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10.1101/001990 | An Improved Search Algorithm to Find G-Quadruplexes in Genome Sequences | Anna Varizhuk;Dmitry Ischenko;Igor Smirnov;Olga Tatarinova;Vyacheslav Severov;Roman Novikov;Vladimir Tsvetkov;Vladimir Naumov;Dmitry Kaluzhny;Galina Pozmogova; | Galina Pozmogova | Institute for Physical-Chemical Medicine | 2014-01-23 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/23/001990.source.xml | A growing body of data suggests that the secondary structures adopted by G-rich polynucleotides may be more diverse than previously thought and that the definition of G-quadruplex-forming sequences should be broadened. We studied solution structures of a series of naturally occurring and model single-stranded DNA fragments defying the G3+NL1G3+NL2G3+NL3G3+ formula, which is used in most of the current GQ-search algorithms. The results confirm the GQ-forming potential of such sequences and suggest the existence of new types of GQs. We developed an improved (broadened) GQ-search algorithm (http://niifhm.ru/nauchnye-issledovanija/otdel-molekuljarnoj-biologii-i-genetiki/laboratorija-iskusstvennogo-antitelogeneza/497-2/) that accounts for the recently reported new types of GQs. | NA | biorxiv | 182 |
10.1101/001982 | An accelerated miRNA-based screen implicates Atf-3 in odorant receptor expression | Shreelatha Bhat;Minjung Shin;Suhyoung Bahk;Young-Joon Kim;Walton D. Jones; | Walton D. Jones | Korea Advanced Institute of Science and Technology (KAIST) | 2014-01-22 | 1 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2014/01/22/001982.source.xml | Large scale genetic screening is tedious and time-consuming. To address this problem, we propose a novel two-tiered screening system comprising an initial \"pooling\" screen that identifies miRNAs whose tissue-specific over-expression causes a phenotype of interest followed by a more focused secondary screen that uses gene-specific RNAi. As miRNAs inhibit translation or direct the destruction of their target mRNAs, any phenotype observed with miRNA over-expression can be attributed to the loss-of-function of one or more target mRNAs. Since miRNA-target pairing is sequence-specific, a list of predicted targets for miRNAs identified in the initial screen serves as a list of candidates for the secondary RNAi-based screen. These predicted miRNA targets can be prioritized by expression pattern, and if multiple miRNAs produce the same phenotype, overlapping target predictions can be given higher priority in the follow-up screen.\n\nSince miRNAs are short, miRNA misexpression will likely uncover artifactual miRNA-target relation-ships. Thus, we are using miRNAs as a tool to accelerate genetic screening rather than focus on the biology of miRNAs themselves. This two-tiered system allows us to rapidly identify individual target genes involved in a phenomenon of interest, often in less than 200 crosses. Here we demonstrate the effectiveness of this method by identifying miRNAs that alter Drosophila odorant receptor expression. With subsequent miRNA target prediction and follow-up RNAi screening we identify and validate a novel role for the transcription factor Atf3 in the expression of the socially relevant receptor Or47b. | 10.1038/srep20109 | biorxiv | 184 |
10.1101/001925 | Complex behavioral manipulation drives mismatch between host and parasite diversity | Fabricio Baccaro;João Araújo;Harry Evans;Jorge Souza;Bill Magnusson;David Hughes; | David Hughes | Penn State | 2014-01-21 | 1 | New Results | cc_by_nc | Ecology | https://www.biorxiv.org/content/early/2014/01/21/001925.source.xml | Parasites and hosts are intimately associated such that changes in the diversity of one partner are thought to lead to changes in the other. We investigated this linked diversity hypothesis in a specialized ant-Ophiocordyceps system in three forests across 750 km in Central Amazonia. All species belonging to the fungal genus Ophiocordyceps associated with ants have evolved some degree of behavioral control to increase their own transmission, but the leaf-biting behavior is the most complex form of host manipulation. Such a system requires control of the mandibular muscles and a distinct shift in behavior, from climbing vegetation to walking on leaves to rasping leaf veins in the seconds before death. The need to induce complex behavior may limit host availability and represent a constraint on parasite diversity. The consequence for community structure is that complex behavioral manipulation leads to a mismatch between ant hosts and the diversity of their fungal parasites. | NA | biorxiv | 185 |
10.1101/001941 | Particle size distribution and optimal capture of aqueous macrobial eDNA | Cameron R. Turner;Matthew A. Barnes;Charles C.Y. Xu;Stuart E. Jones;Christopher L. Jerde;David M. Lodge; | Cameron R. Turner | University of Notre Dame | 2014-01-21 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/01/21/001941.source.xml | O_LIDetecting aquatic macroorganisms with environmental DNA (eDNA) is a new survey method with broad applicability. However, the origin, state, and fate of aqueous macrobial eDNA - which collectively determine how well eDNA can serve as a proxy for directly observing organisms and how eDNA should be captured, purified, and assayed - are poorly understood.\nC_LIO_LIThe size of aquatic particles provides clues about their origin, state, and fate. We used sequential filtration size fractionation to measure, for the first time, the particle size distribution (PSD) of macrobial eDNA, specifically Common Carp (hereafter referred to as Carp) eDNA. We compared it to the PSDs of total eDNA (from all organisms) and suspended particle matter (SPM). We quantified Carp mitochondrial eDNA using a custom qPCR assay, total eDNA with fluorometry, and SPM with gravimetric analysis.\nC_LIO_LIIn a lake and a pond, we found Carp eDNA in particles from >180 to <0.2 m, but it was most abundant from 1-10 m. Total eDNA was most abundant below 0.2 m and SPM was most abundant above 100 m. SPM was [≤]0.1% total eDNA, and total eDNA was [≤]0.0004% Carp eDNA. 0.2 m filtration maximized Carp eDNA capture (85%{+/-}6%) while minimizing total (i.e., non-target) eDNA capture (48%{+/-}3%), but filter clogging limited this pore size to a volume <250 mL. To mitigate this limitation we estimated a continuous PSD model for Carp eDNA and derived an equation for calculating isoclines of pore size and water volume that yield equivalent amounts of Carp eDNA.\nC_LIO_LIOur results suggest that aqueous macrobial eDNA predominantly exists inside mitochondria or cells, and that settling plays an important role in its fate. For optimal eDNA capture, we recommend 0.2 m filtration or a combination of larger pore size and water volume that exceeds the 0.2 m isocline. In situ filtration of large volumes could maximize detection probability when surveying large habitats for rare organisms. Our method for eDNA particle size analysis enables future research to compare the PSDs of eDNA from other organisms and environments, and to easily apply them for ecological monitoring.\nC_LI | 10.1111/2041-210X.12206 | biorxiv | 186 |
