine M, van der Kolk, Lizet E, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Ziogas, Argyrios, Pharoah, Paul D P, Hall, Per, Wessels, Lodewyk F A, Chenevix-Trench, Georgia, Bader, Gary D, Dörk, Thilo, Easton, Douglas F, Canisius, Sander, Schmidt, Marjanka K, Gonzalez Neira, Anna, Andrulis, Irene L., Auer, Paul L., Beckmann, Matthias W., Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Brucker, Sara Y., Chanock, Stephen J., Clarke, Christine L., Couch, Fergus J., Cross, Simon S., Daly, Mary B., Dunn, Janet A., Dunning, Alison M., Earl, Helena M., Eccles, Diana M., Eliassen, A. Heather, Evans, D. Gareth, Fasching, Peter A., Gapstur, Susan M., García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Goldgar, David E., Haiman, Christopher A., Harrington, Patricia A., Hooning, Maartje J., Hopper, John L., Hunter, David J., John, Esther M., Kitahara, Cari M., Milne, Roger L., Neuhausen, Susan L., Newman, William G., Olshan, Andrew F., Olson, Janet E., Prentice, Ross L., Sawyer, Elinor J., Schmutzler, Rita K., Southey, Melissa C., Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Tollenaar, Rob A. E. M., Troester, Melissa A., Vachon, Celine M., van der Kolk, Lizet E., Yang, Xiaohong R., Pharoah, Paul D. P., Wessels, Lodewyk F. A., Bader, Gary D., Easton, Douglas F., Schmidt, Marjanka K., HUS Comprehensive Cancer Center, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, National Institute for Health Research (Reino Unido), German Cancer Research Center, United States of Department of Health & Human Services, Cancer Research UK (Reino Unido), European Commission, Canadian Institutes of Health Research, Ministere de l'Economie, Science et Innovation du Quebec (Canadá), Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Deutsche Krebshilfe, Russian Foundation for Basic Research, Swedish Research Council, Breast Cancer Now (Reino Unido), Medical Oncology, Surgery, National Institute for Health Research (NIHR), German Cancer Research Center (DKFZ, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Cancer Research UK, Canadian Institutes of Health Research (CIHR), Ministere de l'Economie, Science et Innovation du Quebec- CANADA, KWF Kankerbestrijding, Asociacion Espanola Contra el Cancer (AECC), Russian Foundation for Basic Research (RFBR), Breast Cancer Now, London, Unión Europea. Comisión Europea, Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Bojesen, Stig E. [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Caldas, Carlos [0000-0003-3547-1489], Canzian, Federico [0000-0002-4261-4583], Chanock, Stephen J. [0000-0002-2324-3393], Chin, Suet-Feung [0000-0001-5697-1082], Dennis, Joe [0000-0003-4591-1214], Devilee, Peter [0000-0002-8023-2009], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A. [0000-0003-4885-8471], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Giles, Graham G. [0000-0003-4946-9099], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Lambrechts, Diether [0000-0002-3429-302X], Milne, Roger L. [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G. [0000-0002-6382-4678], Olson, Janet E. [0000-0003-4944-7789], Orr, Nick [0000-0003-2866-942X], Peterlongo, Paolo [0000-0001-6951-6855], Punie, Kevin [0000-0002-1162-7963], Ramachandran, Dhanya [0000-0001-8139-7799], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Simard, Jacques [0000-0001-6906-3390], Teixeira, Manuel R. [0000-0002-4896-5982], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Winqvist, Robert [0000-0003-0932-9104], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul D. P. [0000-0001-8494-732X], Bader, Gary D. [0000-0003-0185-8861], Dörk, Thilo [0000-0002-9458-0282], Easton, Douglas F. [0000-0003-2444-3247], Canisius, Sander [0000-0003-3888-8829], Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Andrulis, Irene L [0000-0002-4226-6435], Blomqvist, Carl [0000-0003-3041-1938], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Dunning, Alison M [0000-0001-6651-7166], Earl, Helena M [0000-0003-1549-8094], Fasching, Peter A [0000-0003-4885-8471], García-Sáenz, José A [0000-0001-6880-0301], Giles, Graham G [0000-0003-4946-9099], Howell, Anthony [0000-0002-6233-719X], Milne, Roger L [0000-0001-5764-7268], Newman, William G [0000-0002-6382-4678], Olson, Janet E [0000-0003-4944-7789], Olsson, Håkan [0000-0002-8794-9635], Teixeira, Manuel R [0000-0002-4896-5982], Pharoah, Paul D P [0000-0001-8494-732X], Bader, Gary D [0000-0003-0185-8861], Easton, Douglas F [0000-0003-2444-3247], Schmidt, Marjanka K [0000-0002-2228-429X], and Pharoah, Paul DP [0000-0001-8494-732X]

