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10.1101/005165 | qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots | Stephen D. Turner; | Stephen D. Turner | University of Virginia | 2014-05-14 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/05/14/005165.source.xml | SummaryGenome-wide association studies (GWAS) have identified thousands of human trait-associated single nucleotide polymorphisms. Here, I describe a freely available R package for visualizing GWAS results using Q-Q and manhattan plots. The qqman package enables the flexible creation of manhattan plots, both genome-wide and for single chromosomes, with optional highlighting of SNPs of interest.\n\nAvailabilityqqman is released under the GNU General Public License, and is freely available on the Comprehensive R Archive Network (http://cran.r-project.org/package=qqman). The source code is available on GitHub (https://github.com/stephenturner/qqman).\n\[email protected] | NA | biorxiv | 518 |
10.1101/005215 | Generation of Aggregates of Mouse ES Cells that Show Symmetry Breaking, Polarisation and Emergent Collective Behaviour in vitro. | Peter Baillie-Johnson;Susanne C van den Brink;Tina Balayo;David A Turner;Alfonso Martinez Arias; | David A Turner | University of Cambridge | 2014-05-19 | 2 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2014/05/19/005215.source.xml | Dissociated mouse embryonic stem (ES) cells were cultured to form aggregates in small volumes of basal medium in U-bottomed, non tissue-culture-treated 96-well plates and subsequently maintained in suspension culture. After growth for 48 hours, the aggregates are competent to respond to ubiquitous experimental signals which result in their symmetry-breaking and generation of defined polarised structures by 96 hours. It is envisaged that this system can be applied both to the study of early developmental events and more broadly to the processes of self-organisation and cellular decision-making. It may also provide a suitable niche for the generation of cell types present in the embryo but unobtainable from conventional adherent culture. | 10.3791/53252 | biorxiv | 521 |
10.1101/005173 | Locus architecture affects mRNA expression levels in Drosophila embryos | Tara Lydiard-Martin;Meghan Bragdon;Kelly B Eckenrode;Zeba Wunderlich;Angela H DePace; | Angela H DePace | Harvard University | 2014-05-14 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/05/14/005173.source.xml | Structural variation in the genome is common due to insertions, deletions, duplications and rearrangements. However, little is known about the ways structural variants impact gene expression. Developmental genes are controlled by multiple regulatory sequence elements scattered over thousands of bases; developmental loci are therefore a good model to test the functional impact of structural variation on gene expression. Here, we measured the effect of rearranging two developmental enhancers from the even-skipped (eve) locus in Drosophila melanogaster blastoderm embryos. We systematically varied orientation, order, and spacing of the enhancers in transgenic reporter constructs and measured expression quantitatively at single cell resolution in whole embryos to detect changes in both level and position of expression. We found that the position of expression was robust to changes in locus organization, but levels of expression were highly sensitive to the spacing between enhancers and order relative to the promoter. Our data demonstrate that changes in locus architecture can dramatically impact levels of gene expression. To quantitatively predict gene expression from sequence, we must therefore consider how information is integrated both within enhancers and across gene loci. | NA | biorxiv | 523 |
10.1101/005231 | SraTailor: GUI software for visualizing high-throughput sequence read archives | Shinya Oki;Kazumitsu Maehara;Yasuyuki Ohkawa;Chikara Meno; | Chikara Meno | Kyushu university | 2014-05-16 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/05/16/005231.source.xml | Raw high-throughput sequence data are deposited in public databases as SRAs (Sequence Read Archives) and are publically available to every researcher. However, in order to graphically visualize the sequence data of interest, the corresponding SRAs must be downloaded and converted into BigWig format through complicated command-line processing. This task requires users to possess skill with script languages and sequence data processing, a requirement that prevents a wide range of biologists from exploiting SRAs. To address these challenges, we developed SraTailor, a GUI (Graphical User Interface) software package that automatically converts an SRA into a BigWig-formatted file. Simplicity of use is one of the most notable features of SraTailor: entering an accession number of an SRA and clicking the mouse are the only steps required in order to obtain BigWig-formatted files and to graphically visualize the extents of reads at given loci. SraTailor is also able to make peak calls and files of other formats, and the software also accepts various command-line-like options. Therefore, this software makes SRAs fully exploitable by a wide range of biologists. SraTailor is freely available at http://www.dev.med.kyushu-u.ac.jp/sra_tailor/. | 10.1111/gtc.12190 | biorxiv | 524 |
10.1101/005223 | Strategic Social Learning and the Population Dynamics of Human Behavior: The Game of Go | Bret A Beheim;Calvin Thigpen;Richard McElreath; | Bret A Beheim | University of New Mexico | 2014-05-19 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/19/005223.source.xml | Human culture is widely believed to undergo evolution, via mechanisms rooted in the nature of human cognition. A number of theories predict the kinds of human learning strategies, as well as the population dynamics that result from their action. There is little work, however, that quantitatively examines the evidence for these strategies and resulting cultural evolution within human populations. One of the obstacles is the lack of individual-level data with which to link transmission events to larger cultural dynamics. Here, we address this problem with a rich quantitative database from the East Asian board game known as Go. We draw from a large archive of Go games spanning the last six decades of professional play, and find evidence that the evolutionary dynamics of particular cultural variants are driven by a mix of individual and social learning processes. Particular players vary dramatically in their sensitivity to population knowledge, which also varies by age and nationality. The dynamic patterns of opening Go moves are consistent with an ancient, ongoing arms race within the game itself. | 10.1016/j.evolhumbehav.2014.04.001 | biorxiv | 526 |
10.1101/005256 | A putative antiviral role of plant cytidine deaminases | Susana Martín;José M. Cuevas;Ana Grande-Pérez;Santiago F. Elena; | Santiago F. Elena | IBMCP (CSIC-UPV) | 2014-05-16 | 1 | New Results | cc_by_nc_nd | Microbiology | https://www.biorxiv.org/content/early/2014/05/16/005256.source.xml | A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases (e.g., APOBEC3 proteins) edit viral genomes giving raise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana encodes for nine cytidine deaminases (AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. Here we tested the effects of AtCDAs expression on the pararetrovirus Cauliflower mosaic virus (CaMV). We show that A. thaliana AtCDA1 gene product exerts a mutagenic activity, which indeed generates a negative correlation between the level of AtCDA1 expression and CaMV accumulation in the plant, suggesting that deamination may also work as an antiviral mechanism in plants. | 10.12688/f1000research.11111.2 | biorxiv | 527 |
10.1101/005322 | Adaptation to a novel predator in Drosophila melanogaster: How well are we able to predict evolutionary responses? | Michael DeNieu;William Pitchers;Ian Dworkin; | Ian Dworkin | Michigan State University | 2014-05-19 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/19/005322.source.xml | Evolutionary theory is sufficiently well developed to allow for short-term prediction of evolutionary trajectories. In addition to the presence of heritable variation, prediction requires knowledge of the form of natural selection on relevant traits. While many studies estimate the form of natural selection, few examine the degree to which traits evolve in the predicted direction. In this study we examine the form of natural selection imposed by mantid predation on wing size and shape in the fruitfly, Drosophila melanogaster. We then evolve populations of D. melanogaster under predation pressure, and examine the extent to which wing size and shape have responded in the predicted direction. We demonstrate that wing form partially evolves along the predicted vector from selection, more so than for control lineages. Furthermore, we re-examined phenotypic selection after [~]30 generations of experimental evolution. We observed that the magnitude of selection on wing size and shape was diminished in populations evolving with mantid predators, while the direction of the selection vector differed from that of the ancestral population for shape. We discuss these findings in the context of the predictability of evolutionary responses, and the need for fully multivariate approaches. | NA | biorxiv | 529 |
10.1101/005298 | Ultra fast tissue staining with chemical tags | Johannes Kohl;Julian Ng;Sebastian Cachero;Michael-John Dolan;Ben Sutcliffe;Daniel Krüger;Shahar Frechter;Gregory SXE Jefferis; | Gregory SXE Jefferis | MRC Laboratory of Molecular Biology | 2014-05-19 | 1 | New Results | cc_by_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/05/19/005298.source.xml | Genetically encoded fluorescent proteins and immunostainings are widely used to detect cellular or sub-cellular structures in thick biological samples. However, each approach suffers from limitations, including low signal and limited spectral flexibility or slow speed, poor penetration and high background, respectively. Here we overcome these limitations by using transgenically expressed chemical tags for rapid, even and low-background labeling of thick biological tissues. We construct a platform of widely applicable transgenic Drosophila reporter lines, demonstrating that chemical labeling can accelerate staining of whole-mount fly brains by a factor of 100x. Together, this tag-based approach drastically improves the speed and specificity of labeling genetically marked cells in intact and/or thick biological samples. | NA | biorxiv | 531 |
10.1101/005397 | Differences in sensitivity to EGFR inhibitors could be explained by described biochemical differences between oncogenic Ras mutants | Edward C Stites; | Edward C Stites | Washington University School of Medicine | 2014-05-21 | 1 | New Results | cc_no | Cancer Biology | https://www.biorxiv.org/content/early/2014/05/21/005397.source.xml | Emerging data suggest different activating Ras mutants may have different biological behaviors. The most striking example may be in colon cancer, where activating KRAS mutations generally indicate a lack of benefit to treatment with EGFR inhibitors, although the activating KRAS G13D mutation appears to be an exception. As KRAS G13D generally shares the same biochemical defects as the other oncogenic KRAS mutants, a mechanism for differential sensitivity is not apparent. Here, a previously developed mathematical model of Ras mutant signaling is used to investigate this problem. The purpose of the analysis is to determine whether differential response is consistent with known mechanisms of Ras signaling, and to determine if any known features of Ras mutants provide an explanation for differential sensitivity. Computational analysis of the mathematical model finds that differential response to upstream inhibition between cancers with different Ras mutants is indeed consistent with known mechanisms of Ras biology. Moreover, model analysis demonstrates that the subtle biochemical differences between G13D and G12D (and G12V) mutants are sufficient to enable differential response to upstream inhibition. Simulations suggest that wild-type Ras within the G13D mutant context is more effectively inhibited by upstream inhibitors than when it is in the G12D or G12V contexts. This difference is a consequence of an elevated Km for the G13D mutant. The identification of a single parameter that influences sensitivity is significant in that it suggests an approach to evaluate other, less common, Ras mutations for their anticipated response to upstream inhibition. | NA | biorxiv | 532 |
10.1101/005371 | IVT-seq reveals extreme bias in RNA-sequencing | Nicholas F Lahens;Ibrahim Halil Kavakli;Ray Zhang;Katharina Hayer;Michael B Black;Hannah Dueck;Angel Pizarro;Junhyong Kim;Rafael A Irizarry;Russell S Thomas;Gregory R Grant;John B Hogenesch; | John B Hogenesch | University of Pennsylvania | 2014-05-21 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/05/21/005371.source.xml | BackgroundRNA sequencing (RNA-seq) is a powerful technique for identifying and quantifying transcription and splicing events, both known and novel. However, given its recent development and the proliferation of library construction methods, understanding the bias it introduces is incomplete but critical to realizing its value.\n\nResultsHere we present a method, in vitro transcription sequencing (IVT-seq), for identifying and assessing the technical biases in RNA-seq library generation and sequencing at scale. We created a pool of > 1000 in vitro transcribed (IVT) RNAs from a full-length human cDNA library and sequenced them with poly-A and total RNA-seq, the most common protocols. Because each cDNA is full length and we show IVT is incredibly processive, each base in each transcript should be equivalently represented. However, with common RNA-seq applications and platforms, we find [~]50% of transcripts have > 2-fold and [~]10% have > 10-fold differences in within-transcript sequence coverage. Strikingly, we also find > 6% of transcripts have regions of high, unpredictable sequencing coverage, where the same transcript varies dramatically in coverage between samples, confounding accurate determination of their expression. To get at causal factors, we used a combination of experimental and computational approaches to show that rRNA depletion is responsible for the most significant variability in coverage and that several sequence determinants also strongly influence representation.\n\nConclusionsIn sum, these results show the utility of IVT-seq in promoting better understanding of bias introduced by RNA-seq and suggest caution in its interpretation. Furthermore, we find that rRNA-depletion is responsible for substantial, unappreciated biases in coverage. Perhaps most importantly, these coverage biases introduced during library preparation suggest exon level expression analysis may be inadvisable. | 10.1186/gb-2014-15-6-r86 | biorxiv | 535 |
10.1101/005355 | Inference of phenotype-defining functional modules of protein families for microbial plant biomass degraders | Sebastian Gil Anthony Konietzny;Phillip Byron Pope;Aaron Weimann;Alice Carolyn McHardy; | Alice Carolyn McHardy | Heinrich-Heine-University Düsseldorf | 2014-05-21 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/05/21/005355.source.xml | BackgroundEfficient industrial processes for converting plant lignocellulosic materials into biofuels are a key challenge in global efforts to use alternative energy sources to fossil fuels. Novel cellulolytic enzymes have been discovered from microbial genomes and metagenomes of microbial communities. However, the identification of relevant genes without known homologs, and elucidation of the lignocellulolytic pathways and protein complexes for different microorganisms remain a challenge.\n\nResultsWe describe a new computational method for the targeted discovery of functional modules of plant biomass-degrading protein families based on their co-occurrence patterns across genomes and metagenome datasets, and the strength of association of these modules with the genomes of known degraders. From more than 6.4 million family annotations for 2884 microbial genomes and 332 taxonomic bins from 18 metagenomes, we identified five functional modules that are distinctive for plant biomass degraders, which we call plant biomass degradation modules (PDMs). These modules incorporated protein families involved in the degradation of cellulose, hemicelluloses and pectins, structural components of the cellulosome and additional families with potential functions in plant biomass degradation. The PDMs could be linked to 81 gene clusters in genomes of known lignocellulose degraders, including previously described clusters of lignocellulolytic genes. On average, 70% of the families of each PDM mapped to gene clusters in known degraders, which served as an additional confirmation of their functional relationships. The presence of a PDM in a genome or taxonomic metagenome bin allowed us to predict an organisms ability for plant biomass degradation accurately. For 15 draft genomes of a cow rumen metagenome, we validated by cross-linking with confirmed cellulolytic enzymes that the PDMs identified plant biomass degraders within a complex microbial community.\n\nConclusionsFunctional modules of protein families that realize different aspects of plant cell wall degradation can be inferred from co-occurrence patterns across (meta)genomes with a probabilistic topic model. The PDMs represent a new resource of protein families and candidate genes implicated in microbial plant biomass degradation. They can be used to predict the ability to degrade plant biomass for a genome or taxonomic bin. The method would also be suitable for characterizing other microbial phenotypes. | 10.1186/s13068-014-0124-8 | biorxiv | 536 |
10.1101/005330 | The distribution of deleterious genetic variation in human populations | Kirk E Lohmueller; | Kirk E Lohmueller | UCLA | 2014-05-21 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/21/005330.source.xml | Population genetic studies suggest that most amino-acid changing mutations are deleterious. Such mutations are of tremendous interest in human population genetics as they are important for the evolutionary process and may contribute risk to common disease. Genomic studies over the past 5 years have documented differences across populations in the number of heterozygous deleterious genotypes, numbers of homozygous derived deleterious genotypes, number of deleterious segregating sites and proportion of sites that are potentially deleterious. These differences have been attributed to population history affecting the ability of natural selection to remove deleterious variants from the population. However, recent studies have suggested that the genetic load may not differ across populations, and that the efficacy of natural selection has not differed across human populations. Here I show that these observations are not incompatible with each other and that the apparent differences are due to examining different features of the genetic data and differing definitions of terms. | 10.1016/j.gde.2014.09.005 | biorxiv | 537 |
10.1101/005348 | Inferring human population size and separation history from multiple genome sequences | Stephan Schiffels;Richard Durbin; | Richard Durbin | Sanger Institute | 2014-05-23 | 2 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/05/23/005348.source.xml | The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model their ancestral relationship under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20-30 thousand years ago and to population separations has been limited. Here we present a new method that overcomes these shortcomings. The Multiple Sequentially Markovian Coalescent (MSMC) analyses the observed pattern of mutations in multiple individuals, focusing on the first coalescence between any two individuals. Results from applying MSMC to genome sequences from nine populations across the world suggest that the genetic separation of non-African ancestors from African Yoruban ancestors started long before 50,000 years ago, and give information about human population history as recently as 2,000 years ago, including the bottleneck in the peopling of the Americas, and separations within Africa, East Asia and Europe. | 10.1038/ng.3015 | biorxiv | 539 |
10.1101/003905 | LIMIX: genetic analysis of multiple traits | Christoph Lippert;Francesco Paolo Casale;Barbara Rakitsch;Oliver Stegle; | Christoph Lippert | Microsoft Research | 2014-05-22 | 2 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/05/22/003905.source.xml | Multi-trait mixed models have emerged as a promising approach for joint analyses of multiple traits. In principle, the mixed model framework is remarkably general. However, current methods implement only a very specific range of tasks to optimize the necessary computations. Here, we present a multi-trait modeling framework that is versatile and fast: LIMIX enables to flexibly adapt mixed models for a broad range of applications with different observed and hidden covariates, and variable study designs. To highlight the novel modeling aspects of LIMIX we performed three vastly different genetic studies: joint GWAS of correlated blood lipid phenotypes, joint analysis of the expression levels of the multiple transcript-isoforms of a gene, and pathway-based modeling of molecular traits across environments. In these applications we show that LIMIX increases GWAS power and phenotype prediction accuracy, in particular when integrating stepwise multi-locus regression into multi-trait models, and when analyzing large numbers of traits. An open source implementation of LIMIX is freely available at: https://github.com/PMBio/limix. | NA | biorxiv | 541 |