10.1101/001974 | SINGLE NUCLEOTIDE POLYMORPHISMS SHED LIGHT ON CORRELATIONS BETWEEN ENVIRONMENTAL VARIABLES AND ADAPTIVE GENETIC DIVERGENCE AMONG POPULATIONS IN ONCORHYNCHUS KETA | Xilin Deng;Philippe Henry; | Philippe Henry | University of Northern British Columbia | 2014-01-22 | 1 | Confirmatory Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/01/22/001974.source.xml | Identifying the genetic and ecological basis of adaptation is of immense importance in evolutionary biology. In our study, we applied a panel of 58 biallelic single nucleotide polymorphisms (SNPs) for the economically and culturally important salmonid Oncorhynchus keta. Samples included 4164 individuals from 43 populations ranging from Coastal Western Alaska to southern British Colombia and northern Washington. Signatures of natural selection were detected by identifying seven outlier loci using two independent approaches: one based on outlier detection and another based on environmental correlations. Evidence of divergent selection at two candidate SNP loci, Oke_RFC2-168 and Oke_MARCKS-362, indicates significant environmental correlations, particularly with the number of frost-free days (NFFD). Important associations found between environmental variables and outlier loci indicate that those environmental variables could be the major driving forces of allele frequency divergence at the candidate loci. NFFD, in particular, may play an important adaptive role in shaping genetic variation in O. keta. Correlations between divergent selection and local environmental variables will help shed light on processes of natural selection and molecular adaptation to local environmental conditions. | NA | biorxiv | 187 |
10.1101/001933 | Coalescence 2.0: a multiple branching of recent theoretical developments and their applications | Aurelien Tellier;Christophe Lemaire; | Aurelien Tellier | Technische Universit?t M?nchen | 2014-01-21 | 1 | Confirmatory Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/01/21/001933.source.xml | Population genetics theory has laid the foundations for genomics analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under natural selection and underpinning species adaptation relies on disentangling the respective contribution of random processes (mutation, drift, migration) from that of selection on nucleotide variability. Most theory and statistical tests have been developed using the Kingmans coalescent theory based on the Wright-Fisher population model. However, these theoretical models rely on biological and life-history assumptions which may be violated in many prokaryote, fungal, animal or plant species. Recent theoretical developments of the so called multiple merger coalescent models are reviewed here ({Lambda}-coalescent, beta-coalescent, Bolthausen-Snitzman, {Xi}-coalescent). We explicit how these new models take into account various pervasive ecological and biological characteristics, life history traits or life cycles which were not accounted in previous theories such as 1) the skew in offspring production typical of marine species, 2) fast adapting microparasites (virus, bacteria and fungi) exhibiting large variation in population sizes during epidemics, 3) the peculiar life cycles of fungi and bacteria alternating sexual and asexual cycles, and 4) the high rates of extinction-recolonization in spatially structured populations. We finally discuss the relevance of multiple merger models for the detection of SNPs under selection in these species, for population genomics of very large sample size and advocate to potentially examine the conclusion of previous population genetics studies. | 10.1111/mec.12755 | biorxiv | 188 |
10.1101/002006 | Genome-wide patterns of copy number variation in the diversified chicken genomes using next-generation sequencing | Guoqiang Yi;Lujiang Qu;Jianfeng Liu;Yiyuan Yan;Guiyun Xu;Ning Yang; | Ning Yang | China Agricultural University | 2014-01-23 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/01/23/002006.source.xml | Copy number variation (CNV) is important and widespread in the genome, and is a major cause of disease and phenotypic diversity. Herein, we perform genome-wide CNV analysis in 12 diversified chicken genomes based on whole genome sequencing. A total of 9,025 CNV regions (CNVRs) covering 100.1 Mb and representing 9.6% of the chicken genome are identified, ranging in size from 1.1 to 268.8 kb with an average of 11.1 kb. Sequencing-based predictions are confirmed at high validation rate by two independent approaches, including array comparative genomic hybridization (aCGH) and quantitative PCR (qPCR). The Pearson?s correlation values between sequencing and aCGH results range from 0.395 to 0.740, and qPCR experiments reveal a positive validation rate of 91.71% and a false negative rate of 22.43%. In total, 2,188 predicted CNVRs (24.2%) span 2,182 RefSeq genes (36.8%) associated with specific biological functions. Besides two previously accepted copy number variable genes EDN3 and PRLR, we also find some promising genes with potential in phenotypic variants. FZD6 and LIMS1, two genes related to diseases susceptibility and resistance are covered by CNVRs. Highly duplicated SOCS2 may lead to higher bone mineral density. Entire or partial duplication of some genes like POPDC3 and LBFABP may have great economic importance in poultry breeding. Our results based on extensive genetic diversity provide the first individualized chicken CNV map and genome-wide gene copy number estimates and warrant future CNV association studies for important traits of chickens. | 10.1186/1471-2164-15-962 | biorxiv | 189 |
10.1101/001917 | Modelling and analysis of bacterial tracks suggest an active reorientation mechanism in Rhodobacter sphaeroides | Gabriel Rosser;Ruth E. Baker;Judith P. Armitage;Alexander George Fletcher; | Alexander George Fletcher | University of Oxford | 2014-01-21 | 1 | New Results | cc_by_nc | Microbiology | https://www.biorxiv.org/content/early/2014/01/21/001917.source.xml | Most free-swimming bacteria move in approximately straight lines, interspersed with random reorientation phases. A key open question concerns varying mechanisms by which reorientation occurs. We combine mathematical modelling with analysis of a large tracking dataset to study the poorly-understood reorientation mechanism in the monoflagellate species Rhodobacter sphaeroides. The flagellum on this species rotates counterclockwise to propel the bacterium, periodically ceasing rotation to enable reorientation. When rotation restarts the cell body usually points in a new direction. It has been assumed that the new direction is simply the result of Brownian rotation. We consider three variants of a self-propelled particle model of bacterial motility. The first considers rotational diffusion only, corresponding to a non-chemotactic mutant strain. A further two models also include stochastic reorientations, describing run-and-tumble motility. We derive expressions for key summary statistics and simulate each model using a stochastic computational algorithm. We also discuss the effect of cell geometry on rotational diffusion. Working with a previously published tracking dataset, we compare predictions of the models with data on individual stopping events in R. sphaeroides. This provides strong evidence that this species undergoes some form of active reorientation rather than simple reorientation by Brownian rotation. | 10.1098/rsif.2014.0320 | biorxiv | 192 |
