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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,441 bioRxiv papers from 264,501 authors.

Most downloaded bioRxiv papers, since beginning of last month

56,052 results found. For more information, click each entry to expand.

1: An integrated brain-machine interface platform with thousands of channels
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Posted to bioRxiv 17 Jul 2019

An integrated brain-machine interface platform with thousands of channels
65,513 downloads neuroscience

Elon Musk, Neuralink

Brain-machine interfaces (BMIs) hold promise for the restoration of sensory and motor function and the treatment of neurological disorders, but clinical BMIs have not yet been widely adopted, in part because modest channel counts have limited their potential. In this white paper, we describe Neuralink’s first steps toward a scalable high-bandwidth BMI system. We have built arrays of small and flexible electrode “threads”, with as many as 3,072 electrodes per array distributed across 96 threads. We have also built a neurosurgical robot capable of inserting six threads (192 electrodes) per minute. Each thread can be individually inserted into the brain with micron precision for avoidance of surface vasculature and targeting specific brain regions. The electrode array is packaged into a small implantable device that contains custom chips for low-power on-board amplification and digitization: the package for 3,072 channels occupies less than (23 × 18.5 × 2) mm3. A single USB-C cable provides full-bandwidth data streaming from the device, recording from all channels simultaneously. This system has achieved a spiking yield of up to 70% in chronically implanted electrodes. Neuralink’s approach to BMI has unprecedented packaging density and scalability in a clinically relevant package.

2: Population genomics of the Viking world
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Posted to bioRxiv 17 Jul 2019

Population genomics of the Viking world
7,089 downloads genetics

Ashot Margaryan, Daniel John Lawson, Martin Sikora, Fernando Racimo, Simon Rasmussen, Ida Moltke, Lara Cassidy, Emil Jorsboe, Andres Ingason, Mikkel Winther Pedersen, Thorfinn Sand Korneliussen, Helene Wilhelmson, Magdalena Maria Bus, Peter de Barros Damgaard, Rui Martiniano, Gabriel Renaud, Claude Bherer, J. Victor Moreno-Mayar, Anna Katerina Fotakis, Marie Allen, Martyna Molak, Enrico Cappellini, Gabriele Scorrano, Alexandra Buzhilova, Allison Mary Fox, Anders Albrechtsen, Berit Schutz, Birgitte Skar, Caroline Ahlstrom Arcini, Ceri G. Falys, Charlotte Hedenstierna-Jonson, Dariusz Blaszczyk, Denis Pezhemsky, Gordon Turner-Walker, Hildur Gestsdottir, Inge Lundstrom, Ingrid Gustin, Ingrid Mainland, Inna Potekhina, Italo Maria Muntoni, Jade Cheng, Jesper Stenderup, Jilong Ma, Julie Gibson, Jyri Peets, Jorgen Gustafsson, Katrine Hojholt Iversen, Linzi Simpson, Lisa Mariann Strand, Louise Katherine Loe, Maeve Sikora, Marek Florek, Maria Vretemark, Mark Redknap, Monika Bajka, Tamara Pushkina, Morten Sovso, Natalia Grigoreva, Tom Christensen, Ole Thirup Kastholm, Otto Christian Uldum, Pasquale Favia, Per Holck, Raili Allmae, Sabine Sten, Simun Vilhelm Arge, Sturla Ellingvag, Vayacheslav Moiseyev, Wieslaw Bogdanowicz, Yvonne Magnusson, Ludovic Orlando, Daniel G. Bradley, Marie Louise Schjellerup Jorkov, Jette Arneborg, Niels Lynnerup, Neil Price, M. Thomas Pius Gilbert, Morten E. Allentoft, Jan Bill, Soren Michael Sindbek, Lotte Hedeager, Kristian Kristiansen, Rasmus Nielsen, Thomas Werge, Eske Willerslev