10.1101/005439 | Profiling direct mRNA-microRNA interactions using synthetic biotinylated microRNA-duplexes | Shivangi Wani;Nicole Cloonan; | Nicole Cloonan | QIMR Berghofer Medical Research Institute | 2014-05-22 | 1 | Confirmatory Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/05/22/005439.source.xml | MicroRNAs (miRNAs) are predominantly negative regulators of gene expression that act through the RNA-induced Silencing Complex (RISC) to suppress the translation of protein coding mRNAs. Despite intense study of these regulatory molecules, the specific molecular functions of most miRNAs remain unknown, largely due to the challenge of accurately identifying miRNA targets. Reporter gene assays can determine direct interactions, but are laborious and do not scale to genome-wide screens. Genomic scale methods such as HITS-CLIP do not preserve the direct interactions, and rely on computationally derived predictions of interactions that are plagued by high false positive rates. Here we describe a protocol for the isolation of direct targets of a mature miRNA, using synthetic biotinylated miRNA duplexes. This approach allows sensitive and specific detection of miRNA-mRNA interactions, isolating high quality mRNA suitable for analysis by microarray or RNAseq. | NA | biorxiv | 542 |
10.1101/005413 | A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture | Henriette O'Geen;Isabelle M. Henry;Mital S. Bhakta;Joshua F. Meckler;David J. Segal; | David J. Segal | University of California, Davis | 2014-05-22 | 1 | New Results | cc_no | Molecular Biology | https://www.biorxiv.org/content/early/2014/05/22/005413.source.xml | Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided nucleases have gathered considerable excitement as a tool for genome engineering. However, questions remain about the specificity of their target site recognition. Most previous studies have examined predicted off-target binding sites that differ from the perfect target site by one to four mismatches, which represent only a subset of genomic regions. Here, we use ChIP-seq to examine genome-wide CRISPR binding specificity at gRNA-specific and gRNA-independent sites. For two guide RNAs targeting the murine Snurf gene promoter, we observed very high binding specificity at the intended target site while off-target binding was observed at 2- to 6-fold lower intensities. We also identified significant gRNA-independent off-target binding. Interestingly, we found that these regions are highly enriched in the PAM site, a sequence required for target site recognition by CRISPR. To determine the relationship between Cas9 binding and endonuclease activity, we used targeted sequence capture as a high-throughput approach to survey a large number of the potential off-target sites identified by ChIP-seq or computational prediction. A high frequency of indels was observed at both target sites and one off-target site, while no cleavage activity could be detected at other ChIP-bound regions. Our data is consistent with recent finding that most interactions between the CRISPR nuclease complex and genomic PAM sites are transient and do not lead to DNA cleavage. The interactions are stabilized by gRNAs with good matches to the target sequence adjacent to the PAM site, resulting in target cleavage activity. | 10.1093/nar/gkv137 | biorxiv | 543 |
10.1101/001545 | Exploring community structure in biological networks with random graphs | Pratha Sah;Lisa O. Singh;Aaron Clauset;Shweta Bansal; | Shweta Bansal | Georgetown University | 2014-06-02 | 3 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/02/001545.source.xml | BackgroundCommunity structure is ubiquitous in biological networks. There has been an increased interest in unraveling the community structure of biological systems as it may provide important insights into a systems functional components and the impact of local structures on dynamics at a global scale. Choosing an appropriate community detection algorithm to identify the community structure in an empirical network can be difficult, however, as the many algorithms available are based on a variety of cost functions and are difficult to validate. Even when community structure is identified in an empirical system, disentangling the effect of community structure from other network properties such as clustering coefficient and assortativity can be a challenge.\n\nResultsHere, we develop a generative model to produce undirected, simple, connected graphs with a specified degrees and pattern of communities, while maintaining a graph structure that is as random as possible. Additionally, we demonstrate two important applications of our model: (a) to generate networks that can be used to benchmark existing and new algorithms for detecting communities in biological networks; and (b) to generate null models to serve as random controls when investigating the impact of complex network features beyond the byproduct of degree and modularity in empirical biological networks.\n\nConclusionOur model allows for the systematic study of the presence of community structure and its impact on network function and dynamics. This process is a crucial step in unraveling the functional consequences of the structural properties of biological systems and uncovering the mechanisms that drive these systems. | 10.1186/1471-2105-15-220 | biorxiv | 546 |
10.1101/001370 | Accurate detection of de novo and transmitted INDELs within exome-capture data using micro-assembly | Giuseppe Narzisi;Jason A O'Rawe;Ivan Iossifov;Han Fang;Yoon-ha Lee;Zihua Wang;Yiyang Wu;Gholson J Lyon;Michael Wigler;Michael C Schatz; | Giuseppe Narzisi | Cold Spring Harbor Laboratory | 2014-06-18 | 3 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/18/001370.source.xml | We present a new open-source algorithm, Scalpel, for sensitive and specific discovery of INDELs in exome-capture data. By combining the power of mapping and assembly, Scalpel searches the de Bruijn graph for sequence paths (contigs) that span each exon. The algorithm creates a single path for exons with no INDEL, two paths for an exon with a heterozygous mutation, and multiple paths for more exotic variations. A detailed repeat composition analysis coupled with a self-tuning k-mer strategy allows Scalpel to outperform other state-of-the-art approaches for INDEL discovery. We extensively compared Scalpel with a battery of >10000 simulated and >1000 experimentally validated INDELs between 1 and 100bp against two recent algorithms for INDEL discovery: GATK HaplotypeCaller and SOAPindel. We report anomalies for these tools in their ability to detect INDELs, especially in regions containing near-perfect repeats which contribute to high false positive rates. In contrast, Scalpel demonstrates superior specificity while maintaining high sensitivity. We also present a large-scale application of Scalpel for detecting de novo and transmitted INDELs in 593 families with autistic children from the Simons Simplex Collection. Scalpel demonstrates enhanced power to detect long ([≥]20bp) transmitted events, and strengthens previous reports of enrichment for de novo likely gene-disrupting INDEL mutations in children with autism with many new candidate genes. The source code and documentation for the algorithm is available at http://scalpel.sourceforge.net. | 10.1038/nmeth.3069 | biorxiv | 547 |
10.1101/001834 | Illumina TruSeq synthetic long-reads empower de novo assembly and resolve complex, highly repetitive transposable elements | Rajiv C McCoy;Ryan W Taylor;Timothy A Blauwkamp;Joanna L Kelley;Michael Kertesz;Dmitry Pushkarev;Dmitri A Petrov;Anna-Sophie Fiston-Lavier; | Rajiv C McCoy | Stanford University | 2014-06-17 | 6 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/06/17/001834.source.xml | High-throughput DNA sequencing technologies have revolutionized genomic analysis, including the de novo assembly of whole genomes. Nevertheless, assembly of complex genomes remains challenging, in part due to the presence of dispersed repeats which introduce ambiguity during genome reconstruction. Transposable elements (TEs) can be particularly problematic, especially for TE families exhibiting high sequence identity, high copy number, or present in complex genomic arrangements. While TEs strongly affect genome function and evolution, most current de novo assembly approaches cannot resolve long, identical, and abundant families of TEs. Here, we applied a novel Illumina technology called TruSeq synthetic long-reads, which are generated through highly parallel library preparation and local assembly of short read data and achieve lengths of 1.5-18.5 Kbp with an extremely low error rate ([~]0.03% per base). To test the utility of this technology, we sequenced and assembled the genome of the model organism Drosophila melanogaster (reference genome strain y;cn,bw,sp) achieving an N50 contig size of 69.7 Kbp and covering 96.9% of the euchromatic chromosome arms of the current reference genome. TruSeq synthetic long-read technology enables placement of individual TE copies in their proper genomic locations as well as accurate reconstruction of TE sequences. We entirely recovered and accurately placed 4,229 (77.8%) of the 5,434 of annotated transposable elements with perfect identity to the current reference genome. As TEs are ubiquitous features of genomes of many species, TruSeq synthetic long-reads, and likely other methods that generate long reads, offer a powerful approach to improve de novo assemblies of whole genomes. | 10.1371/journal.pone.0106689 | biorxiv | 552 |
10.1101/002188 | Significantly distinct branches of hierarchical trees: A framework for statistical analysis and applications to biological data | Guoli Sun;Alexander Krasnitz; | Alexander Krasnitz | Cold Spring Harbor Laboratory | 2014-06-05 | 4 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/05/002188.source.xml | BackgroundOne of the most common goals of hierarchical clustering is finding those branches of a tree that form quantifiably distinct data subtypes. Achieving this goal in a statistically meaningful way requires (a) a measure of distinctness of a branch and (b) a test to determine the significance of the observed measure, applicable to all branches and across multiple scales of dissimilarity.\n\nResultsWe formulate a method termed Tree Branches Evaluated Statistically for Tightness (TBEST) for identifying significantly distinct tree branches in hierarchical clusters. For each branch of the tree a measure of distinctness, or tightness, is defined as a rational function of heights, both of the branch and of its parent. A statistical procedure is then developed to determine the significance of the observed values of tightness. We test TBEST as a tool for tree-based data partitioning by applying it to five benchmark datasets, one of them synthetic and the other four each from a different area of biology. For each dataset there is a well-defined partition of the data into classes. In all test cases TBEST performs on par with or better than the existing techniques.\n\nConclusionsBased on our benchmark analysis, TBEST is a tool of choice for detection of significantly distinct branches in hierarchical trees grown from biological data. An R language implementation of the method is available from the Comprehensive R Archive Network: cran.r-project.org/web/packages/TBEST/index.html. | 10.1186/1471-2164-15-1000 | biorxiv | 553 |
10.1101/002345 | Approximation to the distribution of fitness effects across functional categories in human segregating polymorphisms | Fernando Racimo;Joshua G Schraiber; | Fernando Racimo | University of California, Berkeley | 2014-06-19 | 2 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/06/19/002345.source.xml | Quantifying the proportion of polymorphic mutations that are deleterious or neutral is of fundamental importance to our understanding of evolution, disease genetics and the maintenance of variation genome-wide. Here, we develop an approximation to the distribution of fitness effects (DFE) of segregating single-nucleotide mutations in humans. Unlike previous methods, we do not assume that synonymous mutations are neutral or not strongly selected, and we do not rely on fitting the DFE of all new nonsynonymous mutations to a single probability distribution, which is poorly motivated on a biological level. We rely on a previously developed method that utilizes a variety of published annotations (including conservation scores, protein deleteriousness estimates and regulatory data) to score all mutations in the human genome based on how likely they are to be affected by negative selection, controlling for mutation rate. We map this score to a scale of fitness coefficients via maximum likelihood using diffusion theory and a Poisson random field model on SNP data. Our method serves to approximate the deleterious DFE of mutations that are segregating, regardless of their genomic consequence. We can then compare the proportion of mutations that are negatively selected or neutral across various categories, including different types of regulatory sites. We observe that the distribution of intergenic polymorphisms is highly peaked at neutrality, while the distribution of nonsynonymous polymorphisms is bimodal, with a neutral peak and a second peak at s {approx} -10-4. Other types of polymorphisms have shapes that fall roughly in between these two. We find that transcriptional start sites, strong CTCF-enriched elements and enhancers are the regulatory categories with the largest proportion of deleterious polymorphisms.\n\nAuthor SummaryThe relative frequencies of polymorphic mutations that are deleterious, nearly neutral and neutral is traditionally called the distribution of fitness effects (DFE). Obtaining an accurate approximation to this distribution in humans can help us understand the nature of disease and the mechanisms by which variation is maintained in the genome. Previous methods to approximate this distribution have relied on fitting the DFE of new mutations to a single probability distribution, like a normal or an exponential distribution. Generally, these methods also assume that a particular category of mutations, like synonymous changes, can be assumed to be neutral or nearly neutral. Here, we provide a novel method designed to reflect the strength of negative selection operating on any segregating site in the human genome. We use a maximum likelihood mapping approach to fit these scores to a scale of neutral and negative fitness coefficients. Finally, we compare the shape of the DFEs we obtain from this mapping for different types of functional categories. We observe the distribution of polymorphisms has a strong peak at neutrality, as well as a second peak of deleterious effects when restricting to nonsynonymous polymorphisms. | 10.1371/journal.pgen.1004697 | biorxiv | 554 |
10.1101/002428 | Evidence for widespread positive and negative selection in coding and conserved noncoding regions of Capsella grandiflora | Robert J Williamson;Emily B Josephs;Adrian E Platts;Khaled M Hazzouri;Annabelle Haudry;Mathieu Blanchette;Stephen I Wright; | Emily B Josephs | University of Toronto | 2014-06-09 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/09/002428.source.xml | The extent that both positive and negative selection vary across different portions of plant genomes remains poorly understood. Here, we sequence whole genomes of 13 Capsella grandiflora individuals and quantify the amount of selection across the genome. Using an estimate of the distribution of fitness effects, we show that selection is strong in coding regions, but weak in most noncoding regions, with the exception of 5 and 3 untranslated regions (UTRs). However, estimates of selection in noncoding regions conserved across the Brassicaceae family show strong signals of selection. Additionally, we see reductions in neutral diversity around functional substitutions in both coding and conserved noncoding regions, indicating recent selective sweeps at these sites. Finally, using expression data from leaf tissue we show that genes that are more highly expressed experience stronger negative selection but comparable levels of positive selection to lowly expressed genes. Overall, we observe widespread positive and negative selection in coding and regulatory regions, but our results also suggest that both positive and negative selection in plant noncoding sequence are considerably rarer than in animal genomes. | 10.1371/journal.pgen.1004622 | biorxiv | 556 |
10.1101/003194 | Phylogenetic tree shapes resolve disease transmission patterns | Jennifer Gardy;Caroline Colijn; | Caroline Colijn | Imperial College London | 2014-05-28 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/28/003194.source.xml | Whole genome sequencing is becoming popular as a tool for understanding outbreaks of communicable diseases, with phylogenetic trees being used to identify individual transmission events or to characterize outbreak-level overall transmission dynamics. Existing methods to infer transmission dynamics from sequence data rely on well-characterised infectious periods, epidemiological and clinical meta-data which may not always be available, and typically require computationally intensive analysis focussing on the branch lengths in phylogenetic trees. We sought to determine whether the topological structures of phylogenetic trees contain signatures of the overall transmission patterns underyling an outbreak. Here we use simulated outbreaks to train and then test computational classifiers. We test the method on data from two real-world outbreaks. We find that different transmission patterns result in quantitatively different phylogenetic tree shapes. We describe five topological features that summarize a phylogenys structure and find that computational classifiers based on these are capable of predicting an outbreaks transmission dynamics. The method is robust to variations in the transmission parameters and network types, and recapitulates known epidemiology of previously characterized real-world outbreaks. We conclude that there are simple structural properties of phylogenetic trees which, when combined, can distinguish communicable disease outbreaks with a super-spreader, homogeneous transmission, and chains of transmission. This is possible using genome data alone, and can be done during an outbreak. We discuss the implications for management of outbreaks. | 10.1093/emph/eou018 | biorxiv | 558 |
10.1101/003269 | Early warning signs in social-ecological networks | Samir Suweis;Paolo D'Odorico; | Paolo D'Odorico | University of Virginia | 2014-06-16 | 2 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/06/16/003269.source.xml | A number of social-ecological systems exhibit complex behaviour associated with nonlinearities, bifurcations, and interaction with stochastic drivers. These systems are often prone to abrupt and unexpected instabilities and state shifts that emerge as a discontinuous response to gradual changes in environmental drivers. Predicting such behaviours is crucial to the prevention of or preparation for unwanted regime shifts. Recent research in ecology has investigated early warning signs that anticipate the divergence of univariate ecosystem dynamics from a stable attractor. To date, leading indicators of instability in systems with multiple interacting components have remained poorly investigated. This is a major limitation in the understanding of the dynamics of complex social-ecological networks. Here, we develop a theoretical framework to demonstrate that rising variance - measured, for example, by the maximum element of the covariance matrix of the network - is an effective leading indicator of network instability. We show that its reliability and robustness depend more on the sign of the interactions within the network than the network structure or noise intensity. Mutualistic, scale free and small world networks are less stable than their antagonistic or random counterparts but their instability is more reliably predicted by this leading indicator. These results provide new advances in multidimensional early warning analysis and offer a framework to evaluate the resilience of social-ecological networks. | 10.1371/journal.pone.0101851 | biorxiv | 559 |