10.1101/000760 | Linking indices for biodiversity monitoring to extinction risk theory | Michael A. McCarthy;Alana L. Moore;Jochen Krauss;John W Morgan;Christopher F. Clements; | Michael A. McCarthy | The University of Melbourne | 2014-02-07 | 2 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/02/07/000760.source.xml | Biodiversity indices often combine data from different species when used in monitoring programs. Heuristic properties can suggest preferred indices, but we lack objective ways to discriminate between indices with similar heuristics. Biodiversity indices can be evaluated by determining how well they reflect management objectives that a monitoring program aims to support. For example, the Convention on Biological Diversity requires reporting about extinction rates, so simple indices that reflect extinction risk would be valuable. Here we develop three biodiversity indices that are based on simple models of population viability that relate extinction risk to abundance. The first index is based on the geometric mean abundance of species. A second uses a more general power mean. A third integrates both the geometric mean abundance and trend. These indices require the same data as previous indices, but they also relate directly to extinction risk. Field data for butterflies and woodland plants, and experimental studies of protozoan communities show that the indices correlate with local extinction rates. Applying the index based on the geometric mean to global data on changes in avian abundance suggests that the average extinction probability of birds has increased approximately 1% from 1970 to 2009. | 10.1111/cobi.12308 | biorxiv | 196 |
10.1101/000455 | A data repository and analysis framework for spontaneous neural activity recordings in developing retina | Stephen Eglen;Michael Weeks;Mark Jessop;Jennifer Simonotto;Tom Jackson;Evelyne Sernagor; | Stephen Eglen | University of Cambridge | 2014-02-18 | 3 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/02/18/000455.source.xml | BackgroundDuring early development, neural circuits fire spontaneously, generating activity episodes with complex spatiotemporal patterns. Recordings of spontaneous activity have been made in many parts of the nervous system over the last 25 years, reporting developmental changes in activity patterns and the effects of various genetic perturbations.\n\nResultsWe present a curated repository of multielectrode array recordings of spontaneous activity in developing mouse and ferret retina. The data have been annotated with minimal metadata and converted into HDF5. This paper describes the structure of the data, along with examples of reproducible research using these data files. We also demonstrate how these data can be analysed in the CARMEN workflow system. This article is written as a literate programming document; all programs and data described here are freely available.\n\nConclusions1. We hope this repository will lead to novel analysis of spontaneous activity recorded in different laboratories. 2. We encourage published data to be added to the repository. 3. This repository serves as an example of how multielectrode array recordings can be stored for long-term reuse. | 10.1186/2047-217X-3-3 | biorxiv | 198 |
10.1101/001701 | An unmet actin requirement explains the mitotic inhibition of clathrin-mediated endocytosis | Satdip Kaur;Andrew B Fielding;Gisela Gassner;Nicholas J Carter;Stephen J Royle; | Stephen J Royle | University of Warwick | 2014-02-18 | 2 | New Results | cc_by | Cell Biology | https://www.biorxiv.org/content/early/2014/02/18/001701.source.xml | Clathrin-mediated endocytosis (CME) is the major internalisation route for many different receptor types in mammalian cells. CME is shut down during early mitosis, but the mechanism of this inhibition is unclear. Here we show that the mitotic shutdown is due to an unmet requirement for actin in CME. In mitotic cells, membrane tension is increased and this invokes a requirement for the actin cytoskeleton to assist the CME machinery to overcome the increased load. However, the actin cytoskeleton is engaged in the formation of a rigid cortex in mitotic cells and is therefore unavailable for deployment. We demonstrate that CME can be \"restarted\" in mitotic cells despite high membrane tension, by allowing actin to engage in endocytosis. Mitotic phosphorylation of endocytic proteins is maintained in mitotic cells with restored CME, indicating that direct phosphorylation of the CME machinery does not account for shutdown. | 10.7554/eLife.00829 | biorxiv | 199 |
10.1101/001735 | Ecological and Evolutionary Oscillations in Host-Parasite Population Dynamics, and The Red Queen | Jomar Fajardo Rabajante; | Jomar Fajardo Rabajante | University of the Philippines | 2014-01-25 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/01/25/001735.source.xml | In a host-parasite system, the constitutive interaction among the species, regulated by the growth rates and functional response, may induce populations to approach equilibrium or sometimes to exhibit simple cycles or peculiar oscillations, such as chaos. A large carrying capacity coupled with appropriate parasitism effectiveness frequently drives long-term apparent oscillatory dynamics in population size. We name these oscillations due to the structure of the constitutive interaction among species as ecological.\n\nOn the other hand, there are also exceptional cases when the evolving quantitative traits of the hosts and parasites induce oscillating population size, which we call as evolutionary. This oscillatory behavior is dependent on the speed of evolutionary adaptation and degree of evolutionary trade-off. A moderate level of negative trade-off is essential for the existence of oscillations. Evolutionary oscillations due to the host-parasite coevolution (known as the Red Queen) can be observed beyond the ecological oscillations, especially when there are more than two competing species involved.\n\nOne Sentence SummaryWe investigate several cases yielding to oscillating host-parasite populations, and we found that the Red Queen hypothesis can explain some of the exceptional cases.\n\nGraphical Abstract:\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC=\"FIGDIR/small/001735_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\[email protected]@3d6e28org.highwire.dtl.DTLVardef@10b2718org.highwire.dtl.DTLVardef@133a78d_HPS_FORMAT_FIGEXP M_FIG C_FIG | NA | biorxiv | 200 |
10.1101/001958 | Joint variant and de novo mutation identification on pedigrees from high-throughput sequencing data | John G Cleary;Ross Braithwaite;Kurt Gaastra;Brian S Hilbush;Stuart Inglis;Sean A Irvine;Alan Jackson;Richard Littin;Sahar Nohzadeh-Malakshah;Minita Shah;Mehul Rathod;David Ware;Len Trigg;Francisco M De La Vega; | Francisco M De La Vega | Real Time Genomics, Inc. | 2014-01-24 | 2 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/24/001958.source.xml | The analysis of whole-genome or exome sequencing data from trios and pedigrees has being successfully applied to the identification of disease-causing mutations. However, most methods used to identify and genotype genetic variants from next-generation sequencing data ignore the relationships between samples, resulting in significant Mendelian errors, false positives and negatives. Here we present a Bayesian network framework that jointly analyses data from all members of a pedigree simultaneously using Mendelian segregation priors, yet providing the ability to detect de novo mutations in offspring, and is scalable to large pedigrees. We evaluated our method by simulations and analysis of WGS data from a 17 individual, 3-generation CEPH pedigree sequenced to 50X average depth. Compared to singleton calling, our family caller produced more high quality variants and eliminated spurious calls as judged by common quality metrics such as Ti/Tv, Het/Hom ratios, and dbSNP/SNP array data concordance. We developed a ground truth dataset to further evaluate our calls by identifying recombination cross-overs in the pedigree and testing variants for consistency with the inferred phasing, and we show that our method significantly outperforms singleton and population variant calling in pedigrees. We identify all previously validated de novo mutations in NA12878, concurrent with a 7X precision improvement. Our results show that our method is scalable to large genomics and human disease studies and allows cost optimization by rational sequencing capacity distribution. | 10.1089/cmb.2014.0029 | biorxiv | 202 |