The Viking maritime expansion from Scandinavia (Denmark, Norway, and Sweden) marks one of the swiftest and most far-flung cultural transformations in global history. During this time (c. 750 to 1050 CE), the Vikings reached most of western Eurasia, Greenland, and North America, and left a cultural legacy that persists till today. To understand the genetic structure and influence of the Viking expansion, we sequenced the genomes of 442 ancient humans from across Europe and Greenland ranging from the Bronze Age (c. 2400 BC) to the early Modern period (c. 1600 CE), with particular emphasis on the Viking Age. We find that the period preceding the Viking Age was accompanied by foreign gene flow into Scandinavia from the south and east: spreading from Denmark and eastern Sweden to the rest of Scandinavia. Despite the close linguistic similarities of modern Scandinavian languages, we observe genetic structure within Scandinavia, suggesting that regional population differences were already present 1,000 years ago. We find evidence for a majority of Danish Viking presence in England, Swedish Viking presence in the Baltic, and Norwegian Viking presence in Ireland, Iceland, and Greenland. Additionally, we see substantial foreign European ancestry entering Scandinavia during the Viking Age. We also find that several of the members of the only archaeologically well-attested Viking expedition were close family members. By comparing Viking Scandinavian genomes with present-day Scandinavian genomes, we find that pigmentation-associated loci have undergone strong population differentiation during the last millennia. Finally, we are able to trace the allele frequency dynamics of positively selected loci with unprecedented detail, including the lactase persistence allele and various alleles associated with the immune response. We conclude that the Viking diaspora was characterized by substantial foreign engagement: distinct Viking populations influenced the genomic makeup of different regions of Europe, while Scandinavia also experienced increased contact with the rest of the continent.

3: Background free tracking of single RNA in living cells using catalytically inactive CasE
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Posted to bioRxiv 13 May 2019

Background free tracking of single RNA in living cells using catalytically inactive CasE
6,515 downloads molecular biology

Chunyu Han, Feng Gao, Feng Jiang, Xiaoyue Bai, Yue Sun

RNAs have important and diverse functions. Visualizing an isolated RNA in living cells provide us essential information of its roles. By now, there are two kinds of live RNA imaging systems invented, one is the MS2 system and the other is the Cas13a system. In this study, we show that when fused with split-Fp, CasE can be engineered into a live RNA tracking tool.

4: Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming
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Posted to bioRxiv 31 Jul 2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming
4,967 downloads molecular biology

Yuancheng Lu, Anitha Krishnan, Benedikt Brommer, Xiao Tian, Margarita Meer, Daniel L. Vera, Chen Wang, Qiurui Zeng, Doudou Yu, Michael S. Bonkowski, Jae-Hyun Yang, Emma M. Hoffmann, Songlin Zhou, Ekaterina Korobkina, Noah Davidsohn, Michael B. Schultz, Karolina Chwalek, Luis A. Rajman, George M Church, Konrad Hochedlinger, Vadim N Gladyshev, Steve Horvath, Meredith S. Gregory-Ksander, Bruce R. Ksander, Zhigang He, David A. Sinclair

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage. Changes to DNA methylation patterns over time form the basis of an 'ageing clock', but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns don't just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

5: The "sewing machine" for minimally invasive neural recording
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Posted to bioRxiv 14 Mar 2019

The "sewing machine" for minimally invasive neural recording
4,224 downloads neuroscience

Timothy L Hanson, Camilo A Diaz-Botia, Viktor Kharazia, Michel M Maharbiz, Philip N Sabes

We present a system for scalable and customizable recording and stimulation of neural activity. In large animals and humans, the current benchmark for high spatial and temporal resolution neural interfaces are fixed arrays of wire or silicon electrodes inserted into the parenchyma of the brain. However, probes that are large and stiff enough to penetrate the brain have been shown to cause acute and chronic damage and inflammation, which limits their longevity, stability, and yield. One approach to this problem is to separate the requirements of the insertion device, which should to be as stiff as possible, with the implanted device, which should be as small and flexible as possible. Here, we demonstrate the feasibility and scalability of this approach with a system incorporating fine and flexible thin-film polymer probes, a fine and stiff insertion needle, and a robotic insertion machine. Together the system permits rapid and precise implantation of probes, each individually targeted to avoid observable vasculature and to attain diverse anatomical targets. As an initial demonstration of this system, we implanted arrays of electrodes in rat somatosensory cortex, recorded extracellular action potentials from them, and obtained histological images of the tissue response. This approach points the way toward a new generation of scaleable, stable, and safe neural interfaces, both for the basic scientific study of brain function and for clinical applications.