10.1101/003400 | Optimizing Real Time fMRI Neurofeedback for Therapeutic Discovery and Development | Luke Stoeckel;Kathleen A. Garrison;Satrajit S Ghosh;Paul Wighton;Colleen A. Hanlon;Jodi M. Gilman;Stephanie Greer;Nicholas B. Turk-Browne;Megan T. deBettencourt;Dustin Scheinost;Cameron Craddock;Todd Thompson;Vanessa Calderon;Clemens C. Bauer;Mark George;Hans C. Breiter;Susan Whitfield-Gabrieli;John D. Gabrieli;Stephen M. LaConte;Laurence M. Hirshberg;Judson A. Brewer;Michelle Hampson;Andre Van Der Kouwe;Sean Mackey;Anne E Evins; | Luke Stoeckel | Massachusetts General Hospital and Harvard Medical School | 2014-06-20 | 7 | New Results | cc_by_nc | Neuroscience | https://www.biorxiv.org/content/early/2014/06/20/003400.source.xml | While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health (BRAIN, 2013), the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders. | 10.1016/j.nicl.2014.07.002 | biorxiv | 560 |
10.1101/003848 | An experimentally informed evolutionary model improves phylogenetic fit to divergent lactamase homologs | Jesse D Bloom; | Jesse D Bloom | Fred Hutchinson Cancer Research Center | 2014-06-11 | 2 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/11/003848.source.xml | Phylogenetic analyses of molecular data require a quantitative model for how sequences evolve. Traditionally, the details of the site-specific selection that governs sequence evolution are not known a priori, making it challenging to create evolutionary models that adequately capture the heterogeneity of selection at different sites. However, recent advances in high-throughput experiments have made it possible to quantify the effects of all single mutations on gene function. I have previously shown that such high-throughput experiments can be combined with knowledge of underlying mutation rates to create a parameter-free evolutionary model that describes the phylogeny of influenza nucleoprotein far better than commonly used existing models. Here I extend this work by showing that published experimental data on TEM-1 beta-lactamase (Firnberg et al, 2014) can be combined with a few mutation rate parameters to create an evolutionary model that describes beta-lactamase phylogenies much than most common existing models. This experimentally informed evolutionary model is superior even for homologs that are substantially diverged (about 35% divergence at the protein level) from the TEM-1 parent that was the subject of the experimental study. These results suggest that experimental measurements can inform phylogenetic evolutionary models that are applicable to homologs that span a substantial range of sequence divergence. | 10.1093/molbev/msu220 | biorxiv | 561 |
10.1101/004010 | MixMir: microRNA motif discovery from gene expression data using mixed linear models | LIYANG Diao;Antoine Marcais;Scott Norton;Kevin C. Chen; | Kevin C. Chen | Rutgers, The State University of New Jersey | 2014-06-12 | 3 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/06/12/004010.source.xml | microRNAs (miRNAs) are a class of [~]22nt non-coding RNAs that potentially regulate over 60% of human protein-coding genes. miRNA activity is highly specific, differing between cell types, developmental stages and environmental conditions, so the identification of active miRNAs in a given sample is of great interest. Here we present a novel computational approach for analyzing both mRNA sequence and gene expression data, called MixMir. Our method corrects for 3' UTR background sequence similarity between transcripts, which is known to correlate with mRNA transcript abundance. We demonstrate that after accounting for kmer sequence similarities in 3 UTRs, a statistical linear model based on motif presence/absence can effectively discover active miRNAs in a sample. MixMir utilizes fast software implementations for solving mixed linear models which are widely-used in genome-wide association studies (GWAS). Essentially we use 3 UTR sequence similarity in place of population cryptic relatedness in the GWAS problem. Compared to similar methods such as miReduce, Sylamer and cWords, we found that MixMir performed better at discovering true miRNA motifs in three mouse Dicer knockout experiments from different tissues, two of which were collected by our group. We confirmed these results on protein and mRNA expression data obtained from miRNA transfection experiments in human cell lines. MixMir can be freely downloaded from https://github.com/ldiao/MixMir. | 10.1093/nar/gku672 | biorxiv | 563 |
10.1101/004317 | Comprehensive mutational scanning of a kinase in vivo reveals substrate-dependent fitness landscapes | Alexandre Melnikov;Peter Rogov;Li Wang;Andreas Gnirke;Tarjei S Mikkelsen; | Tarjei S Mikkelsen | Broad Institute | 2014-06-10 | 3 | New Results | cc_no | Molecular Biology | https://www.biorxiv.org/content/early/2014/06/10/004317.source.xml | Deep mutational scanning has emerged as a promising tool for mapping sequence-activity relationships in proteins1-4, RNA5 and DNA6-8. In this approach, diverse variants of a sequence of interest are first ranked according to their activities in a relevant pooled assay, and this ranking is then used to infer the shape of the fitness landscape around the wild-type sequence. Little is currently know, however, about the degree to which such fitness landscapes are dependent on the specific assay conditions from which they are inferred. To explore this issue, we performed deep mutational scanning of APH(3)II, a Tn5 transposon-derived kinase that confers resistance to aminoglycoside antibiotics9, in E. coli under selection with each of six structurally diverse antibiotics at a range of inhibitory concentrations. We found that the resulting fitness landscapes showed significant dependence on both antibiotic structure and concentration. This shows that the notion of essential amino acid residues is context-dependent, but also that this dependence can be exploited to guide protein engineering. Specifically, we found that differential analysis of fitness landscapes allowed us to generate synthetic APH(3)II variants with orthogonal substrate specificities. | 10.1093/nar/gku511 | biorxiv | 564 |
10.1101/004994 | An appraisal of the classic forest succession paradigm with the shade tolerance index | Jean F Lienard;Ionut Florescu;Nikolay Strigul; | Nikolay Strigul | Washington State University, Vancouver WA | 2014-06-03 | 2 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/06/03/004994.source.xml | In this paper we revisit the classic theory of forest succession that relates shade tolerance and species replacement and assess its validity to understand patch-mosaic patterns of forested ecosystems of the USA. We introduce a macroscopic parameter called the \"shade tolerance index\" and compare it to the classic continuum index in southern Wisconsin forests. We exemplify shade tolerance driven succession in White Pine-Eastern Hemlock forests using computer simulations and analyzing approximated chronosequence data from the USDA FIA forest inventory. We describe this parameter across the last 50 years in the ecoregions of mainland USA, and demonstrate that it does not correlate with the usual macroscopic characteristics of stand age, biomass, basal area, and biodiversity measures. We characterize the dynamics of shade tolerance index using transition matrices and delimit geographical areas based on the relevance of shade tolerance to explain forest succession. We conclude that shade tolerance driven succession is linked to climatic -variables and can be considered as a primary driving factor of forest dynamics mostly in central-north and northeastern areas in the USA. Overall, the shade tolerance index constitutes a new quantitative approach that can be used to understand and predict succession of forested ecosystems and biogeographic patterns. | 10.1371/journal.pone.0117138 | biorxiv | 565 |
10.1101/005041 | The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin | Bargavi Thyagarajan;Jesse D Bloom; | Jesse D Bloom | Fred Hutchinson Cancer Research Center | 2014-06-23 | 4 | New Results | cc_by | Microbiology | https://www.biorxiv.org/content/early/2014/06/23/005041.source.xml | Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the {approx} 104 amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the proteins structure and function, and can be used to create a model that describes hemagglutinins evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenzas antigenic evolution. | 10.7554/eLife.03300 | biorxiv | 568 |
10.1101/005140 | Collecting reward to defend homeostasis: A homeostatic reinforcement learning theory | Mehdi Keramati;Boris Gutkin; | Mehdi Keramati | Group for Neural Theory, INSERM U960, Ecole Normale Supérieure, Paris, France. | 2014-06-05 | 2 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/06/05/005140.source.xml | Efficient regulation of internal homeostasis and defending it against perturbations requires complex behavioral strategies. However, the computational principles mediating brains homeostatic regulation of reward and associative learning remain undefined. Here we use a definition of primary rewards, as outcomes fulfilling physiological needs, to build a normative theory showing how learning motivated behavior is modulated by the internal state of the animal. The theory proves that seeking rewards is equivalent to the fundamental objective of physiological stability, defining the notion of physiological rationality of behavior. We further give a formal basis for temporal discounting of reward. It also explains how animals learn to act predictively to preclude prospective homeostatic challenges, and attributes a normative computational role to the modulation of midbrain dopaminergic activity by hypothalamic signals. | 10.7554/eLife.04811 | biorxiv | 570 |
10.1101/005405 | Powerful tests for multi-marker association analysis using ensemble learning | Badri Padhukasahasram;Chandan K Reddy;L. Keoki Williams; | Badri Padhukasahasram | Henry Ford Health System | 2014-06-13 | 2 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/13/005405.source.xml | Multi-marker approaches are currently gaining a lot of interest in genome wide association studies and can enhance power to detect new associations under certain conditions. Gene and pathway based association tests are increasingly being viewed as useful complements to the more widely used single marker association analysis which have successfully uncovered numerous disease variants. A major drawback of single-marker based methods is that they do not consider pairwise and higher-order interactions between genetic variants. Here, we describe novel tests for multi-marker association analyses that are based on phenotype predictions obtained from machine learning algorithms. Instead of utilizing only a linear or logistic regression model, we propose the use of ensembles of diverse machine learning algorithms for constructing such association tests. As the true mathematical relationship between a phenotype and any group of genetic and clinical variables is unknown in advance and may be complex, such a strategy gives us a general and flexible framework to approximate this relationship across different sets of SNPs. We show how phenotype prediction obtained from ensemble learning algorithms can be used for constructing tests for the joint association of multiple variants. We first apply our method to simulated datasets to demonstrate its power and correctness. Then, we apply our method to previously studied asthma-related genes in two independent asthma cohorts to conduct association tests. | 10.1371/journal.pone.0143489 | biorxiv | 571 |
10.1101/005504 | The methylome of the human frontal cortex across development | Andrew E Jaffe;Yuan Gao;Ran Tao;Thomas M Hyde;Daniel R Weinberger;Joel E Kleinman; | Andrew E Jaffe | Lieber Institute for Brain Development | 2014-05-27 | 2 | New Results | cc_by_nc_nd | Developmental Biology | https://www.biorxiv.org/content/early/2014/05/27/005504.source.xml | DNA methylation (DNAm) plays an important role in epigenetic regulation of gene expression, orchestrating tissue differentiation and development during all stages of mammalian life. This epigenetic control is especially important in the human brain, with extremely dynamic gene expression during fetal and infant life, and becomes progressively more stable at later periods of development. We characterized the epigenetic state of the developing and aging human frontal cortex in post-mortem tissue from 351 individuals across the lifespan using the Illumina 450k DNA methylation microarray. The largest changes in the methylome occur at birth at varying spatial resolutions - we identify 359,087 differentially methylated loci, which form 23,732 significant differentially methylated regions (DMRs). There were also 298 regions of long-range changes in DNAm, termed \"blocks\", associated with birth that strongly overlap previously published colon cancer \"blocks\". We then identify 55,439 DMRs associated with development and aging, of which 61.9% significantly associate with nearby gene expression levels. Lastly, we find enrichment of genomic loci of risk for schizophrenia and several other common diseases among these developmental DMRs. These data, integrated with existing genetic and transcriptomic data, create a rich genomic resource across brain development. | 10.1038/nn.4181 | biorxiv | 574 |
10.1101/005546 | Alternative splicing detection workflow needs a careful combination of sample prep and bioinformatics analysis | Matteo Carrara;Josephine Lum;Francesca Cordero;Marco Beccuti;Michael Poidinger;Susanna Donatelli;Raffaele A Calogero;Francesca Zolezzi; | Raffaele A Calogero | Department of Molecular Biotechnology and Health Sciences, University of Torino | 2014-05-26 | 1 | New Results | cc_by_nd | Genomics | https://www.biorxiv.org/content/early/2014/05/26/005546.source.xml | BackgroundRNAseq provides remarkable power in the area of biomarkers discovery and disease stratification. The main technical steps affecting the results of RNAseq experiments are Library Sample Preparation (LSP) and Bioinformatics Analysis (BA). At the best of our knowledge, a comparative evaluation of the combined effect of LSP and BA was never considered and it might represent a valuable knowledge to optimize alternative splicing detection, which is a challenging task due to moderate fold change differences to be detected within a complex isoforms background.\n\nResultsDifferent LSPs (TruSeq unstranded/stranded, ScriptSeq, NuGEN) allow the detection of a large common set of isoforms. However, each LSP also detects a smaller set of isoforms, which are characterized both by lower coverage and lower FPKM than that observed for the common ones among LSPs. This characteristic is particularly critical in case of low input RNA NuGEN v2 LSP.\n\nThe effect on statistical detection of alternative splicing considering low input LSP (NuGEN v2) with respect to high input LSP (TruSeq) on statistical detection of alternative splicing was studied using a benchmark dataset, in which both synthetic reads and reads generated from high (TruSeq) and low input (NuGEN) LSPs were spiked-in. Statistical detection of alternative splicing (AltDE) was done using prototypes of BA for isoform-reconstruction (Cuffdiff) and exon-level analysis (DEXSeq). Exon-level analysis performs slightly better than isoform-reconstruction approach although at most only 50% of the spiked-in transcripts are detected. Both isoform-reconstruction and exon-level analysis performances improve by rising the number of input reads.\n\nConclusionData, derived from NuGEN v2, are not the ideal input for AltDE, specifically when exon-level approach is used. It is notable that ribosomal depletion, with respect to polyA+ selection, reduces the amount of coding mappable reads resulting detrimental in the case of AltDE. Furthermore, we observed that both isoform-reconstruction and exon-level analysis performances are strongly dependent on the number of input reads. | 10.1186/1471-2105-16-S9-S2 | biorxiv | 575 |
10.1101/005462 | Human genomic regions with exceptionally high or low levels of population differentiation identified from 911 whole-genome sequences | Vincenza Colonna;Qasim Ayub;Yuan Chen;Luca Pagani;Pierre Luisi;Marc Pybus;Erik Garrison;Yali Xue;Chris Tyler-Smith; | Vincenza Colonna | The Wellcome Trust Sanger Institute | 2014-05-27 | 2 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/05/27/005462.source.xml | BackgroundPopulation differentiation has proved to be effective for identifying loci under geographically-localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes.\n\nResultsWe demonstrate that while sites of low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively.\n\nConclusionsWe have identified known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research. | 10.1186/gb-2014-15-6-r88 | biorxiv | 576 |
10.1101/005587 | Inferring restrictions in the temporal order of mutations during tumor progression: effects of passengers, evolutionary models, and sampling | Ramon Diaz-Uriarte; | Ramon Diaz-Uriarte | Dept. Biochemistry, Universidad Autonoma de Madrid, and IIBM Alberto Sols (UAM-CSIC), Madrid, Spain | 2014-06-22 | 4 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/22/005587.source.xml | Cancer progression is caused by the sequential accumulation of mutations, but not all orders of accumulation of mutations are equally likely. When the fixation of some mutations depends on the presence of previous ones, identifying restrictions in the order of accumulation of mutations can lead to the discovery of therapeutic targets and diagnostic markers. Using simulated data sets, I conducted a comprehensive comparison of the performance of all available methods to identify these restrictions from cross-sectional data. In contrast to previous work, I embedded restrictions within evolutionary models of tumor progression that included passengers (mutations not responsible for the development of cancer, known to be very common). This allowed me to asses the effects of having to filter out passengers, of sampling schemes, and of deviations from order restrictions. Poor choices of method, filtering, and sampling lead to large errors in all performance metrics. Having to filter passengers lead to decreased performance, especially because true restrictions were missed. Overall, the best method for identifying order restrictions were Oncogenetic Trees, a fast and easy to use method that, although unable to recover dependencies of mutations on more than one mutation, showed good performance in most scenarios, superior to Conjunctive Bayesian Networks and Progression Networks. Single cell sampling provided no advantage, but sampling in the final stages of the disease vs. sampling at different stages had severe effects. Evolutionary model and deviations from order restrictions had major, and sometimes counterintuitive, interactions with other factors that affected performance. This paper provides practical recommendations for using these methods with experimental data. Moreover, it shows that it is both possible and necessary to embed assumptions about order restrictions and the nature of driver status within evolutionary models of cancer progression to evaluate the performance of inferential approaches. | 10.1186/s12859-015-0466-7 | biorxiv | 581 |
10.1101/005512 | Dynamics of a combined medea-underdominant population transformation system | Chaitanya Gokhale;Richard Guy Reeves;Floyd A Reed; | Chaitanya Gokhale | Massey University | 2014-05-28 | 2 | New Results | cc_by_nc | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/28/005512.source.xml | BackgroundTransgenic constructs intended to be stably established at high frequencies in wild populations have been demonstrated to \"drive\" from low frequencies in experimental insect populations. Linking such population transformation constructs to genes which render them unable to transmit pathogens could eventually be used to stop the spread of vector-borne diseases like malaria and dengue.\n\nResultsGenerally, population transformation constructs with only a single transgenic drive mechanism have been envisioned. Using a theoretical modelling approach we describe the predicted properties of a construct combining autosomal Medea and underdominant population transformation systems. We show that when combined they can exhibit synergistic properties which in broad circumstances surpass those of the single systems.\n\nConclusionWith combined systems, intentional population transformation and its reversal can be achieved readily. Combined constructs also enhance the capacity to geographically restrict transgenic constructs to targeted populations. It is anticipated that these properties are likely to be of particular value in attracting regulatory approval and public acceptance of this novel technology. | 10.1186/1471-2148-14-98 | biorxiv | 583 |