10.1101/002097 | A Powerful Approach for Identification of Differentially Transcribed mRNA Isoforms | Yuande Tan; | Yuande Tan | Department of Molecular Physiology and Biophysics and Dan L. Duncan Cancer Center, Baylor College of | 2014-01-26 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/26/002097.source.xml | Next generation sequencing is being increasingly used for transcriptome-wide analysis of differential gene expression. The primary goal in profiling expression is to identify genes or RNA isoforms differentially expressed between specific conditions. Yet, the next generation sequence-based count data are essentially different from the microarray data that are continuous type, therefore, the statistical methods developed well over the last decades cannot be applicable. For this reason, a variety of new statistical methods based on count data of transcript reads has been correspondingly developed. But currently the transcriptomic count data coming only from a few replicate libraries have high technical noise and small sample size bias, performances of these new methods are not desirable. We here developed a new statistical method specifically applicable to small sample count data called mBeta t-test for identifying differentially expressed gene or isoforms on the basis of the Beta t-test. The results obtained from simulated and real data showed that the mBeta t-test method significantly outperformed the existing statistical methods in all given scenarios. Findings of our method were validated by qRT-PCR experiments. The mBeta t-test method significantly reduced true false discoveries in differentially expressed genes or isoforms so that it had high work efficiencies in all given scenarios. In addition, the mBeta t-test method showed high stability in performance of statistical analysis and in estimation of FDR. These strongly suggests that our mBeta t-test method would offer us a creditable and reliable result of statistical analysis in practice. | NA | biorxiv | 203 |
10.1101/002048 | Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles | Kyle Beauchamp;Vijay Pande;Rhiju Das; | Rhiju Das | Stanford University | 2014-01-24 | 1 | New Results | cc_no | Biophysics | https://www.biorxiv.org/content/early/2014/01/24/002048.source.xml | Predicting biological structure has remained challenging for systems such as disordered proteins that take on myriad conformations. Hybrid simulation/experiment strategies have been undermined by difficulties in evaluating errors from computa- tional model inaccuracies and data uncertainties. Building on recent proposals from maximum entropy theory and nonequilibrium thermodynamics, we address these issues through a Bayesian Energy Landscape Tilting (BELT) scheme for computing Bayesian \"hyperensembles\" over conformational ensembles. BELT uses Markov chain Monte Carlo to directly sample maximum-entropy conformational ensembles consistent with a set of input experimental observables. To test this framework, we apply BELT to model trialanine, starting from disagreeing simulations with the force fields ff96, ff99, ff99sbnmr-ildn, CHARMM27, and OPLS-AA. BELT incorporation of limited chemical shift and 3J measurements gives convergent values of the peptides , {beta}, and PPII conformational populations in all cases. As a test of predictive power, all five BELT hyperensembles recover set-aside measurements not used in the fitting and report accu- rate errors, even when starting from highly inaccurate simulations. BELTs principled fxramework thus enables practical predictions for complex biomolecular systems from discordant simulations and sparse data. | 10.1016/j.bpj.2014.02.009 | biorxiv | 204 |
10.1101/002063 | Holsteins Favor Heifers, Not Bulls: Biased Milk Production Programmed during Pregnancy as a Function of Fetal Sex | Katie Hinde;Abigail J Carpenter;John C Clay;Barry J Bradford; | Katie Hinde | Harvard University | 2014-01-24 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/01/24/002063.source.xml | Mammalian females pay high energetic costs for reproduction, the greatest of which is imposed by lactation. The synthesis of milk requires, in part, the mobilization of bodily reserves to nourish developing young. Numerous hypotheses have been advanced to predict how mothers will differentially invest in sons and daughters, however few studies have addressed sex-biased milk synthesis. Here we leverage the dairy cow model to investigate such phenomena. Using 2.39 million lactation records from 1.49 million dairy cows, we demonstrate that the sex of the fetus influences the capacity of the mammary gland to synthesize milk during lactation. Cows favor daughters, producing significantly more milk for daughters than for sons across lactation. Using a sub-sample of this dataset (N = 113,750 subjects) we further demonstrate that the effects of fetal sex interact dynamically across parities, whereby the sex of the fetus being gestated can enhance or diminish the production of milk during an established lactation. Moreover the sex of the fetus gestated on the first parity has persistent consequences for milk synthesis on the subsequent parity. Specifically, gestation of a daughter on the first parity increases milk production by [~]445 kg over the first two lactations. Our results identify a dramatic and sustained programming of mammary function by offspring in utero. Nutritional and endocrine conditions in utero are known to have pronounced and long-term effects on progeny, but the ways in which the progeny has sustained physiological effects on the dam have received little attention to date. | 10.1371/journal.pone.0086169 | biorxiv | 205 |
10.1101/002071 | A microRNA profile in Fmr1 knockout mice reveals microRNA expression alterations with possible roles in fragile X syndrome | Ting Liu;Rui-Ping Wan;Ling-Jia Tang;Shu-Jing Liu;Hai-Jun Li;Qi-Hua Zhao;Wei-Ping Liao;Xiao-Fang Sun;Yong-Hong Yi;Yue-Sheng Long; | Yue-Sheng Long | The Second Affiliated Hospital of Guangzhou Medical University | 2014-01-26 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2014/01/26/002071.source.xml | Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is involved in brain functions by interacting with mRNAs and microRNAs (miRNAs) that selectively control gene expression at translational level. However, little is known about the role of FMRP in regulating miRNA expression. Here, we found a development-dependant dynamic expression of Fmr1 mRNA (encoding FMRP) in mouse hippocampus with a small peak at postnatal day 7 (P7). MiRNA microarray analysis showed that the levels of 38 miRNAs showed a significant increase with about 15~250 folds and the levels of 26 miRNAs showed a significant decrease with only about 2~4 folds in the hippocampus of P7 Fmr1 KO mice. Q-PCR assay showed that 9 of the most increased miRNAs (>100 folds in microarrays) were increased about 40~70 folds and their pre-miRNAs were increased about 5~10 folds, but no significant difference in their pri-miRNA levels was observed, suggesting a role of FMRP in regulating miRNA processing from pri-miRNA to pre-miRNA. We further demonstrated that a set of protein-coding mRNAs, potentially targeted by the 9 miRNAs were down-regulated in the hippocampus of Fmr1 KO mice. Finally, luciferase assays demonstrated that miR-34b, miR-340, miR-148a could down-regulate the reporter gene expression by interacting with the Met 3' UTR. Taken together these findings suggest that the miRNA expression alterations resulted from the absence of FMRP might contribute to molecular pathology of FXS. | 10.1007/s12035-014-8770-1 | biorxiv | 206 |