6: Automated Reconstruction of a Serial-Section EM Drosophila Brain with Flood-Filling Networks and Local Realignment
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Posted to bioRxiv 11 Apr 2019

Automated Reconstruction of a Serial-Section EM Drosophila Brain with Flood-Filling Networks and Local Realignment
3,933 downloads neuroscience

Peter H Li, Larry F. Lindsey, Michal Januszewski, Zhihao Zheng, Alexander Shakeel Bates, István Taisz, Mike Tyka, Matthew Nichols, Feng Li, Eric Perlman, Jeremy Maitin-Shepard, Tim Blakely, Laramie Leavitt, Gregory S.X.E. Jefferis, Davi Bock, Viren Jain

Reconstruction of neural circuitry at single-synapse resolution is an attractive target for improving understanding of the nervous system in health and disease. Serial section transmission electron microscopy (ssTEM) is among the most prolific imaging methods employed in pursuit of such reconstructions. We demonstrate how Flood-Filling Networks (FFNs) can be used to computationally segment a forty-teravoxel whole-brain Drosophila ssTEM volume. To compensate for data irregularities and imperfect global alignment, FFNs were combined with procedures that locally re-align serial sections and dynamically adjust image content. The proposed approach produced a largely merger-free segmentation of the entire ssTEM Drosophila brain, which we make freely available. As compared to manual tracing using an efficient skeletonization strategy, the segmentation enabled circuit reconstruction and analysis workflows that were an order of magnitude faster.

7: 7 Tesla MRI of the ex vivo human brain at 100 micron resolution
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Posted to bioRxiv 31 May 2019

7 Tesla MRI of the ex vivo human brain at 100 micron resolution
3,451 downloads neuroscience

Brian L Edlow, Azma Mareyam, Andreas Horn, Jonathan R. Polimeni, Thomas Witzel, M. Dylan Tisdall, Jean Augustinack, Jason P Stockman, Bram R Diamond, Allison Stevens, Lee S. Tirrell, Rebecca D Folkerth, Lawrence L Wald, Bruce Fischl, Andre van der Kouwe

We present an ultra-high resolution magnetic resonance imaging (MRI) dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 micron isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of a T1 parameter map and synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.

8: A Critique of Pure Learning: What Artificial Neural Networks can Learn from Animal Brains
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Posted to bioRxiv 20 Mar 2019

A Critique of Pure Learning: What Artificial Neural Networks can Learn from Animal Brains
2,958 downloads neuroscience

Anthony M Zador

Over the last decade, artificial neural networks (ANNs), have undergone a revolution, catalyzed in large part by better tools for supervised learning. However, training such networks requires enormous data sets of labeled examples, whereas young animals (including humans) typically learn with few or no labeled examples. This stark contrast with biological learning has led many in the ANN community posit that instead of supervised paradigms, animals must rely instead primarily on unsupervised learning, leading the search for better unsupervised algorithms. Here we argue that much of an animal's behavioral repertoire is not the result of clever learning algorithms--supervised or unsupervised--but arises instead from behavior programs already present at birth. These programs arise through evolution, are encoded in the genome, and emerge as a consequence of wiring up the brain. Specifically, animals are born with highly structured brain connectivity, which enables them learn very rapidly. Recognizing the importance of the highly structured connectivity suggests a path toward building ANNs capable of rapid learning.

9: Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations
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Posted to bioRxiv 09 Dec 2018

Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations
2,907 downloads pharmacology and toxicology