Subjects
0301 basic medicine, PTEN, GTP-Binding Protein alpha Subunits, Gq-G11/genetics, 45/43, Gene regulatory network, General Physics and Astronomy, Estrogen receptor, Genome-wide association study, Apoptosis, Disease, CIRCADIAN CLOCK, VARIANTS, Bioinformatics, Genome-wide association studies, Germline, Metastasis, PATHWAY, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Gene Regulatory Networks, lcsh:Science, Multidisciplinary, TUMOR-GROWTH, Receptors, Estrogen/genetics, Prognosis, GTP-Binding Protein alpha Subunits, 3. Good health, Multidisciplinary Sciences, Receptors, Estrogen, 030220 oncology & carcinogenesis, Medical genetics, Science & Technology - Other Topics, Female, Medical Genetics, Signal Transduction, medicine.medical_specialty, Genotype, Science, 3122 Cancers, 631/208/205/2138, Breast Neoplasms, Biology, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, PROTEIN-COUPLED RECEPTORS, SDG 3 - Good Health and Well-being, Circadian Clocks, medicine, Humans, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Science & Technology, 45, Genetic Variation, Computational Biology, General Chemistry, medicine.disease, GENE, Computational biology and bioinformatics, 030104 developmental biology, Germ Cells, GTP-Binding Protein alpha Subunits/genetics, METASTASIS, GTP-Binding Protein alpha Subunits, Gq-G11, 692/4028/67/1347, lcsh:Q, CELL-GROWTH, 631/114, Genome-Wide Association Study
Abstract

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis., In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Published
2020

24. Chromosomal copy number heterogeneity predicts survival rates across cancers

Author

Van Dijk, Erik, Van Den Bosch, Tom, Lenos, Kristiaan J., El Makrini, Khalid, Nijman, Lisanne E., Van Essen, Hendrik F. B., Lansu, Nico, Boekhout, Michiel, Hageman, Joris H., Fitzgerald, Rebecca C., Punt, Cornelis J. A., Tuynman, Jurriaan B., Snippert, Hugo J. G., Kops, Geert J. P. L., Medema, Jan Paul, Ylstra, Bauke, Vermeulen, Louis, and Miedema, Daniël M.

Subjects
14/63, article, 45/23, 631/67/69, 631/114, 631/67/2329, 3. Good health
Abstract

Funder: Amsterdam UMC, AG&M institute talent development grant, Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

25. Integrative functional genomics decodes herpes simplex virus 1

Author

Whisnant, Adam W., Jürges, Christopher S., Hennig, Thomas, Wyler, Emanuel, Prusty, Bhupesh, Rutkowski, Andrzej J., L’hernault, Anne, Djakovic, Lara, Göbel, Margarete, Döring, Kristina, Menegatti, Jennifer, Antrobus, Robin, Matheson, Nicholas J., Künzig, Florian W. H., Mastrobuoni, Guido, Bielow, Chris, Kempa, Stefan, Liang, Chunguang, Dandekar, Thomas, Zimmer, Ralf, Landthaler, Markus, Grässer, Friedrich, Lehner, Paul J., Friedel, Caroline C., Erhard, Florian, and Dölken, Lars

Subjects
631/326/596/1553, article, 49/39, 631/114, 3. Good health, 38/91
Abstract

Funder: Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation); doi: https://doi.org/10.13039/100005156, The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.