10.1101/002139 | VgeneRepertoire.org identifies and stores variable genes of immunoglobulins and T-cell receptors from the genomes of jawed vertebrates | David N Olivieri;Francisco Gambón-Deza; | David N Olivieri | Universidad de Vigo, School of Computer Science | 2014-01-27 | 1 | New Results | cc_no | Immunology | https://www.biorxiv.org/content/early/2014/01/27/002139.source.xml | The VgeneRepertoire.org platform (http://vgenerepertoire.org) is a new public database repository for variable (V) gene sequences that encode immunoglobulin and T-cell receptor molecules. It identifies the nucleic and amino acid sequences of more than 20,000 genes, providing their exon location in either the contig, scaffold, or chromosome region, as well as locus information for more than 100 jawed vertebrate taxa whose genomes have been sequenced. This web repository provides support to immunologists interested in these molecules and aids in comparative phylogenetic studies. | NA | biorxiv | 207 |
10.1101/002147 | The determinants of alpine butterfly richness and composition vary according to the ecological traits of species | Vincent Sonnay;Loïc Pellissier;Jean-Nicolas Pradervand;Luigi Maiorano;Anne Dubuis;Mary S. Wisz;Antoine Guisan; | Lo?c Pellissier | University of Fribourg | 2014-01-27 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/01/27/002147.source.xml | Predicting spatial patterns of species diversity and composition using suitable environmental predictors is an essential element in conservation planning. Although species have distinct relationships to environmental conditions, some similarities may exist among species that share functional characteristics or traits. We investigated the relationship between species richness, composition and abiotic and biotic environment in different groups of butterflies that share ecological characteristics. We inventoried butterfly species richness in 192 sites and classified all inventoried species in three traits categories: the caterpillars diet breadth, the habitat requirements and the dispersal ability of the adults. We studied how environment, including influence butterfly species richness and composition within each trait category. Across four modelling approaches, the relative influence of environmental variables on butterfly species richness differed for specialists and generalists. Climatic variables were the main determinants of butterfly species richness and composition for generalists, whereas habitat diversity, and plant richness were also important for specialists. Prediction accuracy was lower for specialists than for generalists. Although climate variables represent the strongest drivers affecting butterfly species richness and composition for generalists, plant richness and habitat diversity are at least as important for specialist butterfly species. As specialist butterflies are among those species particularly threatened by global changes, devising accurate predictors to model specialist species richness is extremely important. However, our results indicate that this task will be challenging because more complex predictors are required. | NA | biorxiv | 208 |
10.1101/002204 | Genome-wide DNA methylome analysis reveals novel epigenetically dysregulated non-coding RNAs in human breast cancer | Yongsheng Li;Yunpeng Zhang;Shengli Li;Jianping Lu;Juan Chen;Zheng Zhao;Jing Bai;Juan Xu;Xia Li; | Xia Li | Harbin Medical University | 2014-01-28 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/28/002204.source.xml | The development of human breast cancer is driven by changes in the genetic and epigenetic landscape of the cell. Despite growing appreciation of the importance of epigenetics in breast cancers, our knowledge of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancers remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers via a sequencing-based comparative methylome analysis, mainly focusing on two most popular ncRNA biotypes, long non-coding RNAs (lncRNAs) and miRNAs. Besides global hypomethylation and extensive CpG islands (CGIs) hypermethylation, we observed widely aberrant methylation in the promoters of ncRNAs, which was higher than that of protein-coding genes. Specifically, intergenic ncRNAs were observed to contribute a large slice of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of ncRNA promoter aberrant methylation in the context of genomic CGIs, where aberrant methylation occurred not only on the CGIs, but also flanking regions and CGI sparse promoters. Integration with transcriptional datasets, we found that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that were able to discriminate between disease phenotypes (AUCs>0.90). Finally, the potential functions for aberrantly methylated ncRNAs were predicted based on similar patterns, adjacency and/or target genes, highlighting that ncRNAs and coding genes coordinately mediated pathways dysregulation in the development and progression of breast cancers. This study presents the aberrant methylation patterns of ncRNAs, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancers.\n\n[Supplemental material is available online at www.genome.org.] | 10.1038/srep08790 | biorxiv | 209 |
10.1101/002196 | Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling | Nicola Fameli;Oluseye A. Ogunbayo;Cornelis van Breemen;A. Mark Evans; | Nicola Fameli | University of British Columbia | 2014-01-28 | 1 | New Results | cc_by_nc_nd | Cell Biology | https://www.biorxiv.org/content/early/2014/01/28/002196.source.xml | Herein we demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptor-mediated cellular Ca2+ waves. In pulmonary artery smooth muscle cells (PASMCs) it has been proposed that nicotinic acid adenine dinucleotide phosphate (NAADP) triggers increases in cytoplasmic Ca2+ via L-SR junctions, in a manner that requires initial Ca2+ release from lysosomes and subsequent Ca2+-induced Ca2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be < 400 nm and thus beyond the resolution of light microscopy, which has restricted detailed investigations of the junctional coupling process. The present study utilizes standard and tomographic transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. We show that L-SR nanojunctions are prominent features within these cells and estimate that the junctional membrane separation and extension are about 15 nm and 300 nm, respectively. Furthermore, we develop a quantitative model of the L-SR junction using these measurements, prior kinetic and specific Ca2+ signal information as input data. Simulations of NAADP-dependent junctional Ca2+ transients demonstrate that the magnitude of these signals can breach the threshold for CICR via RyR3. By correlation analysis of live cell Ca2+ signals and simulated Ca2+ transients within L-SR junctions, we estimate that \"trigger zones\" with a 60-100 junctions are required to confer a signal of similar magnitude. This is compatible with the 130 lysosomes/cell estimated from our ultrastructural observations. Most importantly, our model shows that increasing the L-SR junctional width above 50 nm lowers the magnitude of junctional [Ca2+] such that there is a failure to breach the threshold for CICR via RyR3. L-SR junctions are therefore a pre-requisite for efficient Ca2+ signal coupling and may contribute to cellular function in health and disease. | 10.12688/f1000research.3986 | biorxiv | 210 |