Esther Omaiye, Kevin J McWhirter, Wentai Luo, James F Pankow, Prue Talbot

While JUUL electronic cigarettes (ECs) have captured the majority of the EC market with a large fraction of their sales going to adolescents, little is known about their cytotoxicity and potential effects on health. The purpose of this study was to determine flavor chemical and nicotine concentrations in the eight currently marketed pre-filled JUUL EC cartridges (pods) and to evaluate the cytotoxicity of the different variants (e.g., Cool Mint and Creme Brulee) using in vitro assays. Nicotine and flavor chemicals were analyzed using gas chromatography/mass spectrometry in pod fluid before and after vaping and in the corresponding aerosols. 59 flavor chemicals were identified in JUUL pod fluids, and three were >1 mg/mL. Duplicate pods were similar in flavor chemical composition and concentration. Nicotine concentrations (average 60.9 mg/mL) were significantly higher than any EC products we have analyzed previously. Transfer efficiency of individual flavor chemicals that were >1mg/mL and nicotine from the pod fluid into aerosols was generally 35 - 80%. All pod fluids were cytotoxic at a 1:10 dilution (10%) in the MTT and neutral red uptake assays when tested with BEAS-2B lung epithelial cells. Most aerosols were cytotoxic in these assays at concentrations >1%. The cytotoxicity of aerosols was highly correlated with nicotine and ethyl maltol concentrations and moderately to weakly correlated with total flavor chemical concentration and menthol concentration. Our study demonstrates that: (1) some JUUL flavor pods have high concentrations of flavor chemicals that may make them attractive to youth, and (2) the concentrations of nicotine and some flavor chemicals (e.g. ethyl maltol) are high enough to be cytotoxic in acute in vitro assays, emphasizing the need to determine if JUUL products will lead to adverse health effects with chronic use.

10: Supercentenarians and the oldest-old are concentrated into regions with no birth certificates and short lifespans
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Posted to bioRxiv 16 Jul 2019

Supercentenarians and the oldest-old are concentrated into regions with no birth certificates and short lifespans
2,867 downloads developmental biology

Saul Justin Newman

The observation of individuals attaining remarkable ages, and their concentration into geographic sub-regions or 'blue zones', has generated considerable scientific interest. Proposed drivers of remarkable longevity include high vegetable intake, strong social connections, and genetic markers. Here, we reveal new predictors of remarkable longevity and 'supercentenarian' status. In the United States, supercentenarian status is predicted by the absence of vital registration. The state-specific introduction of birth certificates is associated with a 69-82% fall in the number of supercentenarian records. In Italy, which has more uniform vital registration, remarkable longevity is instead predicted by low per capita incomes and a short life expectancy. Finally, the designated 'blue zones' of Sardinia, Okinawa, and Ikaria corresponded to regions with low incomes, low literacy, high crime rate and short life expectancy relative to their national average. As such, relative poverty and short lifespan constitute unexpected predictors of centenarian and supercentenarian status, and support a primary role of fraud and error in generating remarkable human age records.

11: Homologous recombination-based genome editing by clade F AAVs is inefficient in the absence of a targeted DNA break
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Posted to bioRxiv 21 Jul 2019

Homologous recombination-based genome editing by clade F AAVs is inefficient in the absence of a targeted DNA break
2,852 downloads synthetic biology

Geoffrey L. Rogers, Hsu-Yu Chen, Heidy Morales, Paula M. Cannon

Adeno-associated virus (AAV) vectors are frequently used as donor templates for genome editing by homologous recombination. Although modification rates are typically under 1%, they are greatly enhanced by targeted double-stranded DNA breaks (DSBs). A recent report described clade F AAVs mediating high-efficiency homologous recombination-based editing in the absence of DSBs. The clade F vectors included AAV9 and a series isolated from human hematopoietic stem/progenitor cells (HSPCs). We evaluated these vectors by packaging homology donors into AAV9 and an AAVHSC capsid and examining their ability to insert GFP at the CCR5 or AAVS1 loci in human HSPCs and cell lines. As a control we used AAV6, which effectively edits HSPCs, but only when combined with a targeted DSB. Each AAV vector promoted GFP insertion in the presence of matched CCR5 or AAVS1 zinc finger nucleases (ZFNs), but none supported detectable editing in the absence of the nucleases. Rates of editing with ZFNs correlated with transduction efficiencies for each vector, implying no differences in the ability of donor sequences delivered by the different vectors to direct genome editing. Our results therefore do not support that clade F AAVs can perform high efficiency genome editing in the absence of a DSB.