10.1101/005603 | Reconstructing Austronesian population history in Island Southeast Asia | Mark Lipson;Po-Ru Loh;Nick Patterson;Priya Moorjani;Ying-Chin Ko;Mark Stoneking;Bonnie Berger;David Reich; | David Reich | Harvard Medical School | 2014-05-27 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/05/27/005603.source.xml | Austronesian languages are spread across half the globe, from Easter Island to Madagascar. Evidence from linguistics and archaeology indicates that the \"Austronesian expansion,\" which began 4-5 thousand years ago, likely had roots in Taiwan, but the ancestry of present-day Austronesian-speaking populations remains controversial. Here, focusing primarily on Island Southeast Asia, we analyze genome-wide data from 56 populations using new methods for tracing ancestral gene flow. We show that all sampled Austronesian groups harbor ancestry that is more closely related to aboriginal Taiwanese than to any present-day mainland population. Surprisingly, western Island Southeast Asian populations have also inherited ancestry from a source nested within the variation of present-day populations speaking Austro-Asiatic languages, which have historically been nearly exclusive to the mainland. Thus, either there was once a substantial Austro-Asiatic presence in Island Southeast Asia, or Austronesian speakers migrated to and through the mainland, admixing there before continuing to western Indonesia. | 10.1038/ncomms5689 | biorxiv | 584 |
10.1101/005454 | Novel Natural Product Discovery from Marine Sponges and their Obligate Symbiotic Organisms | Regina Monaco;Rena Quinlan; | Regina Monaco | Hunter College | 2014-05-24 | 1 | Confirmatory Results | cc_by_nd | Pharmacology and Toxicology | https://www.biorxiv.org/content/early/2014/05/24/005454.source.xml | Discovery of novel natural products is an accepted method for the elucidation of pharmacologically active molecules and drug leads. Best known sources for such discovery have been terrestrial plants and microbes, accounting for about 85% of the approved natural products in pharmaceutical use (1), and about 60% of approved pharmaceuticals and new drug applications annually (2). Discovery in the marine environment has lagged due to the difficulty of exploration in this ecological niche. Exploration began in earnest in the 1950s, after technological advances such as scuba diving allowed collection of marine organisms, primarily at a depth to about 15m.\n\nNatural products from filter feeding marine invertebrates and in particular, sponges, have proven to be a rich source of structurally unique pharmacologically active compounds, with over 16,000 molecules isolated thus far (3, 1) and a continuing pace of discovery at hundreds of novel bioactive molecules per year. All classes of pharmaceuticals have been represented in this discovery process, including antiprotazoals, pesticides, TGF-beta inhibitors, cationic channel blockers, anticancer, cytotoxic, antiviral, anti-inflammatory and antibacterial compounds. Important biosynthetic pathways found in sponges which give rise to these compounds include the terpenoid (4), fatty acid, polyketoid, quinone reductase, alkaloid, isoprenoid (5), and non-ribosomal protein synthase pathways. | NA | biorxiv | 585 |
10.1101/005538 | Hip and knee kinematics display complex and time-varying sagittal kinematics during repetitive stepping: Implications for design of a functional fatigue model of the knee extensors and flexors | Corey Scholes;Michael McDonald;Anthony Parker; | Corey Scholes | Sydney Orthopaedic Research Institute | 2014-05-26 | 1 | New Results | cc_by_nc_nd | Physiology | https://www.biorxiv.org/content/early/2014/05/26/005538.source.xml | The validity of fatigue protocols involving multi-joint movements, such as stepping, has yet to be clearly defined. Although surface electromyography can monitor the fatigue state of individual muscles, the effects of joint angle and velocity variation on signal parameters are well established. Therefore, the aims of this study were to i) describe sagittal hip and knee kinematics during repetitive stepping ii) identify periods of high inter-trial variability and iii) determine within-test reliability of hip and knee kinematic profiles. A group of healthy men (N = 15) ascended and descended from a knee-high platform wearing a weighted vest (10%BW) for 50 consecutive trials. The hip and knee underwent rapid flexion and extension during step ascent and descent. Variability of hip and knee velocity peaked between 20-40% of the ascent phase and 80-100% of the descent. Significant (p<0.05) reductions in joint range of motion and peak velocity during step ascent were observed, while peak flexion velocity increased during descent. Healthy individuals use complex hip and knee motion to negotiate a knee-high step with kinematic patterns varying across multiple repetitions. These findings have important implications for future studies intending to use repetitive stepping as a fatigue model for the knee extensors and flexors. | NA | biorxiv | 586 |
10.1101/005496 | Different profile of transcriptome between wheat Yunong 201 and its high-yield mutant Yunong 3114 | Feng Chen;Zhongdong Dong;Ning Zhang;Xiangfen Zhang;Dangqun Cui; | Feng Chen | Henan Agricultural University | 2014-05-27 | 1 | New Results | cc_by_nc | Plant Biology | https://www.biorxiv.org/content/early/2014/05/27/005496.source.xml | Wheat is one of the most important crops in the world. With the exponentially increasing population and the need for ever increased food and feed production, an increased yield of wheat grain (as well as rice, maize and other grains) will be critical. Modern technologies are utilized to assist breeding programs. Such as the transcriptome sequencing, which greatly improves our genetic understanding, provides a platform for functional genomics research on crops. Herein, to get an overview of transcriptome characteristics of Yunong 3114, which is screened from the EMS mutagenized population of, a high quality Chinese winter noodle wheat, due to its different plant architecture as well as larger kernel size and higher grain weight, a high-throughput RNA sequencing based on next generation sequencing technology (Illumina) were performed. These unigenes were annotated by Blastx alignment against the NCBI non-redundant (nr), Clusters of orthologous groups (COG), gene orthology (GO), and the Kyoto Encyclopedia of Genesand Genomes (KEGG) databases. The 90.96% of the unigenes matched with protein in the NCBI nr database. Functional analysis identified that changes in several GO categories, including recognition of pollen, apoptotic process, defense response, receptor activity, protein kinase activity, DNA integration and so forth, played crucial roles in the high-yield characteristics of the mutant. Real-time PCR analysis revealed that the recognition of pollen related gene GsSRK is significantly up-regulated in Yunong 3114. In addition, alternative splicing (AS) analysis results indicated that mutation influence AS ratio, especially the retained introns, including the pollen related genes. Furthermore, the digital gene expression spectrum (DGE) profiling data provides comprehensive information at the transcriptional level that facilitates our understanding of the molecular mechanisms of various physiological aspects including development and high-yield of wheat. Together, these studies substantially increase our knowledge of potential genes and pathways for the genetic improvement of wheat and provide new insights into the yield and breeding strategies. | NA | biorxiv | 587 |
10.1101/005611 | A comparative study of techniques for differential expression analysis on RNA-Seq data | Zong Hong Zhang;Dhanisha J. Jhaveri;Vikki M. Marshall;Denis C. Bauer;Janette Edson;Ramesh K. Narayanan;Gregory J. Robinson;Andreas E. Lundberg;Perry F. Bartlett;Naomi R. Wray;Qiongyi Zhao; | Qiongyi Zhao | The University of Queensland, Queensland Brain Institute | 2014-05-28 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/05/28/005611.source.xml | Recent advances in next-generation sequencing technology allow high-throughput cDNA sequencing (RNA-Seq) to be widely applied in transcriptomic studies, in particular for detecting differentially expressed genes between groups. Many software packages have been developed for the identification of differentially expressed genes (DEGs) between treatment groups based on RNA-Seq data. However, there is a lack of consensus on how to approach an optimal study design and choice of suitable software for the analysis. In this comparative study we evaluate the performance of three of the most frequently used software tools: Cufflinks-Cuffdiff2, DESeq and edgeR. A number of important parameters of RNA-Seq technology were taken into consideration, including the number of replicates, sequencing depth, and balanced vs. unbalanced sequencing depth within and between groups. We benchmarked results relative to sets of DEGs identified through either quantitative RT-PCR or microarray. We observed that edgeR performs slightly better than DESeq and Cuffdiff2 in terms of the ability to uncover true positives. Overall, DESeq or taking the intersection of DEGs from two or more tools is recommended if the number of false positives is a major concern in the study. In other circumstances, edgeR is slightly preferable for differential expression analysis at the expense of potentially introducing more false positives. | 10.1371/journal.pone.0103207 | biorxiv | 588 |
10.1101/005645 | Artificially inducing close apposition of endoplasmic reticulum and mitochondria induces mitochondrial fragmentation. | Victoria J Miller;David J Stephens; | David J Stephens | University of Bristol | 2014-05-28 | 1 | New Results | cc_by_nc | Cell Biology | https://www.biorxiv.org/content/early/2014/05/28/005645.source.xml | Cycles of mitochondrial fission and fission are essential for normal cell physiology. Defects in the machinery controlling these processes lead to neurodegenerative disease. While we are beginning to understand the machinery that drives fission, our knowledge of the spatial and temporal control of this event is lacking. Here we use a rapamycin-inducible heterodimerization system comprising both ER and mitochondrial transmembrane components to bring the ER membrane into close physical proximity with mitochondria. We show that this artificial apposition of membranes is sufficient to cause rapid mitochondrial fragmentation. Resulting mitochondrial fragments are shown to be distinct entities using fluorescence recovery after photobleaching. We also show that these fragments retain a mitochondrial membrane potential. In contrast, inducible tethering of the peripheral ER exit site protein TFG does not cause mitochondrial fragmentation suggesting that very close apposition of the two membranes is required. | NA | biorxiv | 590 |
10.1101/005652 | Cis-regulatory elements and human evolution | Adam Siepel;Leonardo Arbiza; | Adam Siepel | Cornell University | 2014-05-28 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/05/28/005652.source.xml | Modification of gene regulation has long been considered an important force in human evolution, particularly through changes to cis-regulatory elements (CREs) that function in transcriptional regulation. For decades, however, the study of cis-regulatory evolution was severely limited by the available data. New data sets describing the locations of CREs and genetic variation within and between species have now made it possible to study CRE evolution much more directly on a genome-wide scale. Here, we review recent research on the evolution of CREs in humans based on large-scale genomic data sets. We consider inferences based on primate divergence,human polymorphism, and combinations of divergence and polymorphism. We then consider "new frontiers" in this field stemming from recent research on transcriptional regulation. | 10.1016/j.gde.2014.08.011 | biorxiv | 591 |
10.1101/005629 | Extensive Regulation of Metabolism and Growth during the Cell Division Cycle | Nikolai Slavov;David Botstein;Amy Caudy; | Nikolai Slavov | Harvard University | 2014-05-28 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/05/28/005629.source.xml | Yeast cells grown in culture can spontaneously synchronize their respiration, metabolism, gene expression and cell division. Such metabolic oscillations in synchronized cultures reflect single-cell oscillations, but the relationship between the oscillations in single cells and synchronized cultures is poorly understood. To understand this relationship and the coordination between metabolism and cell division, we collected and analyzed DNA-content, gene-expression and physiological data, at hundreds of time-points, from cultures metabolically-synchronized at different growth rates, carbon sources and biomass densities. The data enabled us to extend and generalize our mechanistic model, based on ensemble average over phases (EAP), connecting the population-average gene-expression of asynchronous cultures to the gene-expression dynamics in the single-cells comprising the cultures. The extended model explains the carbon-source specific growth-rate responses of hundreds of genes. Our physiological data demonstrate that the frequency of metabolic cycling in synchronized cultures increases with the biomass density, suggesting that this cycling is an emergent behavior, resulting from the entraining of the single-cell metabolic cycle by a quorum-sensing mechanism, and thus underscoring the difference between metabolic cycling in single cells and in synchronized cultures. Measurements of constant levels of residual glucose across metabolically synchronized cultures indicate that storage carbohydrates are required to fuel not only the G1/S transition of the division cycle but also the metabolic cycle. Despite the large variation in profiled conditions and in the scale of their dynamics, most genes preserve invariant dynamics of coordination with each other and with the rate of oxygen consumption. Similarly, the G1/S transition always occurs at the beginning, middle or end of the high oxygen consumption phases, analogous to observations in human and drosophila cells. These results highlight evolutionary conserved coordination among metabolism, cell growth and division. | NA | biorxiv | 593 |
10.1101/005694 | The genetic basis of energy conservation in the sulfate-reducing bacterium Desulfovibrio alaskensis G20 | Morgan Price;Jayashree Ray;Kelly M Wetmore;Jennifer V. Kuehl;Stefan Bauer;Adam M Deutschbauer;Adam P Arkin; | Morgan Price | Lawrence Berkeley Lab | 2014-05-31 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/05/31/005694.source.xml | Sulfate-reducing bacteria play major roles in the global carbon and sulfur cycles, but it remains unclear how reducing sulfate yields energy. To determine the genetic basis of energy conservation, we measured the fitness of thousands of pooled mutants of Desulfovibrio alaskensis G20 during growth in 12 different combinations of electron donors and acceptors. We show that ion pumping by the ferredoxin:NADH oxidoreductase Rnf is required whenever substrate-level phosphorylation is not possible. The uncharacterized complex Hdr/flox-1 (Dde_1207:13) is sometimes important alongside Rnf and may perform an electron bifurcation to generate more reduced ferredoxin from NADH to allow further ion pumping. Similarly, during the oxidation of malate or fumarate, the electron-bifurcating transhydrogenase NfnAB-2 (Dde_1250:1) is important and may generate reduced ferredoxin to allow additional ion pumping by Rnf. During formate oxidation, the periplasmic [NiFeSe] hydrogenase HysAB is required, which suggests that hydrogen forms in the periplasm, diffuses to the cytoplasm, and is used to reduce ferredoxin, thus providing a substrate for Rnf. During hydrogen utilization, the transmembrane electron transport complex Tmc is important and may move electrons from the periplasm into the cytoplasmic sulfite reduction pathway. Finally, mutants of many other putative electron carriers have no clear phenotype, which suggests that they are not important under our growth conditions. | 10.3389/fmicb.2014.00577 | biorxiv | 597 |
10.1101/005736 | Phylogenetic Identification and Functional Characterization of Orthologs and Paralogs across Human, Mouse, Fly, and Worm | Yi-Chieh Wu;Mukul S Bansal;Matthew D Rasmussen;Javier Herrero;Manolis Kellis; | Manolis Kellis | Massachusetts Institute of Technology | 2014-05-31 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/05/31/005736.source.xml | Model organisms can serve the biological and medical community by enabling the study of conserved gene families and pathways in experimentally-tractable systems. Their use, however, hinges on the ability to reliably identify evolutionary orthologs and paralogs with high accuracy, which can be a great challenge at both small and large evolutionary distances. Here, we present a phylogenomics-based approach for the identification of orthologous and paralogous genes in human, mouse, fly, and worm, which forms the foundation of the comparative analyses of the modENCODE and mouse ENCODE projects. We study a median of 16,101 genes across 2 mammalian genomes (human, mouse), 12 Drosophila genomes, 5 Caenorhabditis genomes, and an outgroup yeast genome, and demonstrate that accurate inference of evolutionary relationships and events across these species must account for frequent gene-tree topology errors due to both incomplete lineage sorting and insufficient phylogenetic signal. Furthermore, we show that integration of two separate phylogenomic pipelines yields increased accuracy, suggesting that their sources of error are independent, and finally, we leverage the resulting annotation of homologous genes to study the functional impact of gene duplication and loss in the context of rich gene expression and functional genomic datasets of the modENCODE, mouse ENCODE, and human ENCODE projects. | NA | biorxiv | 598 |
10.1101/005728 | Boymaw, Overexpressed in Brains with Major Psychiatric Disorders, May Encode a Small Protein to Inhibit Mitochondrial Function and Protein Translation | Baohu Ji;Minjung Kim;Kerin Higa;Xianjin Zhou; | Xianjin Zhou | University of California San Diego | 2014-05-31 | 1 | New Results | cc_by | Neuroscience | https://www.biorxiv.org/content/early/2014/05/31/005728.source.xml | The t(1,11) chromosome translocation co-segregates with major psychiatric disorders in a large Scottish family. The translocation disrupts the DISC1 and Boymaw (DISC1FP1) genes on chromosomes 1 and 11, respectively. After translocation, two fusion genes are generated. Our recent studies found that the DISC1-Boymaw fusion protein is localized in mitochondria and inhibits oxidoreductase activity, rRNA expression, and protein translation. Mice carrying the DISC1-Boymaw fusion genes display intermediate behavioral phenotypes related to major psychiatric disorders. Here, we report that the Boymaw gene encodes a small protein predominantly localized in mitochondria. The Boymaw protein inhibits oxidoreductase activity, rRNA expression, and protein translation in the same way as the DISC1-Boymaw fusion protein. Interestingly, Boymaw expression is up-regulated by different stressors at RNA and/or protein translational levels. In addition, we found that Boymaw RNA expression is significantly increased in the postmortem brains of patients with major psychiatric disorders. Our studies therefore suggest that the Boymaw gene is a potential susceptibility gene for major psychiatric disorders in both the Scottish t(1,11) family and the general population of patients. | 10.1002/ajmg.b.32311 | biorxiv | 599 |
10.1101/005710 | Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders | Baohu Ji;Kerin Higa;Minjung Kim;Lynn Zhou;Jared Young;Mark Geyer;Xianjin Zhou; | Xianjin Zhou | University of California, San Diego | 2014-05-31 | 1 | New Results | cc_by | Neuroscience | https://www.biorxiv.org/content/early/2014/05/31/005710.source.xml | The t(1; 11) translocation appears to be the causal genetic lesion with 70% penetrance for schizophrenia, major depression, and other psychiatric disorders in a Scottish family. Molecular studies identified the disruption of the DISC1 (disrupted-in-schizophrenia 1) gene by chromosome translocation at chromosome 1q42. Our previous studies, however, revealed that the translocation also disrupted another gene, Boymaw (also termed DISC1FP1), on chromosome 11. After translocation, two fusion genes (the DISC1-Boymaw (DB7) and the Boymaw-DISC1 (BD13)) are generated between the DISC1 and Boymaw genes. In the present study, we report that expression of the DB7 fusion gene inhibits both intracellular NADH oxidoreductase activities and protein translation. We generated humanized DISC1-Boymaw mice with gene targeting to examine the in vivo functions of the fusion genes. Consistent with the in vitro studies on the DB7 fusion gene, protein translation activity is decreased in the hippocampus and in cultured primary neurons from the brains of the humanized mice. Expression of Gad67, Nmdar1, and Psd95 proteins are also reduced. The humanized mice display prolonged and increased responses to the NMDA receptor antagonist, ketamine, on various mouse genetic backgrounds. Abnormal information processing of acoustic startle and depressive-like behaviors are also observed. In addition, the humanized mice display abnormal erythropoiesis, which was reported to associate with depression in humans. Expression of the DB7 fusion gene may reduce protein translation to impair brain functions and thereby contribute to the pathogenesis of major psychiatric disorders. | 10.1093/hmg/ddu285 | biorxiv | 600 |