10.1101/002170 | Transcriptome pyrosequencing of abnormal phenotypes in Trypanosoma cruzi epimastigotes after ectopic expression of a small zinc finger protein | Gaston Westergaard;Marc Laverriere;Santiago Revale;Marina Reinert;Javier De Gaudenzi;Adriana Jager;Martin P Vazquez; | Martin P Vazquez | INDEAR | 2014-01-28 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/01/28/002170.source.xml | The TcZFPs are a family of small zinc finger proteins harboring WW domains or Proline rich motifs. In Trypanosoma brucei, ZFPs are involved during stage specific differentiation. TcZFPs interact with each other using the WW domain (ZFP2 and ZFP3) and the proline rich motif (ZFP1). The tcZFP1b member is exclusive to Trypanosoma cruzi and it is only expressed in trypomastigote stage. We used a tetracycline inducible vector to express ectopically tcZFP1b in the epimastigote stage. Upon induction of tcZFP1b, the parasites stopped dividing completely after five days. Visual inspection showed abnormal distorted-morphology (monster) cells with multiple flagella and increased DNA contents. We were interested in investigate global transcription changes occurred during the generation of this abnormal phenotype. Thus, we performed RNA-seq transcriptome profiling with a 454 pyrosequencer to analyze the global changes after ectopic expression of tcZFP1b. The total mRNAs sequenced from induced and non-induced control epimastigotes showed, after filtering the data, a set of 70 genes having equal or more than 3X fold change upregulation, while 35 genes showed equal or more than 3X fold downregulation. Interestingly, several trans-sialidase-like genes and pseudogenes were upregulated along with several genes in the categories of amino acid catabolism and carbohydrate metabolism. On the other hand, hypothetical proteins, fatty acid biosynthesis and mitochondrial functions dominated the group of downregulated genes. Our data showed that several mRNAs sharing related functions and pathways changed their levels in a concerted pattern resembling post-transcriptional regulons. We also found two different motifs in the 3'UTRs of the majority of mRNAs, one for upregulated and other for downregulated genes | NA | biorxiv | 211 |
10.1101/002261 | Impact of RNA degradation on measurements of gene expression | Irene Gallego Romero;Athma A. Pai;Jenny Tung;Yoav Gilad; | Yoav Gilad | University of Chicago | 2014-01-30 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/01/30/002261.source.xml | The use of low quality RNA samples in whole-genome gene expression profiling remains controversial. It is unclear if transcript degradation in low quality RNA samples occurs uniformly, in which case the effects of degradation can be normalized, or whether different transcripts are degraded at different rates, potentially biasing measurements of expression levels. This concern has rendered the use of low quality RNA samples in whole-genome expression profiling problematic. Yet, low quality samples are at times the sole means of addressing specific questions - e.g., samples collected in the course of fieldwork. We sought to quantify the impact of variation in RNA quality on estimates of gene expression levels based on RNA-seq data. To do so, we collected expression data from tissue samples that were allowed to decay for varying amounts of time prior to RNA extraction. The RNA samples we collected spanned the entire range of RNA Integrity Number (RIN) values (a quality metric commonly used to assess RNA quality). We observed widespread effects of RNA quality on measurements of gene expression levels, as well as a slight but significant loss of library complexity in more degraded samples. While standard normalizations failed to account for the effects of degradation, we found that a simple linear model that controls for the effects of RIN can correct for the majority of these effects. We conclude that in instances where RIN and the effect of interest are not associated, this approach can help recover biologically meaningful signals in data from degraded RNA samples. | NA | biorxiv | 218 |
10.1101/002329 | Improving Protein Docking with Constraint Programming and Coevolution Data | Ludwig Krippahl;Fábio Madeira; | Fábio Madeira | Centria-DI, Universidade Nova de Lisboa | 2014-02-03 | 1 | Confirmatory Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/03/002329.source.xml | BackgroundConstraint programming (CP) is usually seen as a rigid approach, focusing on crisp, precise, distinctions between what is allowed as a solution and what is not. At first sight, this makes it seem inadequate for bioinformatics applications that rely mostly on statistical parameters and optimization. The prediction of protein interactions, or protein docking, is one such application. And this apparent problem with CP is particularly evident when constraints are provided by noisy data, as it is the case when using the statistical analysis of Multiple Sequence Alignments (MSA) to extract coevolution information. The goal of this paper is to show that this first impression is misleading and that CP is a useful technique for improving protein docking even with data as vague and noisy as the coevolution indicators that can be inferred from MSA.\n\nResultsHere we focus on the study of two protein complexes. In one case we used a simplified estimator of interaction propensity to infer a set of five candidate residues for the interface and used that set to constrain the docking models. Even with this simplified approach and considering only the interface of one of the partners, there is a visible focusing of the models around the correct configuration. Considering a set of 400 models with the best geometric contacts, this constraint increases the number of models close to the target (RMSD {inverted exclamation}5[A]) from 2 to 5 and decreases the RMSD of all retained models from 26[A] to 17.5[A]. For the other example we used a more standard estimate of coevolving residues, from the Co-Evolution Analysis using Protein Sequences (CAPS) software. Using a group of three residues identified from the sequence alignment as potentially co-evolving to constrain the search, the number of complexes similar to the target among the 50 highest scoring docking models increased from 3 in the unconstrained docking to 30 in the constrained docking.\n\nConclusionsAlthough only a proof-of-concept application, our results show that, with suitably designed constraints, CP allows us to integrate coevolution data, which can be inferred from databases of protein sequences, even though the data is noisy and often \"fuzzy\", with no well-defined discontinuities. This also shows, more generally, that CP in bioinformatics needs not be limited to the more crisp cases of finite domains and explicit rules but can also be applied to a broader range of problems that depend on statistical measurements and continuous data. | NA | biorxiv | 219 |