12: Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
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Posted to bioRxiv 26 May 2016

Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
2,840 downloads cancer biology

Michael Wyde, Mark Cesta, Chad Blystone, Susan Elmore, Paul Foster, Michelle Hooth, Grace Kissling, David Malarkey, Robert Sills, Matthew Stout, Nigel Walker, Kristine Witt, Mary Wolfe, John Bucher

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program's cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.

13: Dissociation of solid tumour tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase associated stress responses
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Posted to bioRxiv 27 Jun 2019

Dissociation of solid tumour tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase associated stress responses
2,722 downloads genomics

Ciara H O'Flanagan, Kieran R Campbell, Allen W Zhang, Farhia Kabeer, Jamie LP Lim, Justina Biele, Peter Eirew, Daniel Lai, Andrew McPherson, Esther Kong, Cherie Bates, Kelly Borkowski, Matt Wiens, James Hopkins, Brittany Hewitson, Nicholas Ceglia, Richard Moore, Andy J. Mungall, Jessica N. McAlpine, The CRUK IMAXT Grand Challenge Team, Sohrab P Shah, Samuel Aparicio

Background: Single-cell RNA sequencing (scRNAseq) is a powerful tool for studying complex biological systems, such as tumour heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumour tissues and patient-derived mouse xenografts for scRNAseq, are not well understood. Here, we used low temperature (6C) protease and collagenase (37C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNAseq dataset comprising 128,481 cells from patient cancer tissues, patient-derived breast cancer xenografts and cancer cell lines. Results: We observe substantial variation in standard quality control (QC) metrics of cell viability across conditions and tissues. From FACS sorted populations gated for cell viability, we identify a sub-population of dead cells that would pass standard data filtering practices, and quantify the extent to which their transcriptomes differ from live cells. We identify a further subpopulation of transcriptomically "dying" cells that exhibit up-regulation of MHC class I transcripts, in contrast with live and fully dead cells. From the contrast between tissue protease dissociation at 37C or 6C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37C), which are minimized by dissociation with a cold active protease (6C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. We observe that the yield of cancer and non-cancer cell types varies between tissues and dissociation methods. Conclusions: The method and conditions of tumour dissociation influence cell yield and transcriptome state and are both tissue and cell type dependent. Interpretation of stress pathway expression differences in cancer single cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with identification of such effects in dissociated scRNA-seq experiments.

14: The Genetic History of France
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Posted to bioRxiv 23 Jul 2019

The Genetic History of France
2,516 downloads genetics

Aude SAINT PIERRE, Joanna Giemza, Mathilde Karakachoff, Isabel Alves, Philippe Amouyel, Jean-Francois Dartigues, Christophe Tzourio, Martial Monteil, Pilar Galan, Serge Hercberg, Richard Redon, Emmanuelle Genin, Christian Dina

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and their actual stratification. Although France occupies a particular location at the end of the European peninsula and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2 184 individuals born in France who were enrolled in two independent population cohorts. Using FineStructure, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters match extremely well the geography and overlap with historical and linguistic divisions of France. By modeling the relationship between genetics and geography using EEMS software, we were able to detect gene flow barriers that are similar in the two cohorts and corresponds to major French rivers or mountains. Estimations of effective population sizes using IBDNe program also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to what was observed in other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the fourteenth century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in the genetic studies in Europe that would be useful to medical geneticists but also historians and archeologists.

15: A guide to performing Polygenic Risk Score analyses
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Posted to bioRxiv 14 Sep 2018

A guide to performing Polygenic Risk Score analyses
2,511 downloads genomics

Shing Wan Choi, Timothy Mak, Paul F O'Reilly

The application of polygenic risk scores (PRS) has become routine in genetic epidemiological studies. Among a range of applications, PRS are commonly used to assess shared aetiology among different phenotypes and to evaluate the predictive power of genetic data, while they are also now being exploited as part of study design, in which experiments are performed on individuals, or their biological samples (eg. tissues, cells), at the tails of the PRS distribution and contrasted. As GWAS sample sizes increase and PRS become more powerful, they are also set to play a key role in personalised medicine. Despite their growing application and importance, there are limited guidelines for performing PRS analyses, which can lead to inconsistency between studies and misinterpretation of results. Here we provide detailed guidelines for performing polygenic risk score analyses relevant to different methods for their calculation, outlining standard quality control steps and offering recommendations for best-practice. We also discuss different methods for the calculation of PRS, common misconceptions regarding the interpretation of results and future challenges.