10.1101/005702 | High-throughput functional annotation of influenza A virus genome at single-nucleotide resolution | Nicholas C. Wu;Arthur P. Young;Laith Q. Al-Mawsawi;C. Anders Olson;Jun Feng;Hangfei Qi;Shu-Hwa Chen;I-Hsuan Lu;Chung-Yen Lin;Robert G. Chin;Harding H. Luan;Nguyen Nguyen;Stanley F. Nelson;Xinmin Li;Ting-Ting Wu;Ren Sun; | Ren Sun | University of California, Los Angeles | 2014-05-31 | 1 | New Results | cc_by | Systems Biology | https://www.biorxiv.org/content/early/2014/05/31/005702.source.xml | A novel genome-wide genetics platform is presented in this study, which permits functional interrogation of all point mutations across a viral genome in parallel. Here we generated the first fitness profile of individual point mutations across the influenza virus genome. Critical residues on the viral genome were systematically identified, which provided a collection of subdomain data informative for structure-function studies and for effective rational drug and vaccine design. Our data was consistent with known, well-characterized structural features. In addition, we have achieved a validation rate of 68% for severely attenuated mutations and 94% for neutral mutations. The approach described in this study is applicable to other viral or microbial genomes where a means of genetic manipulation is available. | NA | biorxiv | 601 |
10.1101/005249 | A field test for frequency-dependent selection on mimetic colour patterns in Heliconius butterflies | Patricio Alejandro Salazar Carrión;Martin Stevens;Robert T. Jones;Imogen Ogilvie;Chris Jiggins; | Patricio Alejandro Salazar Carri?n | Universidad Tecnol?gica Indoam?rica | 2014-06-02 | 1 | Contradictory Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/02/005249.source.xml | Mullerian mimicry, the similarity among unpalatable species, is thought to evolve by frequency-dependent selection. Accordingly, phenotypes that become established in an area are positively selected because predators have learnt to avoid these forms, while introduced phenotypes are eliminated because predators have not yet learnt to associate these other forms with unprofitability. We tested this prediction in two areas where different colour morphs of the mimetic species Heliconius erato and H. melpomene have become established, as well as in the hybrid zone between these morphs. In each area we tested for selection on three colour patterns: the two parental and the most common hybrid. We recorded bird predation on butterfly models with paper wings, matching the appearance of each morph to bird vision, and plasticine bodies. We did not detect differences in survival between colour morphs, but all morphs were more highly attacked in the hybrid zone. This finding is consistent with recent evidence from controlled experiments with captive birds, which suggest that the effectiveness of warning signals decreases when a large signal diversity is available to predators. This is likely to occur in the hybrid zone where over twenty hybrid phenotypes coexist. | NA | biorxiv | 602 |
10.1101/005835 | Bacillus Calmette-Guerin infection in NADPH oxidase deficiency: defective mycobacterial sequestration and granuloma formation | Christine Deffert;Michela G. Schäppi;Jean-Claude Pache;Julien Cachat;Dominique Vesin;Ruth Bisig;Xiaojuan Ma Mulone;Tiina Kelkka;Rikard Holmdahl;Irene Garcia;Maria L. Olleros;Karl-Heinz Krause; | Christine Deffert | Medical Faculty and University of Geneva | 2014-06-03 | 1 | New Results | cc_no | Microbiology | https://www.biorxiv.org/content/early/2014/06/03/005835.source.xml | Patients with chronic granulomatous disease (CGD) lack generation of reactive oxygen species (ROS) through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M.bovis BCG was most commonly recovered (74%). The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and NOX2 knock-out mice. In addition we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter). Wild type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality ([~] 50%). Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-, IFN-{gamma}, IL-17 and IL-12) to BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine production and impaired granuloma formation. | 10.1371/journal.ppat.1004325 | biorxiv | 603 |
10.1101/005793 | How the tortoise beats the hare: Slow and steady adaptation in structured populations suggests a rugged fitness landscape in bacteria | Joshua R. Nahum;Peter Godfrey-Smith;Brittany N. Harding;Joseph H. Marcus;Jared Carlson-Stevermer;Benjamin Kerr; | Joshua R. Nahum | Michigan State University | 2014-06-03 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/03/005793.source.xml | AbstractIn the context of Wrights adaptive landscape, genetic epistasis can yield a multipeaked or \"rugged\" topography. In an unstructured population, a lineage with selective access to multiple peaks is expected to rapidly fix on one, which may not be the highest peak. Contrarily, beneficial mutations in a population with spatially restricted migration take longer to fix, allowing distant parts of the population to explore the landscape semi-independently. Such a population can simultaneous discover multiple peaks and the genotype at the highest discovered peak is expected to fix eventually. Thus, structured populations sacrifice initial speed of adaptation for breadth of search. As in the Tortoise-Hare fable, the structured population (Tortoise) starts relatively slow, but eventually surpasses the unstructured population (Hare) in average fitness. In contrast, on single-peak landscapes (e.g., systems lacking epistasis), all uphill paths converge. Given such \"smooth\" topography, breadth of search is devalued, and a structured population only lags behind an unstructured population in average fitness (ultimately converging). Thus, the Tortoise-Hare pattern is an indicator of ruggedness. After verifying these predictions in simulated populations where ruggedness is manipulable, we then explore average fitness in metapopulations of Escherichia coli. Consistent with a rugged landscape topography, we find a Tortoise-Hare pattern. Further, we find that structured populations accumulate more mutations, suggesting that distant peaks are higher. This approach can be used to unveil landscape topography in other systems, and we discuss its application for antibiotic resistance, engineering problems, and elements of Wrights Shifting Balance Process.\n\nSignificance StatementAdaptive landscapes are a way of describing how mutations interact with each other to produce fitness. If an adaptive landscape is rugged, organisms achieve higher fitness with more difficulty because the mutations to reach high fitness genotypes may not be always beneficial. By evolving populations of Escherichia coli with different degrees of spatial structure, we identified a Tortoise-Hare pattern, where structured populations were initially slower, but overtook less structured populations in mean fitness. These results, combined with genetic sequencing and computational simulation, indicate this bacterial adaptive landscape is rugged. Our findings address one of the most enduring questions in evolutionary biology, in addition to, providing insight into how evolution may influence medicine and engineering. | 10.1073/pnas.1410631112 | biorxiv | 604 |
10.1101/005751 | Genomic, transcriptomic and phenomic variation reveals the complex adaptation of modern maize breeding | Haijun Liu;Xiaqing Wang;Marilyn Warburton;Weiwei Wen;Minliang Jin;Min Deng;Jie Liu;Hao Tong;Qingchun Pan;Xiaohong Yang;Jianbing Yan; | Jianbing Yan | National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University | 2014-06-03 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/03/005751.source.xml | The temperate-tropical division of early maize germplasm to different agricultural environments was arguably the greatest adaptation process associated with the success and near ubiquitous importance of global maize production. Deciphering this history is challenging, but new insight has been gained from the genomic, transcriptomic and phenotypic variation collected from 368 diverse temperate and tropical maize inbred lines in this study. This is the first attempt to systematically explore the mechanisms of the adaptation process. Our results indicated that divergence between tropical and temperate lines seem occur 3,400-6,700 years ago. A number of genomic selection signals and transcriptomic variants including differentially expressed individual genes and rewired co-expression networks of genes were identified. These candidate signals were found to be functionally related to stress response and most were associated with directionally selected traits, which may have been an advantage under widely varying environmental conditions faced by maize as it was migrated away from its domestication center. Its also clear in our study that such stress adaptation could involve evolution of protein-coding sequences as well as transcriptome-level regulatory changes. This latter process may be a more flexible and dynamic way for maize to adapt to environmental changes over this dramatically short evolutionary time frame. | 10.1016/j.molp.2015.01.016 | biorxiv | 606 |
10.1101/005892 | Power analysis of artificial selection experiments using efficient whole genome simulation of quantitative traits | Darren Kessner;John Novembre; | John Novembre | University of Chicago | 2014-06-04 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/06/04/005892.source.xml | Evolve and resequence studies combine artificial selection experiments with massively parallel sequencing technology to study the genetic basis for complex traits. In these experiments, individuals are selected for extreme values of a trait, causing alleles at quantitative trait loci (QTLs) to increase or decrease in frequency in the experimental population. We present a new analysis of the power of artificial selection experiments to detect and localize quantitative trait loci. This analysis uses a simulation framework that explicitly models whole genomes of individuals, quantitative traits, and selection based on individual trait values. We find that explicitly modeling QTL provides produces qualitatively different insights than considering independent loci with constant selection coefficients. Specifically, we observe how interference between QTLs under selection impacts the trajectories and lengthens the fixation times of selected alleles. We also show that a substantial portion of the genetic variance of the trait (50-100%) can be explained by detected QTLs in as little as 20 generations of selection, depending on the trait architecture and experimental design. Furthermore, we show that power depends crucially on the opportunity for recombination during the experiment. Finally, we show that an increase in power is obtained by leveraging founder haplotype information to obtain allele frequency estimates. | 10.1534/genetics.115.175075 | biorxiv | 607 |
10.1101/005900 | Complete plastid genome assembly of invasive plant, Centaurea diffusa | Kathryn G Turner;Christopher J Grassa; | Kathryn G Turner | University of British Columbia | 2014-06-11 | 2 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/06/11/005900.source.xml | New genomic tools are needed to elucidate the evolution of invasive, non-model organisms. Here we present the completed plastome assembly for the problematic invasive weed, Centaurea diffusa. This new tool represents a significant contribution to future studies of the ecological genomics of invasive plants, particularly this weedy genus, and studies of the Asteraceae in general. | NA | biorxiv | 609 |
10.1101/005918 | Simultaneous estimation of transcript abundances and transcript specific fragment distributions of RNA-Seq data with the Mix2 model | Andreas Tuerk;Gregor Wiktorin; | Andreas Tuerk | Lexogen GmbH | 2014-06-04 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/04/005918.source.xml | Quantification of RNA transcripts with RNA-Seq is inaccurate due to positional fragmentation bias, which is not represented appropriately by current statistical models of RNA-Seq data. Another, less investigated, source of error is the inaccuracy of transcript start and end annotations.\n\nThis article introduces the Mix2 (rd. \"mixquare\") model, which uses a mixture of probability distributions to model the transcript specific positional fragment bias. The parameters of the Mix2 model can be efficiently trained with the EM algorithm and are tied between similar transcripts. Transcript specific shift and scale parameters allow the Mix2 model to automatically correct inaccurate transcript start and end annotations. Experiments are conducted on synthetic data covering 7 genes of different complexity, 4 types of fragment bias and correct as well as incorrect transcript start and end annotations. Abundance estimates obtained by Cufflinks 2.2.0, PennSeq and the Mix2 model show superior performance of the Mix2 model in the vast majority of test conditions.\n\nThe Mix2 software is available at http://www.lexogen.com/fileadmin/uploads/bioinfo/mix2model.tgz, subject to the enclosed license.\n\nAdditional experimental data are available in the supplement. | NA | biorxiv | 610 |
10.1101/005777 | Osmunda pulchella sp. nov. from the Jurassic of Sweden&#151;reconciling molecular and fossil evidence in the phylogeny of Osmundaceae | Benjamin Bomfleur;Guido W Grimm;Stephen McLoughlin; | Guido W Grimm | Swedish Museum of Natural History | 2014-06-04 | 1 | New Results | cc_by_nc | Paleontology | https://www.biorxiv.org/content/early/2014/06/04/005777.source.xml | The systematic classification of Osmundaceae has long remained controversial. Recent molecular data indicate that Osmunda is paraphyletic, and needs to be separated into Osmundastrum and Osmunda s. str. Here we describe an exquisitely preserved Jurassic Osmunda rhizome (O. pulchella sp. nov.) that combines diagnostic features of Osmundastrum and Osmunda, calling molecular evidence for paraphyly into question. We assembled a new morphological matrix based on rhizome anatomy, and used network analyses to establish phylogenetic relationships between fossil and extant members of modern Osmundaceae. We re-analysed the original molecular data to evaluate root-placement support. Finally, we integrated morphological and molecular data-sets using the evolutionary placement algorithm. Osmunda pulchella and five additional, newly identified Jurassic Osmunda species show anatomical character suites intermediate between Osmundastrum and Osmunda. Molecular evidence for paraphyly is ambiguous: a previously unrecognized signal from spacer sequences favours an alternative root placement that would resolve Osmunda s.l. as monophyletic. Our evolutionary placement analysis identifies fossil species as ancestral members of modern genera and subgenera. Altogether, the seemingly conflicting evidence from morphological, anatomical, molecular, and palaeontological data can be elegantly reconciled under the assumption that Osmunda is indeed monophyletic; the recently proposed root-placement in Osmundaceae--based solely on molecular data--likely results from un- or misinformative out-group signals. | 10.1186/s12862-015-0400-7 | biorxiv | 612 |
10.1101/005991 | iRAP - an integrated RNA-seq Analysis Pipeline | Nuno A. Fonseca;Robert Petryszak;John Marioni;Alvis Brazma; | Nuno A. Fonseca | EMBL-EBI | 2014-06-06 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/06/005991.source.xml | RNA-sequencing (RNA-Seq) has become the technology of choice for whole-transcriptome profiling. However, processing the millions of sequence reads generated requires considerable bioinformatics skills and computational resources. At each step of the processing pipeline many tools are available, each with specific advantages and disadvantages. While using a specific combination of tools might be desirable, integrating the different tools can be time consuming, often due to specificities in the formats of input/output files required by the different programs. Here we present iRAP, an integrated RNA-seq analysis pipeline that allows the user to select and apply their preferred combination of existing tools for mapping reads, quantifying expression, testing for differential expression. iRAP also includes multiple tools for gene set enrichment analysis and generates web browsable reports of the results obtained in the different stages of the pipeline. Depending upon the application, iRAP can be used to quantify expression at the gene, exon or transcript level. iRAP is aimed at a broad group of users with basic bioinformatics training and requires little experience with the command line. Despite this, it also provides more advanced users with the ability to customise the options used by their chosen tools. | NA | biorxiv | 614 |
10.1101/003889 | Spatial epidemiology of networked metapopulation: An overview | Lin WANG;Xiang Li; | Lin WANG | The University of Hong Kong | 2014-06-04 | 1 | New Results | cc_no | Biophysics | https://www.biorxiv.org/content/early/2014/06/04/003889.source.xml | An emerging disease is one infectious epidemic caused by a newly transmissible pathogen, which has either appeared for the first time or already existed in human populations, having the capacity to increase rapidly in incidence as well as geographic range. Adapting to human immune system, emerging diseases may trigger large-scale pandemic spreading, such as the transnational spreading of SARS, the global outbreak of A(H1N1), and the recent potential invasion of avian influenza A(H7N9). To study the dynamics mediating the transmission of emerging diseases, spatial epidemiology of networked metapopulation provides a valuable modeling framework, which takes spatially distributed factors into consideration. This review elaborates the latest progresses on the spatial metapopulation dynamics, discusses empirical and theoretical findings that verify the validity of networked metapopulations, and the application in evaluating the effectiveness of disease intervention strategies as well. | 10.1007/s11434-014-0499-8 | biorxiv | 615 |
10.1101/005868 | Origin and evolution of the self-organizing cytoskeleton in the network of eukaryotic organelles | Gáspár Jékely; | G?sp?r J?kely | Max Planck Institute for Developmental Biology | 2014-06-04 | 1 | Confirmatory Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/04/005868.source.xml | The eukaryotic cytoskeleton evolved from prokaryotic cytomotive filaments. Prokaryotic filament systems show bewildering structural and dynamic complexity, and in many aspects prefigure the self-organizing properties of the eukaryotic cytoskeleton. Here I compare the dynamic properties of the prokaryotic and eukaryotic cytoskeleton, and discuss how these relate to function and the evolution of organellar networks. The evolution of new aspects of filament dynamics in eukaryotes, including severing and branching, and the advent of molecular motors converted the eukaryotic cytoskeleton into a self-organizing active gel, the dynamics of which can only be described with computational models. Advances in modeling and comparative genomics hold promise of a better understanding of the evolution of the self-organizing cytoskeleton in early eukaryotes, and its role in the evolution of novel eukaryotic functions, such as amoeboid motility, mitosis, and ciliary swimming. | 10.1101/cshperspect.a016030 | biorxiv | 616 |
10.1101/006072 | Gene co-expression modules underlying polymorphic and monomorphic zooids in the colonial hydrozoan, Hydractinia symbiolongicarpus | David C Plachetzki;M. Sabrina Pankey;Brian R Johnson;Eric J Ronne;Artyom Kopp;Richard K Grosberg; | David C Plachetzki | The University of New Hampshire | 2014-06-07 | 1 | New Results | cc_by_nc_nd | Developmental Biology | https://www.biorxiv.org/content/early/2014/06/07/006072.source.xml | Advances in sequencing technology have forced a quantitative revolution in Evolutionary Biology. One important feature of this renaissance is that comprehensive genomic resources can be obtained quickly for almost any taxon, thus speeding the development of new model organisms. Here we analyze 20 RNA-seq libraries from morphologically, sexually, and genetically distinct polyp types from the gonochoristic colonial hydrozoan, Hydractinia symbiolongicarpus (Cnidaria). Analyses of these data using Weighted Gene Co-expression Networks highlights deeply conserved genetic elements of animal spermatogenesis and demonstrate the utility of these methods in identifying modules of genes that correlate with different zooid types across various statistical contrasts. RNAseq data and analytical scripts described here are deposited in publicly available databases. | 10.1093/icb/icu080 | biorxiv | 619 |