10.1101/002121 | FALDO: A semantic standard for describing the location of nucleotide and protein feature annotation. | Jerven Bolleman;Christopher J Mungall;Francesco Strozzi;Joachim Baran;Michel Dumontier;Raoul J P Bonnal;Robert Buels;Robert Hoehndorf;Takatomo Fujisawa;Toshiaki Katayama;Peter J A Cock; | Jerven Bolleman | SIB Swiss Institute of Bioinformatics | 2014-02-02 | 3 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/02/002121.source.xml | Background Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples.\n\nDescription We have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned \"omics\" areas. Using the same data format to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations.\n\nConclusions Our ontology allows users to uniformly describe - and potentially merge - sequence annotations from multiple sources. Data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores. | 10.1186/s13326-016-0067-z | biorxiv | 223 |
10.1101/002303 | Stress, heritability, tissue type and human methylome variation in mother-newborn dyads. | David A. Hughes;Nicole C. Rodney;Connie J. Mulligan; | David A. Hughes | Institute of Evolutionary Biology (CSIC - Universitat Pompeu Fabra) | 2014-01-31 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/01/31/002303.source.xml | DNA methylation variation has been implicated as a factor that influences inter-individual and inter-tissue phenotypic variation in numerous organisms and under various conditions. Here, using a unique collection of three tissues, derived from 24 mother-newborn dyads from war-torn Democratic Republic of Congo, we estimate how stress, heritability, tissue type and genomic/regulatory context influence genome-wide DNA methylation. We also evaluate if stress-associated variation may mediate an observed phenotype - newborn birthweight. On average, a minimal influence of stress and heritability are observed, while in contrast extensive among tissues and context dependency is evident. However, a notable overlap in heritable and stress-associated variation is observed and that variation is commonly correlated with birthweight variation. Finally, we observe that variation outside of promoter regions, particularly in enhancers, is far more dynamic across tissues and across conditions than in promoters, suggesting that variation outside of promoters may play a larger role in expression variation than variation found within promoter regions. | NA | biorxiv | 225 |
10.1101/002279 | Diverse and widespread contamination evident in the unmapped depths of high throughput sequencing data | Richard W Lusk; | Richard W Lusk | University of Michigan | 2014-02-06 | 2 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/02/06/002279.source.xml | BackgroundTrace quantities of contaminating DNA are widespread in the laboratory environment, but their presence has received little attention in the context of high throughput sequencing. This issue is highlighted by recent works that have rested controversial claims upon sequencing data that appear to support the presence of unexpected exogenous species.\n\nResultsI used reads that preferentially aligned to alternate genomes to infer the distribution of potential contaminant species in a set of independent sequencing experiments. I confirmed that dilute samples are more exposed to contaminating DNA, and, focusing on four single-cell sequencing experiments, found that these contaminants appear to originate from a wide diversity of clades. Although negative control libraries prepared from blank samples recovered the highest-frequency contaminants, low-frequency contaminants, which appeared to make heterogeneous contributions to samples prepared in parallel within a single experiment, were not well controlled for. I used these results to show that, despite heavy replication and plausible controls, contamination can explain all of the observations used to support a recent claim that complete genes pass from food to human blood.\n\nConclusionsContamination must be considered a potential source of signals of exogenous species in sequencing data, even if these signals are replicated in independent experiments, vary across conditions, or indicate a species which seems a priori unlikely to contaminate. Negative control libraries processed in parallel are essential to control for contaminant DNAs, but their limited ability to recover low-frequency contaminants must be recognized. | 10.1371/journal.pone.0110808 | biorxiv | 227 |
10.1101/002311 | The organization and dynamics of corticostriatal pathways link the medial orbitofrontal cortex to future decisions | Timothy Verstynen; | Timothy Verstynen | CMU | 2014-02-03 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2014/02/03/002311.source.xml | Accurately making a decision in the face of incongruent options increases the efficiency of making similar congruency decisions in the future. This adaptive process is modulated by reward, suggesting that ventral corticostriatal circuits may contribute to the process of conflict adaptation. To evaluate this possibility, a group of healthy adults (N = 30) were tested using functional MRI (fMRI) while they performed a color-word Stroop task. In a conflict-related region of the medial orbitofrontal cortex (mOFC), stronger BOLD responses predicted faster response times (RTs) on the next trial. More importantly, the degree of behavioral conflict adaptation on RTs was correlated with the magnitude of mOFC-RT associations on the previous trial, but only after accounting for network-level interactions with prefrontal and striatal regions. This suggests that conflict adaptation may rely on interactions between distributed corticostriatal circuits. The convergence of white matter projections fro ... | NA | biorxiv | 228 |
10.1101/002352 | SNP-guided identification of monoallelic DNA-methylation events from enrichment-based sequencing data | Sandra Steyaert;Wim Van Criekinge;Ayla De Paepe;Simon Denil;Klaas Mensaert;Katrien Vandepitte;Wim Vanden Berghe;Geert Trooskens;Tim De Meyer; | Sandra Steyaert | University of Ghent | 2014-02-04 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/04/002352.source.xml | Monoallelic gene expression is typically initiated early in the development of an organism. Dysregulation of monoallelic gene expression has already been linked to several non-Mendelian inherited genetic disorders. In humans, DNA-methylation is deemed to be an important regulator of monoallelic gene expression, but only few examples are known. One important reason is that current, cost-affordable truly genome-wide methods to assess DNA-methylation are based on sequencing post enrichment. Here, we present a new methodology that combines methylomic data from MethylCap-seq with associated SNP profiles to identify monoallelically methylated loci. Using the Hardy-Weinberg theorem for each SNP locus, it could be established whether the observed frequency of samples featured by biallelic methylation was lower than randomly expected. Applied on 334 MethylCap-seq samples of very diverse origin, this resulted in the identification of 80 genomic regions featured by monoallelic DNA-methylation. Of these 80 loci, 49 are located in genic regions of which 25 have already been linked to imprinting. Further analysis revealed statistically significant enrichment of these loci in promoter regions, further establishing the relevance and usefulness of the method. Additional validation of the found loci was done using 14 whole-genome bisulfite sequencing data sets. Importantly, the developed approach can be easily applied to other enrichment-based sequencing technologies, such as the ChIP-seq-based identification of monoallelic histone modifications. | 10.1093/nar/gku847 | biorxiv | 231 |