26. Integrative functional genomics decodes herpes simplex virus 1

Author

Adam W. Whisnant, Christopher S. Jürges, Thomas Hennig, Emanuel Wyler, Bhupesh Prusty, Andrzej J. Rutkowski, Anne L’hernault, Lara Djakovic, Margarete Göbel, Kristina Döring, Jennifer Menegatti, Robin Antrobus, Nicholas J. Matheson, Florian W. H. Künzig, Guido Mastrobuoni, Chris Bielow, Stefan Kempa, Chunguang Liang, Thomas Dandekar, Ralf Zimmer, Markus Landthaler, Friedrich Grässer, Paul J. Lehner, Caroline C. Friedel, Florian Erhard, Lars Dölken, Whisnant, Adam W. [0000-0003-2039-2809], Jürges, Christopher S. [0000-0001-5617-6601], Wyler, Emanuel [0000-0002-9884-1806], Prusty, Bhupesh [0000-0001-7051-4670], Djakovic, Lara [0000-0002-9368-9403], Matheson, Nicholas J. [0000-0002-3318-1851], Künzig, Florian W. H. [0000-0003-3730-3905], Mastrobuoni, Guido [0000-0003-4509-1295], Bielow, Chris [0000-0001-5756-3988], Kempa, Stefan [0000-0002-0696-9299], Liang, Chunguang [0000-0002-0305-2522], Dandekar, Thomas [0000-0003-1886-7625], Landthaler, Markus [0000-0002-1075-8734], Friedel, Caroline C. [0000-0003-3569-4877], Erhard, Florian [0000-0002-3574-6983], Dölken, Lars [0000-0002-4651-3544], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, Science, viruses, article, 49/39, 38/91, Cardiovascular and Metabolic Diseases, 631/326/596/1553, ddc:570, lcsh:Q, ddc:610, 631/114, Technology Platforms, lcsh:Science
Abstract

The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.

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27. Inferring structural variant cancer cell fraction

Author

Cmero, Marek, Yuan, Ke, Ong, Cheng Soon, Schröder, Jan, Corcoran, Niall M., Papenfuss, Tony, Hovens, Christopher M., Markowetz, Florian, Macintyre, Geoff, Adams, David J., Anur, Pavana, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Campbell, Peter J., Cao, Shaolong, Christie, Elizabeth L., Cun, Yupeng, Dawson, Kevin J., Demeulemeester, Jonas, Dentro, Stefan C., Deshwar, Amit G., Donmez, Nilgun, Drews, Ruben M., Eils, Roland, Fan, Yu, Fittall, Matthew W., Garsed, Dale W., Gerstung, Moritz, Getz, Gad, Gonzalez, Santiago, Ha, Gavin, Haase, Kerstin, Imielinski, Marcin, Jerman, Lara, Ji, Yuan, Jolly, Clemency, Kleinheinz, Kortine, Lee, Juhee, Lee-Six, Henry, Leshchiner, Ignaty, Livitz, Dimitri, Malikic, Salem, Martincorena, Iñigo, Mitchell, Thomas J., Morris, Quaid D., Mustonen, Ville, Oesper, Layla, Peifer, Martin, Peto, Myron, Raphael, Benjamin J., Rosebrock, Daniel, Rubanova, Yulia, Sahinalp, S. Cenk, Salcedo, Adriana, Schlesner, Matthias, Schumacher, Steven E., Sengupta, Subhajit, Shi, Ruian, Shin, Seung Jun, Spellman, Paul T., Spiro, Oliver, Stein, Lincoln D., Tarabichi, Maxime, Van Loo, Peter, Vembu, Shankar, Vázquez-García, Ignacio, Wang, Wenyi, Wedge, David C., Wheeler, David A., Wintersinger, Jeffrey A., Yang, Tsun-Po, Yao, Xiaotong, Yu, Kaixian, and Zhu, Hongtu

Subjects
631/67, 45, article, 139, 129, 631/114, 631/114/1305, 119, 3. Good health
Abstract

We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity.

28. Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Author

Srinivas Gorur-Shandilya, Timothy O'Leary, Eve Marder, Apollo - University of Cambridge Repository, and O'Leary, Timothy [0000-0002-1029-0158]

Subjects
0301 basic medicine, Cell biology, Physiology, Population, Biophysics, lcsh:Medicine, Biology, Ion Channels, Compensation (engineering), Arthropod Proteins, 03 medical and health sciences, 0302 clinical medicine, Crustacea, Developmental biology, Animals, Homeostasis, 631/443, lcsh:Science, education, Ion channel, Cell Size, Feedback, Physiological, Neurons, education.field_of_study, 631/57, Multidisciplinary, Mechanism (biology), lcsh:R, article, Central pattern generator, Robustness (evolution), Models, Theoretical, Computational biology and bioinformatics, 030104 developmental biology, lcsh:Q, 631/80, 631/114, 631/136, 631/378, 030217 neurology & neurosurgery, Gene Deletion, Communication channel, Neuroscience
Abstract

In many species, excitable cells preserve their physiological properties despite significant variation in physical size across time and in a population. For example, neurons in crustacean central pattern generators generate similar firing patterns despite several-fold increases in size between juveniles and adults. This presents a biophysical problem because the electrical properties of cells are highly sensitive to membrane area and channel density. It is not known whether specific mechanisms exist to sense membrane area and adjust channel expression to keep a consistent channel density, or whether regulation mechanisms that sense activity alone are capable of compensating cell size. We show that destabilising effects of growth can be specifically compensated by feedback mechanism that senses average calcium influx and jointly regulate multiple conductances. However, we further show that this class of growth-compensating regulation schemes is necessarily sensitive to perturbations that alter the expression of subsets of ion channel types. Targeted perturbations of specific ion channels can trigger a pathological response of the regulation mechanism and a failure of homeostasis. Our findings suggest that physiological regulation mechanisms that confer robustness to growth may be specifically vulnerable to deletions or mutations that affect subsets of ion channels.

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29. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author

Escala-Garcia, Maria, Abraham, Jean, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Ashworth, Alan, Auer, Paul L., Auvinen, Päivi, Beckmann, Matthias W., Beesley, Jonathan, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y., Burwinkel, Barbara, Caldas, Carlos, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J., Chin, Suet-Feung, Clarke, Christine L., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Dennis, Joe, Devilee, Peter, Dunn, Janet A., Dunning, Alison M., Dwek, Miriam, Earl, Helena M., Eccles, Diana M., Eliassen, A. Heather, Ellberg, Carolina, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., George, Angela, Giles, Graham G., Goldgar, David E., González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Guo, Qi, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Harrington, Patricia A., Hiller, Louise, Hooning, Maartje J., Hopper, John L., Howell, Anthony, Huang, Chiun-Sheng, Huang, Guanmengqian, Hunter, David J., Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Kitahara, Cari M., Koppert, Linetta B., Kraft, Peter, Kristensen, Vessela N., Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L., Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orr, Nick, Peterlongo, Paolo, Petridis, Christos, Prentice, Ross L., Presneau, Nadege, Punie, Kevin, Ramachandran, Dhanya, Rennert, Gad, Romero, Atocha, Sachchithananthan, Mythily, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schwentner, Lukas, Scott, Christopher, Simard, Jacques, Sohn, Christof, Southey, Melissa C., Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teixeira, Manuel R., Terry, Mary Beth, Thorne, Heather, Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Turnbull, Clare, Vachon, Celine M., Van Der Kolk, Lizet E., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Ziogas, Argyrios, Pharoah, Paul D. P., Hall, Per, Wessels, Lodewyk F. A., Chenevix-Trench, Georgia, Bader, Gary D., Dörk, Thilo, Easton, Douglas F., Canisius, Sander, and Schmidt, Marjanka K.

Subjects
45, 631/208/205/2138, 45/43, article, 692/4028/67/1347, 631/114, 3. Good health
Abstract

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

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