10.1101/006080 | Efficient isolation of specific genomic regions retaining molecular interactions by the iChIP system using recombinant exogenous DNA-binding proteins | Toshitsugu Fujita;Hodaka Fujii; | Hodaka Fujii | Research Institute for Microbial Diseases, Osaka University | 2014-06-07 | 1 | New Results | cc_by | Biochemistry | https://www.biorxiv.org/content/early/2014/06/07/006080.source.xml | BackgroundComprehensive understanding of mechanisms of genome functions requires identification of molecules interacting with genomic regions of interest in vivo. We have developed the insertional chromatin immunoprecipitatin (iChIP) technology to isolate specific genomic regions retaining molecular interactions and identify their associated molecules. iChIP consists of locus-tagging and affinity purification. The recognition sequences of an exogenous DNA-binding protein such as LexA are inserted into a genomic region of interest in the cell to be analyzed. The exogenous DNA-binding protein fused with a tag(s) is expressed in the cell and the target genomic region is purified with antibody against the tag(s). In this study, we developed the iChIP system using recombinant DNA-binding proteins to make iChIP more straightforward.\n\nResultsIn this system, recombinant 3xFNLDD-D (r3xFNLDD-D) consisting of the 3xFLAG-tag, a nuclear localization signal, the DNA-binding domain plus the dimerization domain of the LexA protein, and the Dock-tag is used for isolation of specific genomic regions. 3xFNLDD-D was expressed using a silkworm-baculovirus expression system and purified by affinity purification. iChIP using r3xFNLDD-D could efficiently isolate the single-copy chicken Pax5 (cPax5) locus, in which LexA binding elements were inserted, with negligible contamination of other genomic regions. In addition, we could detect RNA associated with the cPax5 locus using this form of the iChIP system combined with RT-PCR.\n\nConclusionsThe iChIP system using r3xFNLDD-D can isolate specific genomic regions retaining molecular interactions without expression of the exogenous DNA-binding protein in the cell to be analyzed. iChIP using r3xFNLDD-D would be more straightforward and useful for analysis of specific genomic regions to elucidate their functions. | 10.1186/s12867-014-0026-0 | biorxiv | 622 |
10.1101/005983 | Avoiding test set bias with rank-based prediction | Prasad Patil;Peirre-Olivier Bachant-Winner;Benjamin Haibe-Kains;Jeffrey T Leek; | Jeffrey T Leek | Johns Hopkins Bloomberg School of Public Health | 2014-06-06 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/06/06/005983.source.xml | Background: Prior to applying genomic predictors to clinical samples, the genomic data must be properly normalized. The most effective normalization methods depend on the data from multiple patients. From a biomedical perspective this implies that predictions for a single patient may change depending on which other patient samples they are normalized with. This test set bias will occur when any cross-sample normalization is used before clinical prediction. Methods: We developed a new prediction modeling framework based on the relative ranks of features within a sample in order to prevent the need for cross-sample normalization, therefore effectively avoiding test set bias. We employed modeling with previously published Top-Scoring Pairs (TSPs) methodology to build the rank-based predictors. We further investigated the robustness of the rank-based models in case of heterogeneous datasets using diverse microarray technologies. Results: We demonstrated that results from existing genetic signatures which rely on normalizing test data may be unreproducible when the patient population changes compo- sition or size. Using pairwise comparisons of features, we produced a ten gene, platform- robust, and interpretable alternative to the PAM50 subtyping signature and evaluated the robustness of our signature across 6,297 patients samples from 28 curated breast cancer microarray datasets spanning 15 different platforms. Conclusion: We propose a new approach to developing genomic signatures that avoids test set bias through the robustness of rank-based features. Our small, interpretable alter- native to PAM50 produces comparable predictions and patient survival differentiation to the original signature. Additionally, we are able to ensure that the same patient will be classified the same way in every context. | 10.1093/bioinformatics/btv157 | biorxiv | 624 |
10.1101/006106 | Characterization of a rationally engineered phaCAB operon with a hybrid promoter design | Iain Bower;Bobby Wenqiang Chi;Matthew Ho Wai Chin;Sisi Fan;Margarita Kopniczky;Jemma Pilcher;James Strutt;Richard Kelwick;Alexander Webb;Kirsten Jensen;Guy-Bart Stan;Richard Kitney;Paul Freemont; | Richard Kelwick | Imperial College London | 2014-06-09 | 1 | New Results | cc_by_nc_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2014/06/09/006106.source.xml | Biopolymers, such as poly-3-hydroxy-butyrate (P(3HB)) are produced as a carbon store in an array of organisms and exhibit characteristics which are similar to oil-derived plastics, yet have the added advantages of biodegradability and biocompatibility. Despite these advantages, P(3HB) production is currently more expensive than the production of oil-derived plastics, and therefore more efficient P(3HB) production processes are required. In this study, we describe the model-guided design and experimental characterization of several engineered P(3HB) producing operons. In particular, we describe the characterization of a novel hybrid phaCAB operon that consists of a dual promoter (native and J23104) and RBS (native and B0034) design. P(3HB) production was around six-fold higher in hybrid phaCAB engineered Escherichia coli in comparison to E. coli engineered with the native phaCAB operon from Ralstonia eutropha H16. The hybrid phaCAB operon represents a step towards the more efficient production of P(3HB), which has an array of applications from 3D printing to tissue engineering. | NA | biorxiv | 625 |
10.1101/005967 | Identification, annotation and visualisation of extreme changes in splicing from RNA-seq experiments with SwitchSeq | Mar Gonzàlez-Porta;Alvis Brazma; | Alvis Brazma | EMBL-EBI | 2014-06-06 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/06/005967.source.xml | In the past years, RNA sequencing has become the method of choice for the study of transcriptome composition. When working with this type of data, several tools exist to quantify differences in splicing across conditions and to address the significance of those changes. However, the number of genes predicted to undergo differential splicing is often high, and further interpretation of the results becomes a challenging task. Here we present SwitchSeq, a novel set of tools designed to help the users in the interpretation of differential splicing events that affect protein coding genes. More specifically, we provide a framework to identify switch events, i.e., cases where, for a given gene, the identity of the most abundant transcript changes across conditions. The identified events are then annotated by incorporating information from several public databases and third-party tools, and are further visualised in an intuitive manner with the independent R package tviz. All the results are displayed in a self-contained HTML document, and are also stored in txt and json format to facilitate the integration with any further downstream analysis tools. Such analysis approach can be used complementarily to Gene Ontology and pathway enrichment analysis, and can also serve as an aid in the validation of predicted changes in mRNA and protein abundance. The latest version of SwitchSeq, including installation instructions and use cases, can be found at https://github.com/mgonzalezporta/SwitchSeq. Additionally, the plot capabilities are provided as an independent R package at https://github.com/mgonzalezporta/tviz. | NA | biorxiv | 627 |
10.1101/006049 | A comparison of the gobiid fauna between a shoal and an island habitat in the central Visayas (Philippines) | Klaus M. Stiefel;Alistair Merrifield;Matt Reed;David B. Joyce; | Klaus M. Stiefel | University of Western Sydney | 2014-06-06 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/06/06/006049.source.xml | We surveyed the marine gobies of Malapascua island (Philippines), the surrounding islets and the nearby Monad shoal. We found 59 species in 19 genera, including 2 undescribed species of the genus Trimma, and 3 geographic and 6 depth range expansions. Furthermore we describe a new type of mimicry between the goby Koumasetta hectori and the cardinalfish Apogon nigrofasciatus. The comparison of the island versus shoal goby fauna showed a lesser species richness of shrimp-associated gobies at the shoal. This likely reflects the fact that hydrodynamic features of the environment play a dominant role in selecting which gobiid species, or their symbiotic shrimp, will be found in a certain location. We also observed a bias towards hovering species (of the genus Trimma) and away from shrimp-associated gobies at greater depths. These findings are in accord with the suspected shift of gobies towards planctotrophy with increasing depth.\n\nWe furthermore compare this study to previous surveys of goby faunas, and plot the recorded species numbers against the survey areas. This species-area plot provides support for the notion of high speciation rates in gobies due to their low mobility. | NA | biorxiv | 629 |
10.1101/006205 | The rugged adaptive landscape of an emerging plant RNA virus | Jasna Lalic;Santiago F. Elena; | Santiago F. Elena | CSIC | 2014-06-11 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/11/006205.source.xml | RNA viruses are the main source of emerging infectious diseases owed to the evolutionary potential bestowed by their fast replication, large population sizes and high mutation and recombination rates. However, an equally important parameter, which is usually neglected, is the topography of the fitness landscape, that is, how many fitness maxima exist and how well connected they are, which determines the number of accessible evolutionary pathways. To address this question, we have reconstructed the fitness landscape describing the adaptation of Tobacco etch potyvirus to its new host, Arabidopsis thaliana. Fitness was measured for most of the genotypes in the landscape, showing the existence of peaks and holes. We found prevailing epistatic effects between mutations, with cases of reciprocal sign epistasis being common at latter stages. Therefore, results suggest that the landscape was rugged and holey, with several local fitness peaks and a very limited number of potential neutral paths. The viral genotype fixed at the end of the evolutionary process was not on the global fitness optima but stuck into a suboptimal peak. | NA | biorxiv | 630 |
10.1101/006056 | Transcriptomic analysis of the lesser spotted catshark (Scyliorhinus canicula) pancreas, liver and brain reveals molecular level conservation of vertebrate pancreas function | John F Mulley;Adam D Hargreaves;Matthew J Hegarty;R. Scott Heller;Martin T Swain; | John F Mulley | Bangor University | 2014-06-06 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/06/06/006056.source.xml | BackgroundUnderstanding the evolution of the vertebrate pancreas is key to understanding its functions. The chondrichthyes (cartilaginous fish such as sharks and rays) have been suggested to possess the most ancient example of a distinct pancreas with both hormonal (endocrine) and digestive (exocrine) roles, although the lack of genetic, genomic and transcriptomic data for cartilaginous fish has hindered a more thorough understanding of the molecular-level functions of the chondrichthyan pancreas, particularly with respect to their \"unusual\" energy metabolism (where ketone bodies and amino acids are the main oxidative fuel source) and their paradoxical ability to both maintain stable blood glucose levels and tolerate extensive periods of hypoglycemia. In order to shed light on some of these processes we have carried out the first large-scale comparative transcriptomic survey of multiple cartilaginous fish tissues: the pancreas, brain and liver of the lesser spotted catshark, Scyliorhinus canicula.\n\nResultsWe generated a mutli-tissue assembly comprising 86,006 contigs, of which 44,794 were assigned to a particular tissue or combination of tissue based on mapping of sequencing reads. We have characterised transcripts encoding genes involved in insulin regulation, glucose sensing, transcriptional regulation, signaling and digestion, as well as many peptide hormone precursors and their receptors for the first time. Comparisons to published mammalian pancreas transcriptomes reveals that mechanisms of glucose sensing and insulin regulation used to establish and maintain a stable internal environment are conserved across jawed vertebrates and likely pre-date the vertebrate radiation. Conservation of pancreatic hormones and genes encoding digestive proteins support the single, early evolution of a distinct pancreatic gland with endocrine and exocrine functions in vertebrates, although the peptide diversity of the early vertebrate pancreas has been overestimated as a result of the use of cross-reacting antisera in earlier studies. A three hormone islet organ is therefore the basal vertebrate condition, later elaborated upon only in the tetrapod lineage.\n\nConclusionsThe cartilaginous fish are a great untapped resource for the reconstruction of patterns and processes of vertebrate evolution and new approaches such as those described in this paper will greatly facilitate their incorporation into the rank of \"model organism\". | 10.1186/1471-2164-15-1074 | biorxiv | 631 |
10.1101/006163 | Genome-wide Identification of Zero Nucleotide Recursive Splicing in Drosophila | Michael O Duff;Sara Olson;Xintao Wei;Ahmad Osman;Alex Plocik;Mohan Bolisetty;Susan Celniker;Brenton Graveley; | Brenton Graveley | UConn Health Center | 2014-06-11 | 1 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/06/11/006163.source.xml | Recursive splicing is a process in which large introns are removed in multiple steps by resplicing at ratchet points - 5 splice sites recreated after splicing1. Recursive splicing was first identified in the Drosophila Ultrabithorax (Ubx) gene1 and only three additional Drosophila genes have since been experimentally shown to undergo recursive splicing2,3. Here, we identify 196 zero nucleotide exon ratchet points in 130 introns of 115 Drosophila genes from total RNA sequencing data generated from developmental time points, dissected tissues, and cultured cells. Recursive splicing events were identified by splice junctions that map to annotated 5 splice sites and unannotated intronic 3 splice sites, the presence of the sequence AG/GT at the 3 splice site, and a 5 to 3 gradient of decreasing RNA-Seq read density indicative of co-transcriptional splicing. The sequential nature of recursive splicing was confirmed by identification of lariat introns generated by splicing to and from the ratchet points. We also show that recursive splicing is a constitutive process, and that the sequence and function of ratchet points are evolutionarily conserved. Together these results indicate that recursive splicing is commonly used in Drosophila and provides insight into the mechanisms by which some introns are removed. | 10.1038/nature14475 | biorxiv | 633 |
10.1101/006130 | Validation of methods for Low-volume RNA-seq | Peter Acuña Combs;Michael B Eisen; | Peter Acu?a Combs | University of California, Berkeley | 2014-06-10 | 1 | Confirmatory Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/06/10/006130.source.xml | Recently, a number of protocols extending RNA-sequencing to the single-cell regime have been published. However, we were concerned that the additional steps to deal with such minute quantities of input sample would introduce serious biases that would make analysis of the data using existing approaches invalid. In this study, we performed a critical evaluation of several of these low-volume RNA-seq protocols, and found that they performed slightly less well in metrics of interest to us than a more standard protocol, but with at least two orders of magnitude less sample required. We also explored a simple modification to one of these protocols that, for many samples, reduced the cost of library preparation to approximately $20/sample. | 10.7717/peerj.869 | biorxiv | 634 |
10.1101/006221 | Accounting for biases in riboprofiling data indicates a major role for proline and not positive amino acids in stalling translation | Carlo G. Artieri;Hunter B. Fraser; | Hunter B. Fraser | Stanford | 2014-06-11 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/06/11/006221.source.xml | The recent advent of ribosome profiling - sequencing of short ribosome-bound fragments of mRNA - has offered an unprecedented opportunity to interrogate the sequence features responsible for modulating translational rates. Nevertheless, numerous analyses of the first riboprofiling dataset have produced equivocal and often incompatible results. Here we analyze three independent yeast riboprofiling data sets, including two with much higher coverage than previously available, and find that all three show substantial technical sequence biases that confound interpretations of ribosomal occupancy. After accounting for these biases, we find no effect of previously implicated factors on ribosomal pausing. Rather, we find that incorporation of proline, whose unique side-chain stalls peptide synthesis in vitro, also slows the ribosome in vivo. We also reanalyze a recent method that reported positively charged amino acids as the major determinant of ribosomal stalling and demonstrate that its assumptions lead to false signals of stalling in low-coverage data. Our results suggest that any analysis of riboprofiling data should account for sequencing biases and sparse coverage. To this end, we establish a robust methodology that enables analysis of ribosome profiling data without prior assumptions regarding which positions spanned by the ribosome cause stalling. | 10.1101/gr.175893.114 | biorxiv | 635 |
10.1101/006270 | Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state | Yarden Katz;Feifei Li;Nicole Lambert;Ethan M Sokol;Wai-Leong Tam;Albert W Cheng;Edoardo M Airoldi;Christopher J Lengner;Piyush B Gupta;Zhengquan Yu;Rudolf Jaenisch;Christopher B Burge; | Yarden Katz | MIT | 2014-06-12 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/06/12/006270.source.xml | SummaryThe conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but mostly absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers, and associated with an epithelial-luminal cell state. Using ribosome footprint profiling and RNA-seq analysis of genetic mouse models in neuronal and mammary cell types, we found that Msis regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT) and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited translation of genes required for EMT, including Jagged1, and repressed EMT in cell culture and in mammary gland in vivo, while knockdown in epithelial cancer cells led to loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program and promote an epithelial-luminal state in both neural and breast cell types.\n\nHighlightsO_LIMsi proteins bind UAG motifs in vitro and in 3 UTRs of mRNAs\nC_LIO_LIMsi proteins are markers of epithelial state in brain and breast tumors, and cell lines\nC_LIO_LIThe Notch regulator Jag1 mRNA is bound and translationally repressed by Msi\nC_LIO_LIMsi overexpression represses EMT in the mammary gland in vivo\nC_LI | 10.7554/eLife.03915 | biorxiv | 636 |
10.1101/006288 | Mitochondrial DNA variation and structure among North American populations of Megaselia scalaris | Bret S Lesavoy;Suzanne E McGaugh;Mohamed A.F. Noor; | Mohamed A.F. Noor | Duke University | 2014-06-13 | 1 | New Results | cc_by | Zoology | https://www.biorxiv.org/content/early/2014/06/13/006288.source.xml | The scuttle fly Megaselia scalaris is a pest species whose larvae consume living or dead plant or animal tissue, and parasitize humans. Although known to exist on most continents, often transported passively with humans, the connectivity between populations has not been investigated. We use mitochondrial cytochrome B sequences to investigate structure among North American isolates of this species. Despite small sample sizes, we detected statistically significant structure among populations. This finding suggests that local measures may be effective in controlling this pest species. | NA | biorxiv | 638 |
10.1101/006338 | Evaluation of de novo transcriptome assemblies from RNA-Seq data | Bo Li;Nathanael Fillmore;Yongsheng Bai;Mike Collins;James A Thomson;Ron Stewart;Colin Dewey; | Colin Dewey | University of Wisconsin-Madison | 2014-06-13 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/13/006338.source.xml | De novo RNA-Seq assembly facilitates the study of transcriptomes for species without sequenced genomes, but it is challenging to select the most accurate assembly in this context. To address this challenge, we developed a model-based score, RSEM-EVAL, for evaluating assemblies when the ground truth is unknown. Our experiments show that RSEM-EVAL correctly reflects assembly accuracy, as measured by REF-EVAL, a refined set of ground-truth-based scores that we also developed. With the guidance of RSEM-EVAL, we assembled the transcriptome of the regenerating axolotl limb; this assembly compares favorably to a previous assembly. | 10.1186/s13059-014-0553-5 | biorxiv | 639 |