16: Comprehensive integration of single cell data
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Posted to bioRxiv 02 Nov 2018

Comprehensive integration of single cell data
2,336 downloads genomics

Tim Stuart, Andrew Butler, Paul Hoffman, Christoph Hafemeister, Efthymia Papalexi, William M. Mauck, Marlon Stoeckius, Peter Smibert, Rahul Satija

Single cell transcriptomics (scRNA-seq) has transformed our ability to discover and annotate cell types and states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, including high-dimensional immunophenotypes, chromatin accessibility, and spatial positioning, a key analytical challenge is to integrate these datasets into a harmonized atlas that can be used to better understand cellular identity and function. Here, we develop a computational strategy to "anchor" diverse datasets together, enabling us to integrate and compare single cell measurements not only across scRNA-seq technologies, but different modalities as well. After demonstrating substantial improvement over existing methods for data integration, we anchor scRNA-seq experiments with scATAC-seq datasets to explore chromatin differences in closely related interneuron subsets, and project single cell protein measurements onto a human bone marrow atlas to annotate and characterize lymphocyte populations. Lastly, we demonstrate how anchoring can harmonize in-situ gene expression and scRNA-seq datasets, allowing for the transcriptome-wide imputation of spatial gene expression patterns, and the identification of spatial relationships between mapped cell types in the visual cortex. Our work presents a strategy for comprehensive integration of single cell data, including the assembly of harmonized references, and the transfer of information across datasets. Availability: Installation instructions, documentation, and tutorials are available at: https://www.satijalab.org/seurat

17: Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression
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Posted to bioRxiv 14 Mar 2019

Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression
2,222 downloads genomics

Christoph Hafemeister, Rahul Satija

Single-cell RNA-seq (scRNA-seq) data exhibits significant cell-to-cell variation due to technical factors, including the number of molecules detected in each cell, which can confound biological heterogeneity with technical effects. To address this, we present a modeling framework for the normalization and variance stabilization of molecular count data from scRNA-seq experiments. We propose that the Pearson residuals from 'regularized negative binomial regression', where cellular sequencing depth is utilized as a covariate in a generalized linear model, successfully remove the influence of technical characteristics from downstream analyses while preserving biological heterogeneity. Importantly, we show that an unconstrained negative binomial model may overfit scRNA-seq data, and overcome this by pooling information across genes with similar abundances to obtain stable parameter estimates. Our procedure omits the need for heuristic steps including pseudocount addition or log-transformation, and improves common downstream analytical tasks such as variable gene selection, dimensional reduction, and differential expression. Our approach can be applied to any UMI-based scRNA-seq dataset and is freely available as part of the R package sctransform (https://github.com/ChristophH/sctransform), with a direct interface to our single-cell toolkit Seurat.

18: A 6-nm ultra-photostable DNA Fluorocube for fluorescence imaging
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Posted to bioRxiv 27 Jul 2019

A 6-nm ultra-photostable DNA Fluorocube for fluorescence imaging
2,182 downloads biophysics

Stefan Niekamp, Nico Stuurman, Ronald D Vale

Photobleaching limits extended imaging of fluorescent biological samples. Here, we developed DNA origami-based Fluorocubes that are similar in size to the green fluorescent protein (GFP), have single-point attachment to proteins, have a 50-fold higher photobleaching lifetime and emit 40-fold more photons than single organic dyes. We demonstrate that DNA Fluorocubes provide outstanding tools for single-molecule imaging, allowing the tracking of single motor proteins for >800 steps with nanometer precision.