10.1101/006312 | Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition | Xiao-Yong Li;Melissa Harrison;Tommy Kaplan;Michael Eisen; | Michael Eisen | University of California Berkeley | 2014-06-13 | 1 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2014/06/13/006312.source.xml | A conspicuous feature of early animal development is the lack of transcription from the embryonic genome, and it typically takes several hours to several days (depending on the species) until widespread transcription of the embryonic genome begins. Although this transition is ubiquitous, relatively little is known about how the shift from a transcriptionally quiescent to transcriptionally active genome is controlled. We describe here the genome-wide distributions and temporal dynamics of nucleosomes and post-translational histone modifications through the maternal-to-zygotic transition in embryos of the pomace fly Drosophila melanogaster. At mitotic cycle 8, when few zygotic genes are being transcribed, embryonic chromatin is in a relatively simple state: there are few nucleosome free regions, undetectable levels of the histone methylation marks characteristic of mature chromatin, and low levels of histone acetylation at a relatively small number of loci. Histone acetylation increases by cycle 11, but it is not until cycle 13 that nucleosome free regions and domains of histone methylation become widespread. Early histone acetylation is strongly associated with regions that we have previously shown are bound in early embryos by the maternally deposited transcription factor Zelda. Most of these Zelda-bound regions are destined to be enhancers or promoters active during mitotic cycle 14, and our data demonstrate that they are biochemically distinct long before they become active, raising the possibility that Zelda triggers a cascade of events, including the accumulation of specific histone modifications, that plays a role in the subsequent activation of these sequences. Many of these Zelda-associated active regions occur in larger domains that we find strongly enriched for histone marks characteristic of Polycomb-mediated repression, suggesting a dynamic balance between Zelda activation and Polycomb repression. Collectively, these data paint a complex picture of a genome in transition from a quiescent to an active state, and highlight the role of Zelda in mediating this transition. | 10.7554/eLife.03737 | biorxiv | 640 |
10.1101/006247 | Comparison of the 3D organization of sperm and fibroblast genomes using the Hi-C approach | Nariman Battulin;Veniamin S Fishman;Alexander M Mazur;Mikhail Pomaznoy;Anna A Khabarova;Dmitry A Afonnikov;Egor B Prokhortchouk;Oleg L Serov; | Oleg L Serov | Institute of Cytology and Genetics, Novosibirsk, Russia | 2014-06-16 | 1 | New Results | cc_by_nd | Developmental Biology | https://www.biorxiv.org/content/early/2014/06/16/006247.source.xml | The 3D organization of the genome is tightly connected to its biological function. The Hi-C approach was recently introduced as a method that can be used to identify higher-order chromatin interactions genome-wide. The aim of this study was to determine genome-wide chromatin interaction frequencies using the Hi-C approach in mouse sperm cells and embryonic fibroblasts. The obtained results demonstrated that the 3D genome organizations of sperm and fibroblast cells show a high degree of similarity both with each other and with the previously described mouse embryonic stem (ES) cells. Both A- and B-compartments and topologically associated domains (TADs) are present in spermatozoa and fibroblasts. Nevertheless, sperm cells and fibroblasts exhibited statistically significant differences between each other in the contact probabilities of defined loci. Tight packaging of the sperm genome resulted in an enrichment of long-range contacts compared with the fibroblasts. However, only 30% of the differences in the number of contacts are based on differences in the densities of their genome packages; the main source of the differences is the gain or loss of contacts that are specific for defined genome regions. An analysis of interchromosomal contacts in both cell types demonstrated that the large chromosomes showed a tendency to interact with each other more than with the small chromosomes and vice versa. We found that the dependence of the contact probability P(s) on genomic distance for sperm is in a good agreement with the fractal globular folding of chromatin. The similarity of the spatial DNA organization in sperm and somatic cell genomes suggests the stability of the 3D structure of genomes through generations. | 10.1186/s13059-015-0642-0 | biorxiv | 641 |
10.1101/006395 | Error correction and assembly complexity of single molecule sequencing reads. | Hayan Lee;James Gurtowski;Shinjae Yoo;Shoshana Marcus;W. Richard McCombie;Michael Schatz; | Michael Schatz | Cold Spring Harbor Laboratory | 2014-06-18 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/18/006395.source.xml | Third generation single molecule sequencing technology is poised to revolutionize genomics by enabling the sequencing of long, individual molecules of DNA and RNA. These technologies now routinely produce reads exceeding 5,000 basepairs, and can achieve reads as long as 50,000 basepairs. Here we evaluate the limits of single molecule sequencing by assessing the impact of long read sequencing in the assembly of the human genome and 25 other important genomes across the tree of life. From this, we develop a new data-driven model using support vector regression that can accurately predict assembly performance. We also present a novel hybrid error correction algorithm for long PacBio sequencing reads that uses pre-assembled Illumina sequences for the error correction. We apply it several prokaryotic and eukaryotic genomes, and show it can achieve near-perfect assemblies of small genomes (< 100Mbp) and substantially improved assemblies of larger ones. All source code and the assembly model are available open-source. | NA | biorxiv | 642 |
10.1101/006403 | Beyond library size: a field guide to NGS normalization | Jelena Aleksic;Sarah H Carl;Michaela Frye; | Jelena Aleksic | University of Cambridge | 2014-06-19 | 1 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/19/006403.source.xml | BackgroundNext generation sequencing (NGS) is a widely used technology in both basic research and clinical settings and it will continue to have a major impact on biomedical sciences. However, the use of incorrect normalization methods can lead to systematic biases and spurious results, making the selection of an appropriate normalization strategy a crucial and often overlooked part of NGS analysis.
ResultsWe present a basic introduction to the currently available normalization methods for differential expression and ChIP-seq applications, along with best use recommendations for different experimental techniques and datasets.
We demonstrate that the choice of normalization technique can have a significant impact on the number of genes called as differentially expressed in an RNA-seq experiment or peaks called in a ChIP-seq experiment.
ConclusionsThe choice of the most adequate normalization method depends on both the distribution of signal in the dataset and the intended downstream applications. Depending on the design and purpose of the study, appropriate bias correction should also be considered. | NA | biorxiv | 644 |
10.1101/006353 | Combining genome-scale Drosophila 3D neuroanatomical data by bridging template brains | James D. Manton;Aaron D. Ostrovsky;Lea Goetz;Marta Costa;Torsten Rohlfing;Gregory S. X. E. Jefferis; | Gregory S. X. E. Jefferis | Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge, CB2?0QH, UK | 2014-06-19 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2014/06/19/006353.source.xml | To analyse neuron data at scale, neuroscientists expend substantial effort reading documentation, installing dependencies and moving between analysis and visualisation environments. To facilitate this, we have developed a suite of interoperable open-source R packages called the natverse. The natverse allows users to read local and remote data, perform popular analyses including visualisation, clustering and graph-theoretic analysis of neuronal branching. Unlike most tools, the natverse enables comparison of morphology and connectivity across many neurons after imaging or co-registration within a common template space. The natverse also enables transformations between different template spaces and imaging modalities. We demonstrate tools that integrate the vast majority of Drosophila neuroanatomical light microscopy and electron microscopy connectomic datasets. The natverse is an easy-to-use environment for neuroscientists to solve complex, large-scale analysis challenges as well as an open platform to create new code and packages to share with the community. | NA | biorxiv | 646 |
10.1101/006213 | Using Polysome Isolation with Mechanism Alteration to Uncover Transcriptional and Translational Dynamics in Key Genes | Bradly Alicea; | Bradly Alicea | Orthogonal Research | 2014-06-20 | 1 | Confirmatory Results | cc_by_nc | Cell Biology | https://www.biorxiv.org/content/early/2014/06/20/006213.source.xml | What does it mean when we say a cells biochemistry is regulated during changes to the phenotype? While there are a plethora of potential mechanisms and contributions to the final outcome, a more tractable approach is to examine the dynamics of mRNA. This way, we can assess the contributions of both known and unknown decay and aggregation processes for maintaining levels of gene product on a gene-by-gene basis. In this extended protocol, drug treatments that target specific cellular functions (termed mechanism disruption) can be used in tandem with mRNA extraction from the polysome to look at the dynamics of mRNA levels associated with transcription and translation at multiple stages during a physiological perturbation. This is accomplished through validating the polysome isolation method in human cells and comparing fractions of mRNA for each experimental treatment at multiple points in time. First, three different drug treatments corresponding to the arrest of various cellular processes are administered to populations of human cells. For each treatment, the transcriptome and translatome are compared directly at different time points by assaying both cell-type specific and non-specific genes. There are two findings of note. First, extraction of mRNA from the polysome and comparison with the transcriptome can yield interesting information about the regulation of cellular mRNA during a functional challenge to the cell. In addition, the conventional application of such drugs to assess mRNA decay is an incomplete picture of how severely challenged or senescent cells regulate mRNA in response. This extended protocol demonstrates how the gene- and process-variable degradation of mRNA might ultimately require investigations into the course-grained dynamics of cellular mRNA, from transcription to ribosome. | NA | biorxiv | 647 |
10.1101/006361 | Finite-state discrete-time Markov chain models of gene regulatory networks | Vladimir Skornyakov;Maria Skornyakova;Antonina Shurygina;Pavel Skornyakov; | Vladimir Skornyakov | Kogan Research Institute of Neurocybernetics, Southern Federal University, Rostov-on-Don, Russia | 2014-06-23 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/23/006361.source.xml | In this study Markov chain models of gene regulatory networks (GRN) are developed. These models gives the ability to apply the well known theory and tools of Markov chains to GRN analysis. We introduce a new kind of the finite graph of the interactions called the combinatorial net that formally represent a GRN and the transition graphs constructed from interaction graphs. System dynamics are defined as a random walk on the transition graph that is some Markovian chain. A novel concurrent updating scheme (evolution rule) is developed to determine transitions in a transition graph. Our scheme is based on the firing of a random set of non-steady state vertices of a combinatorial net. We demonstrate that this novel scheme gives an advance in the modeling of the asynchronicity. Also we proof the theorem that the combinatorial nets with this updating scheme can asynchronously compute a maximal independent sets of graphs. As proof of concept, we present here a number of simple combinatorial models: a discrete model of auto-repression, a bi-stable switch, the Elowitz repressilator, a self-activation and show that this models exhibit well known properties. | 10.12688/f1000research.4669.1 | biorxiv | 650 |
10.1101/006478 | Estimating cellular pathways from an ensemble of heterogeneous data sources | Alexander Franks;Florian Markowetz;Edoardo Airoldi; | Alexander Franks | Harvard University | 2014-06-23 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/06/23/006478.source.xml | Building better models of cellular pathways is one of the major challenges of systems biology and functional genomics. There is a need for methods to build on established expert knowledge and reconcile it with results of high-throughput studies. Moreover, the available data sources are heterogeneous and need to be combined in a way specific for the part of the pathway in which they are most informative. Here, we present a compartment specific strategy to integrate edge, node and path data for the refinement of a network hypothesis. Specifically, we use a local-move Gibbs sampler for refining pathway hypotheses from a compendium of heterogeneous data sources, including novel methodology for integrating protein attributes. We demonstrate the utility of this approach in a case study of the pheromone response MAPK pathway in the yeast S. cerevisiae. | NA | biorxiv | 651 |
10.1101/006031 | Testing the Toxicofera: comparative reptile transcriptomics casts doubt on the single, early evolution of the reptile venom system | Adam D Hargreaves;Martin T Swain;Darren W Logan;John F Mulley; | John F Mulley | Bangor University | 2014-06-06 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/06/006031.source.xml | Background The identification of apparently conserved gene complements in the venom and salivary glands of a diverse set of reptiles led to the development of the Toxicofera hypothesis the idea that there was a single, early evolution of the venom system in reptiles. However, this hypothesis is based largely on relatively small scale EST-based studies of only venom or salivary glands and toxic effects have been assigned to only some of these putative Toxcoferan toxins in some species. We set out to investigate the distribution of these putative venom toxin transcripts in order to investigate to what extent conservation of gene complements may reflect a bias in previous sampling efforts. Results We have carried out the first large-scale test of the Toxicofera hypothesis and found it lacking in a number of regards. Our quantitative transcriptomic analyses of venom and salivary glands and other body tissues in five species of reptile, together with the use of available RNA-Seq datasets for additional species shows that the majority of genes used to support the establishment and expansion of the Toxicofera are in fact expressed in multiple body tissues and most likely represent general maintenance or housekeeping genes. The apparent conservation of gene complements across the Toxicofera therefore reflects an artefact of incomplete tissue sampling. In other cases, the identification of a non-toxic paralog of a gene encoding a true venom toxin has led to confusion about the phylogenetic distribution of that venom component. Conclusions Venom has evolved multiple times in reptiles. In addition, the misunderstanding regarding what constitutes a toxic venom component, together with the misidentification of genes and the classification of identical or near-identical sequences as distinct genes has led to an overestimation of the complexity of reptile venoms in general, and snake venom in particular, with implications for our understanding of (and development of treatments to counter) the molecules responsible for the physiological consequences of snakebite. | 10.1016/j.toxicon.2014.10.004 | biorxiv | 652 |
10.1101/000992 | Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas | Alejandro Reyes;Carolin Blume;Vicent Pelechano;Petra Jakob;Lars M Steinmetz;Thorsten Zenz;Wolfgang Huber; | Alejandro Reyes | European Molecular Biology Laboratory | 2014-07-13 | 3 | New Results | cc_by | Cancer Biology | https://www.biorxiv.org/content/early/2014/07/13/000992.source.xml | BackgroundGenome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.\n\nResultsTo start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.\n\nAmong these genes, we found UQCC and RPL31; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1.\n\nConclusionsOur results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.\n\nValidation studies on larger cohorts and model systems are required to extend these findings. | NA | biorxiv | 654 |
10.1101/000653 | An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells | David A Turner;Jamie Trott;Penelope Hayward;Pau Rué;Alfonso Martinez Arias; | Alfonso Martinez Arias | Department of Genetics. University of Cambridge. Cambridge CB2 3EH. UK. | 2014-06-30 | 5 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2014/06/30/000653.source.xml | Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst, retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analyzed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a \"race for fates\" at the level of single cells in which the neuroectodermal fate has an advantage. | 10.1242/bio.20148409 | biorxiv | 655 |
10.1101/001677 | Beyond species: why ecological interaction networks vary through space and time | Timothée Poisot;Daniel B Stouffer;Dominique Gravel; | Timothée Poisot | Université du Québec à Rimouski | 2014-07-21 | 4 | New Results | cc_by | Ecology | https://www.biorxiv.org/content/early/2014/07/21/001677.source.xml | Community ecology is tasked with the considerable challenge of predicting the structure, and properties, of emerging ecosystems. It requires the ability to understand how and why species interact, as this will allow the development of mechanism-based predictive models, and as such to better characterize how ecological mechanisms act locally on the existence of interspecific interactions. Here we argue that the current conceptualization of species interaction networks is ill-suited for this task. Instead, we propose that future research must start to account for the intrinsic variability of species interactions, then scale up from here onto complex networks. This can be accomplished simply by recognizing that there exists intra-specific variability, in traits or properties related to the establishment of species interactions. By shifting the scale towards population-based processes, we show that this new approach will improve our predictive ability and mechanistic understanding of how species interact over large spatial or temporal scales. | 10.1111/oik.01719 | biorxiv | 656 |
10.1101/002295 | Modeling bi-modality improves characterization of cell cycle on gene expression in single cells | Lucas Dennis;Andrew McDavid;Patrick Danaher;Greg Finak;Michael Krouse;Alice Wang;Philippa Webster;Joseph Beechem;Raphael Gottardo; | Raphael Gottardo | Fred Hutchinson Cancer Research Center | 2014-07-10 | 2 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/07/10/002295.source.xml | Advances in high-throughput, single cell gene expression are allowing interrogation of cell heterogeneity. However, there is concern that the cell cycle phase of a cell might bias characterizations of gene expression at the single-cell level. We assess the effect of cell cycle phase on gene expression in single cells by measuring 333 genes in 930 cells across three phases and three cell lines. We determine each cells phase non-invasively without chemical arrest and use it as a covariate in tests of differential expression. We observe bi-modal gene expression, a previously-described phenomenon, wherein the expression of otherwise abundant genes is either strongly positive, or undetectable within individual cells. This bi-modality is likely both biologically and technically driven. Irrespective of its source, we show that it should be modeled to draw accurate inferences from single cell expression experiments. To this end, we propose a semi-continuous modeling framework based on the generalized linear model, and use it to characterize genes with consistent cell cycle effects across three cell lines. Our new computational framework improves the detection of previously characterized cell-cycle genes compared to approaches that do not account for the bi-modality of single-cell data. We use our semi-continuous modelling framework to estimate single cell gene co-expression networks. These networks suggest that in addition to having phase-dependent shifts in expression (when averaged over many cells), some, but not all, canonical cell cycle genes tend to be co-expressed in groups in single cells. We estimate the amount of single cell expression variability attributable to the cell cycle. We find that the cell cycle explains only 5%-17% of expression variability, suggesting that the cell cycle will not tend to be a large nuisance factor in analysis of the single cell transcriptome. | 10.1371/journal.pcbi.1003696 | biorxiv | 658 |
10.1101/002709 | Differential gene expression and alternative splicing in insect immune specificity | Carolyn Riddell;Juan David Lobaton Garces;Sally Adams;Seth M Barribeau;David Twell;Eamonn Mallon; | Eamonn Mallon | University of Leicester | 2014-06-30 | 5 | New Results | cc_by_nc | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/30/002709.source.xml | Ecological studies routinely show genotype-genotype interactions between insects and their parasites. The mechanisms behind these interactions are not clearly understood. Using the bumblebee Bombus terrestris / trypanosome Crithidia bombi model system, we have carried out a transcriptome-wide analysis of gene expression and alternative splicing in bees during C. bombi infection. We have performed four analyses, 1) comparing gene expression in infected and non-infected bees 24 hours after infection by Crithidia bombi, 2) comparing expression at 24 and 48 hours after C.bombi infection, 3) searching for differential gene expression associated with the host-parasite genotype-genotype interaction at 24 hours after infection and 4) searching for alternative splicing associated with the host-parasite genotype-genotype interaction at 24 hours post infection. We found a large number of genes differentially regulated related to numerous canonical immune pathways. These genes include receptors, signaling pathways and effectors. We discovered a possible interaction between the peritrophic membrane and the insect immune system in defense against Crithidia. Most interestingly we found differential expression and alternative splicing of Dscam related transcripts and a novel immunoglobulin related gene Twitchin depends on the genotype-genotype interactions of the given bumblebee colony and Crithidia strain. | 10.1186/1471-2164-15-1031 | biorxiv | 659 |
10.1101/003988 | Sharing of Very Short IBD Segments between Humans, Neandertals, and Denisovans | Gundula Povysil;Sepp Hochreiter; | Sepp Hochreiter | Johannes Kepler University, Linz | 2014-07-15 | 2 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/07/15/003988.source.xml | We analyze the sharing of very short identity by descent (IBD) segments between humans, Neandertals, and Denisovans to gain new insights into their demographic history. Short IBD segments convey information about events far back in time because the shorter IBD segments are, the older they are assumed to be. The identification of short IBD segments becomes possible through next generation sequencing (NGS), which offers high variant density and reports variants of all frequencies. However, only recently HapFABIA has been proposed as the first method for detecting very short IBD segments in NGS data. HapFABIA utilizes rare variants to identify IBD segments with a low false discovery rate.\n\nWe applied HapFABIA to the 1000 Genomes Project whole genome sequencing data to identify IBD segments that are shared within and between populations. Many IBD segments have to be old since they are shared with Neandertals or Denisovans, which explains their shorter lengths compared to segments that are not shared with these ancient genomes. The Denisova genome most prominently matches IBD segments that are shared by Asians. Many of these segments were found exclusively in Asians and they are longer than segments shared between other continental populations and the Denisova genome. Therefore, we could confirm an introgression from Deniosvans into ancestors of Asians after their migration out of Africa. While Neandertal-matching IBD segments are most often shared by Asians, Europeans share a considerably higher percentage of IBD segments with Neandertals compared to other populations, too. Again, many of these Neandertal-matching IBD segments are found exclusively in Asians, whereas Neandertal-matching IBD segments that are shared by Europeans are often found in other populations, too. Neandertal-matching IBD segments that are shared by Asians or Europeans are longer than those observed in Africans. These IBD segments hint at a gene flow from Neandertals into ancestors of Asians and Europeans after they left Africa. Interestingly, many Neandertal-and/or Denisova-matching IBD segments are predominantly observed in Africans -- some of them even exclusively. IBD segments shared between Africans and Neandertals or Denisovans are strikingly short, therefore we assume that they are very old. Consequently, we conclude that DNA regions from ancestors of humans, Neandertals, and Denisovans have survived in Africans. As expected, IBD segments on chromosome X are on average longer than IBD segments on the autosomes. Neandertal-matching IBD segments on chromosome X confirm gene flow from Neandertals into ancestors of Asians and Europeans outside Africa that was already found on the autosomes. Interestingly, there is hardly any signal of Denisova introgression on the X chromosome. | NA | biorxiv | 661 |
10.1101/004283 | Weight Loss in Response to Food Deprivation Predicts The Extent of Diet Induced Obesity in C57BL/6J Mice | Matthew J. Peloqiun;Dave Bridges; | Dave Bridges | UTHSC | 2014-06-30 | 3 | New Results | cc_by | Physiology | https://www.biorxiv.org/content/early/2014/06/30/004283.source.xml | Inbred C57BL/6J mice have been used to study diet-induced obesity and the detrimental physiological effects associated with it. Little is understood about predictive factors that predispose an animal to weight gain. To address this, mice were fed a high fat diet, control diet or normal chow diet. Several measurements including pre-diet serum hormone levels and pre-diet body weight were analyzed, but these had limited predictive value regarding weight gain. However, baseline measurements of weight loss in response to food deprivation showed a strong negative correlation with high fat diet-induced weight gain. These data suggest that fasting-induced weight loss in adolescent mice is a useful predictor of diet-induced weight gain. | NA | biorxiv | 662 |
10.1101/004481 | Predicting evolutionary site variability from structure in viral proteins: buriedness, packing, flexibility, and design | Amir Shahmoradi;Dariya K. Sydykova;Stephanie J. Spielman;Eleisha L. Jackson;Eric T. Dawson;Austin G. Meyer;Claus O. Wilke; | Claus O. Wilke | The University of Texas at Austin | 2014-07-21 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/07/21/004481.source.xml | Several recent works have shown that protein structure can predict site-specific evolutionary sequence variation. In particular, sites that are buried and/or have many contacts with other sites in a structure have been shown to evolve more slowly, on average, than surface sites with few contacts. Here, we present a comprehensive study of the extent to which numerous structural properties can predict sequence variation. The quantities we considered include buriedness (as measured by relative solvent accessibility), packing density (as measured by contact number), structural flexibility (as measured by B factors, root-mean-square fluctuations, and variation in dihedral angles), and variability in designed structures. We obtained structural flexibility measures both from molecular dynamics simulations performed on 9 non-homologous viral protein structures and from variation in homologous variants of those proteins, where available. We obtained measures of variability in designed structures from flexible-backbone design in the Rosetta software. We found that most of the structural properties correlate with site variation in the majority of structures, though the correlations are generally weak (correlation coefficients of 0.1 to 0.4). Moreover, we found that buriedness and packing density were better predictors of evolutionary variation than was structural flexibility. Finally, variability in designed structures was a weaker predictor of evolutionary variability than was buriedness or packing density, but it was comparable in its predictive power to the best structural flexibility measures. We conclude that simple measures of buriedness and packing density are better predictors of evolutionary variation than are more complicated predictors obtained from dynamic simulations, ensembles of homologous structures, or computational protein design. | 10.1007/s00239-014-9644-x | biorxiv | 663 |
10.1101/004671 | The Landscape of Human STR Variation | Thomas F. Willems;Melissa Gymrek;Gareth Highnam;- The 1000 Genomes Project;David Mittelman;Yaniv Erlich; | Yaniv Erlich | Whitehead Institute for Biomedical Research | 2014-07-10 | 3 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/07/10/004671.source.xml | Short Tandem Repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across over 1,000 individuals in phase 1 of the 1000 Genomes Project. This process nearly saturated common STR variations. After employing a series of quality controls, we utilize this call set to analyze determinants of STR variation, assess the human reference genomes representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. The resource is publicly available at http://strcat.teamerlich.org/ both in raw format and via a graphical interface. | 10.1101/gr.177774.114 | biorxiv | 664 |
10.1101/005207 | RNA-seq gene profiling - a systematic empirical comparison | Nuno A Fonseca;John A Marioni;Alvis Brazma; | Alvis Brazma | EMBL-EBI | 2014-07-16 | 3 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/07/16/005207.source.xml | Accurately quantifying gene expression levels is a key goal of experiments using RNA-sequencing to assay the transcriptome. This typically requires aligning the short reads generated to the genome or transcriptome before quantifying expression of pre-defined sets of genes. Differences in the alignment/quantification tools can have a major effect upon the expression levels found with important consequences for biological interpretation. Here we address two main issues: do different analysis pipelines affect the gene expression levels inferred from RNA-seq data? And, how close are the expression levels inferred to the \"true\" expression levels?\n\nWe evaluate fifty gene profiling pipelines in experimental and simulated data sets with different characteristics (e.g, read length and sequencing depth). In the absence of knowledge of the ground truth in real RNAseq data sets, we used simulated data to assess the differences between the \"true\" expression and those reconstructed by the analysis pipelines. Even though this approach does not take into account all known biases present in RNAseq data, it still allows to estimate the accuracy of the gene expression values inferred by different analysis pipelines. The results show that i) overall there is a high correlation between the expression levels inferred by the best pipelines and the true quantification values; ii) the error in the estimated gene expression values can vary considerably across genes; and iii) a small set of genes have expression estimates with consistently high error (across data sets and methods). Finally, although the mapping software is important, the quantification method makes a greater difference to the results. | 10.1371/journal.pone.0107026 | biorxiv | 665 |
10.1101/005470 | Bio-inspired design of ice-retardant devices based on benthic marine invertebrates: the effect of surface texture | Homayun Mehrabani;Neil Ray;Kyle Tse;Dennis Evangelista; | Dennis Evangelista | University of North Carolina at Chapel Hill | 2014-06-26 | 2 | New Results | cc_no | Biophysics | https://www.biorxiv.org/content/early/2014/06/26/005470.source.xml | Growth of ice on surfaces poses a challenge for both organisms and for devices that come into contact with liquids below the freezing point. Resistance of some organisms to ice formation and growth, either in subtidal environments (e.g. Antarctic anchor ice), or in environments with moisture and cold air (e.g. plants, intertidal) begs examination of how this is accomplished. Several factors may be important in promoting or mitigating ice formation. As a start, here we examine the effect of surface texture alone. We tested four candidate surfaces, inspired by hard-shelled marine invertebrates and constructed using a three-dimensional printing process. We screened biological and artifical samples for ice formation and accretion in submerged conditions using previous methods, and developed a new test to examine ice formation from surface droplets as might be encountered in environments with moist, cold air. It appears surface texture plays only a small role in delaying the onset of ice formation: a stripe feature (corresponding to patterning found on valves of blue mussels, Mytilus edulis, or on the spines of the Antarctic sea urchin Sterechinus neumayeri) slowed ice formation an average of 25% compared to a grid feature (corresponding to patterning found on sub-polar butterclams, Saxidomas nuttalli). The geometric dimensions of the features have only a small ([~]6%) effect on ice formation. Surface texture affects ice formation, but does not explain by itself the large variation in ice formation and species-specific ice resistance observed in other work. This suggests future examination of other factors, such as material elastic properties and coatings, and their interaction with surface pattern. | 10.7717/peerj.588 | biorxiv | 666 |
10.1101/005942 | Copy number networks to guide combinatorial therapy for cancer and other disorders | Andy Lin;Desmond James Smith; | Desmond James Smith | UCLA | 2014-06-24 | 2 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/06/24/005942.source.xml | The dwindling drug pipeline is driving increased interest in the use of genome datasets to inform drug treatment. In particular, networks based on transcript data and protein-protein interactions have been used to design therapies that employ drug combinations. But there has been less focus on employing human genetic interaction networks constructed from copy number alterations (CNAs). These networks can be charted with sensitivity and precision by seeking gene pairs that tend to be amplified and/or deleted in tandem, even when they are located at a distance on the genome. Our experience with radiation hybrid (RH) panels, a library of cell clones that have been used for genetic mapping, have shown this tool can pinpoint statistically significant patterns of co-inherited gene pairs. In fact, we were able to identify gene pairs specifically associated with the mechanism of cell survival at single gene resolution. The strategy of seeking correlated CNAs can also be used to map survival networks for cancer. Although the cancer networks have lower resolution, the RH network can be leveraged to provide single gene specificity in the tumor networks. In a survival network for glioblastoma possessing single gene resolution, we found that the epidermal growth factor receptor (EGFR) oncogene interacted with 46 genes. Of these genes, ten (22%) happened to be targets for existing drugs. Here, we briefly review the previous use of molecular networks to design novel therapies. We then highlight the potential of using correlated CNAs to guide combinatorial drug treatment in common medical conditions. We focus on therapeutic opportunities in cancer, but also offer examples from autoimmune disorders and atherosclerosis. | NA | biorxiv | 668 |
10.1101/005876 | Rapid transcriptional response to physiological neuronal activity in vivo revealed by transcriptome sequencing | Yarden Katz;Tarciso Velho;Vincent Butty;Christopher B. Burge;Carlos Lois; | Yarden Katz | MIT | 2014-06-26 | 2 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/06/26/005876.source.xml | Neuronal activity serves as a gateway between external stimulus from environment and the brain, often inducing gene expression changes. Alternative splicing (AS) is a widespread mechanism of increasing the number of transcripts produced from a single gene and has been shown to alter properties of neuronal genes, such as ion channels (Xie and Black 2001) and neurotransmitter receptors (Mu et al. 2003). Patterns of neural tissue-specific AS have been identified, often regulated by neuron-specific splicing factors that are essential for survival (Jensen et al. 2000; Li et al. 2007), demonstrating the importance of AS in neurons. In vitro studies of neuronal activity found AS changes in response to neuronal activity in addition to transcriptional ones, raising the question of whether such changes are recapitulated in vivo on behaviorally relevant timescales. We developed a paradigm for studying physiological neuronal activity through controlled stimulation of the olfactory bulb, and performed RNA-Seq transcriptome analysis of olfactory bulbs from odor-deprived and stimulated mice. We found that physiological stimulation induces large, rapid and reproducible changes in transcription in vivo, and that the activation of a core set of activity-regulated factors is recapitulated in an in vitro model of neuronal stimulation. However, physiological activity did not induce global changes in post-transcriptional mRNA processing, such as AS or alternative cleavage and polyadenylation. In contrast, analysis of RNA-Seq from in vitro stimulation models showed rapid activity-dependent changes in both transcription and mRNA processing. Our results provide the first genome-wide look at neuronal activity-dependent mRNA processing and suggest that rapid changes in AS might not be the dominant form of transcriptome alterations that take place during olfactory rodent behavior. | NA | biorxiv | 669 |
10.1101/006445 | False facts and false views: coalescent analysis of truncated data | Einar Árnason; | Einar Árnason | University of Iceland | 2014-06-30 | 2 | Contradictory Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/30/006445.source.xml | Darwins dictum on false facts and false views points the way to opening the road to truth via cogent criticism of the published record. Here I discuss a case in which a truncated dataset (false facts) is used for coalescent analysis of historical demography that reaches a foregone conclusion of a bottleneck of numbers (false views). | NA | biorxiv | 670 |
10.1101/006551 | Compression of short-read sequences using path encoding | Carl Kingsford;Rob Patro; | Carl Kingsford | Carnegie Mellon University | 2014-06-24 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/06/24/006551.source.xml | Storing, transmitting, and archiving the amount of data produced by next generation sequencing is becoming a significant computational burden. For example, large-scale RNA-seq meta-analyses may now routinely process tens of terabytes of sequence. We present here an approach to biological sequence compression that reduces the difficulty associated with managing the data produced by large-scale transcriptome sequencing. Our approach offers a new direction by sitting between pure reference-based compression and reference-free compression and combines much of the benefit of reference-based approaches with the flexibility of de novo encoding. Our method, called path encoding, draws a connection between storing paths in de Bruijn graphs --- a common task in genome assembly --- and context-dependent arithmetic coding. Supporting this method is a system, called a bit tree, to compactly store sets of kmers that is of independent interest. Using these techniques, we are able to encode RNA-seq reads using 3% -- 11% of the space of the sequence in raw FASTA files, which is on average more than 34% smaller than recent competing approaches. We also show that even if the reference is very poorly matched to the reads that are being encoded, good compression can still be achieved. | 10.1093/bioinformatics/btv071 | biorxiv | 671 |
10.1101/006486 | Are phylogenetic patterns the same in anthropology and biology? | David Morrison; | David Morrison | Uppsala University | 2014-06-24 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/06/24/006486.source.xml | The use of phylogenetic methods in anthropological fields such as archaeology, linguistics and stemmatology (involving what are often called \"culture data\") is based on an analogy between human cultural evolution and biological evolution. We need to understand this analogy thoroughly, including how well anthropology data fit the model of a phylogenetic tree, as used in biology. I provide a direct comparison of anthropology datasets with both phenotype and genotype datasets from biology. The anthropology datasets fit the tree model approximately as well as do the genotype data, which is detectably worse than the fit of the phenotype data. This is true for datasets with <500 parsimony-informative characters, as well as for larger datasets. This implies that cross-cultural (horizontal) processes have been important in the evolution of cultural artifacts, as well as branching historical (vertical) processes, and thus a phylogenetic network will be a more appropriate model than a phylogenetic tree. | NA | biorxiv | 672 |
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