19: Mapping Vector Field of Single Cells
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Posted to bioRxiv 09 Jul 2019

Mapping Vector Field of Single Cells
2,147 downloads systems biology

Xiaojie Qiu, Yan Zhang, Dian Yang, Shayan Hosseinzadeh, Li Wang, Ruoshi Yuan, Song Xu, Yian Ma, Joseph Replogle, Spyros Darmanis, Jianhua Xing, Jonathan Weissman

Understanding how gene expression in single cells progress over time is vital for revealing the mechanisms governing cell fate transitions. RNA velocity, which infers immediate changes in gene expression by comparing levels of new (unspliced) versus mature (spliced) transcripts (La Manno et al. 2018), represents an important advance to these efforts. A key question remaining is whether it is possible to predict the most probable cell state backward or forward over arbitrary time-scales. To this end, we introduce an inclusive model (termed Dynamo) capable of predicting cell states over extended time periods, that incorporates promoter state switching, transcription, splicing, translation and RNA/protein degradation by taking advantage of scRNA-seq and the co-assay of transcriptome and proteome. We also implement scSLAM-seq by extending SLAM-seq to plate-based scRNA-seq (Hendriks et al. 2018; Erhard et al. 2019; Cao, Zhou, et al. 2019) and augment the model by explicitly incorporating the metabolic labelling of nascent RNA. We show that through careful design of labelling experiments and an efficient mathematical framework, the entire kinetic behavior of a cell from this model can be robustly and accurately inferred. Aided by the improved framework, we show that it is possible to reconstruct the transcriptomic vector field from sparse and noisy vector samples generated by single cell experiments. The reconstructed vector field further enables global mapping of potential landscapes that reflects the relative stability of a given cell state, and the minimal transition time and most probable paths between any cell states in the state space. This work thus foreshadows the possibility of predicting long-term trajectories of cells during a dynamic process instead of short time velocity estimates. Our methods are implemented as an open source tool, dynamo (https://github.com/aristoteleo/dynamo-release).

20: The Genomic Formation of South and Central Asia
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Posted to bioRxiv 31 Mar 2018

The Genomic Formation of South and Central Asia
2,116 downloads genomics

Vagheesh M Narasimhan, Nick J Patterson, Priya Moorjani, Iosif Lazaridis, Lipson Mark, Swapan Mallick, Nadin Rohland, Rebecca Bernardos, Alexander M Kim, Nathan Nakatsuka, Inigo Olalde, Alfredo Coppa, James Mallory, Vyacheslav Moiseyev, Janet Monge, Luca M Olivieri, Nicole Adamski, Nasreen Broomandkhoshbacht, Francesca Candilio, Olivia Cheronet, Brendan J Culleton, Matthew Ferry, Daniel Fernandes, Beatriz Gamarra, Daniel Gaudio, Mateja Hajdinjak, Eadaoin Harney, Thomas K Harper, Denise Keating, Ann-Marie Lawson, Megan Michel, Mario Novak, Jonas Oppenheimer, Niraj Rai, Kendra Sirak, Viviane Slon, Kristin Stewardson, Zhao Zhang, Gaziz Akhatov, Anatoly N Bagashev, Baurzhan Baitanayev, Gian Luca Bonora, Tatiana Chikisheva, Anatoly Derevianko, Enshin Dmitry, Katerina Douka, Nadezhda Dubova, Andrey Epimakhov, Suzanne Freilich, Dorian Fuller, Alexander Goryachev, Andrey Gromov, Bryan Hanks, Margaret Judd, Erlan Kazizov, Aleksander Khokhlov, Egor Kitov, Elena Kupriyanova, Pavel Kuznetsov, Donata Luiselli, Farhad Maksudov, Chris Meiklejohn, Deborah C Merrett, Roberto Micheli, Oleg Mochalov, Zahir Muhammed, Samridin Mustafakulov, Ayushi Nayak, Rykun M Petrovna, Davide Pettner, Richard Potts, Dmitry Razhev, Stefania Sarno, Kulyan Sikhymbaevae, Sergey M Slepchenko, Nadezhda Stepanova, Svetlana Svyatko, Sergey Vasilyev, Massimo Vidale, Dima Voyakin, Antonina Yermolayeva, Alisa Zubova, Vasant S Shinde, Carles Lalueza-Fox, Matthias Meyer, David Anthony, Nicole Boivin, Kumarasmy Thangaraj, Douglas Kennett, Michael Frachetti, Ron Pinhasi, David Reich

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia — consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC — and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.

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