10.1101/002360 | A phase diagram for gene selection and disease classification | Hong-Dong Li;Qing-Song Xu;Yi-Zeng Liang; | Hong-Dong Li | Central South University | 2014-02-05 | 2 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/05/002360.source.xml | Identifying a small subset of discriminate genes is important for predicting clinical outcomes and facilitating disease diagnosis. Based on the model population analysis framework, we present a method, called PHADIA, which is able to output a phase diagram displaying the predictive ability of each variable, which provides an intuitive way for selecting informative variables. Using two publicly available microarray datasets, its demonstrated that our method can selects a few informative genes and achieves significantly better or comparable classification accuracy compared to the reported results in the literature. The source codes are freely available at: www.libpls.net. | NA | biorxiv | 233 |
10.1101/002378 | Evolutionary dynamics of shared niche construction | Philip Gerlee;Alexander RA Anderson; | Philip Gerlee | Moffitt Cancer Center | 2014-02-05 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/05/002378.source.xml | Many species engage in niche construction that ultimately leads to an increase in the carrying capacity of the population. We have investigated how the specificity of this behaviour affects evolutionary dynamics using a set of coupled logistic equations, where the carrying capacity of each genotype consists of two components: an intrinsic part and a contribution from all genotypes present in the population. The relative contribution of the two components is controlled by a specificity parameter{gamma} , and we show that the ability of a mutant to invade a resident population depends strongly on this parameter. When the carrying capacity is intrinsic, selection is almost exclusively for mutants with higher carrying capacity, while a shared carrying capacity yields selection purely on growth rate. This result has important implications for our understanding of niche construction, in particular the evolutionary dynamics of tumor growth. | NA | biorxiv | 234 |
10.1101/002386 | Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes, and glucose homeostasis | Bethann S Hromatka;Joyce Y Tung;Amy K Kiefer;Chuong B Do;David A Hinds;Nicholas Eriksson; | Nicholas Eriksson | 23andMe | 2014-02-04 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/02/04/002386.source.xml | Roughly one in three individuals is highly susceptible to motion sickness and yet the underlying causes of this condition are not well understood. Despite high heritability, no associated genetic factors have been discovered to date. Here, we conducted the first genome-wide association study on motion sickness in 80,494 individuals from the 23andMe database who were surveyed about car sickness. Thirty-five single-nucleotide polymorphisms (SNPs) were associated with motion sickness at a genome-wide-significant level (p< 5e-8). Many of these SNPs are near genes involved in balance, and eye, ear, and cranial development (e.g., PVRL3, TSHZ1, MUTED, HOXB3, HOXD3). Other SNPs may affect motion sickness through nearby genes with roles in the nervous system, glucose homeostasis, or hypoxia. We show that several of these SNPs display sex-specific effects, with as much as three times stronger effects in women. We searched for comorbid phenotypes with motion sickness, confirming associations with known comorbidities including migraines, postoperative nausea and vomiting (PONV), vertigo, and morning sickness, and observing new associations with altitude sickness and many gastrointestinal conditions. We also show that two of these related phenotypes (PONV and migraines) share underlying genetic factors with motion sickness. These results point to the importance of the nervous system in motion sickness and suggest a role for glucose levels in motion-induced nausea and vomiting, a finding that may provide insight into other nausea-related phenotypes such as PONV. They also highlight personal characteristics (e.g., being a poor sleeper) that correlate with motion sickness, findings that could help identify risk factors or treatments. | 10.1093/hmg/ddv028 | biorxiv | 235 |
10.1101/002444 | Methods to study toxic transgenes in C. elegans: an analysis of protease-dead separase in the C. elegans embryo | Diana M Mitchell;Lindsey R Uehlein;Joshua Bembenek; | Joshua Bembenek | UT Knoxville | 2014-02-06 | 1 | New Results | cc_no | Cell Biology | https://www.biorxiv.org/content/early/2014/02/06/002444.source.xml | We investigated whether the protease activity of separase, which is required for chromosome segregation, is also required for its other roles during anaphase in C. elegans given that non-proteolytic functions of separase have been identified in other organisms. We find that expression of protease-dead separase is dominant-negative in C. elegans embryos. The C. elegans embryo is an ideal system to study developmental processes in a genetically tractable system. However, a major limitation is the lack of an inducible gene expression system for the embryo. The most common method for embryonic expression involves generation of integrated transgenes under the control of the pie-1 promoter, using unc-119 as a selection marker. However expression of dominant-negative proteins kills the strain preventing analysis of mutants. We have developed two methods that allow for the propagation of lines carrying dominant-negative transgenes in order to study protease-dead separase in embryos. The first involves feeding gfp RNAi to eliminate transgene expression and allows propagation of transgenic lines indefinitely. Animals removed from gfp RNAi for several generations recover transgene expression and associated phenotypes. The second involves propagation of the transgene with the female specific pie-1 promoter via the male germline and analysis of phenotypes in embryos from F1 heterozygous hermaphrodites that express the protein. Using these methods, we show that protease-dead separase causes chromosome nondisjunction and cytokinesis failures. These methods are immediately applicable for studies of dominant-negative transgenes and should open new lines of investigation in the C. elegans embryo. | 10.1371/journal.pone.0108188 | biorxiv | 236 |
10.1101/002436 | Biochemical ‘Cambrian’ explosion-implosions: the generation and pruning of genetic codes | Rodrick Wallace; | Rodrick Wallace | New York State Psychiatric Institute | 2014-02-06 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/06/002436.source.xml | Tlusty's topological analysis of the genetic code suggests ecosystem changes in available metabolic free energy that predated the aerobic transition enabled a punctuated sequence of increasingly complex genetic codes and protein translators. These coevolved via a `Cambrian explosion' until, very early on, the ancestor of the present narrow spectrum of protein machineries became evolutionarily locked in at a modest level of fitness reflecting a modest embedding metabolic free energy ecology. Similar biochemical `Cambrian singularities' must have occurred at different scales and levels of organization on Earth, with competition or chance-selected outcomes frozen at a far earlier period than the physical bauplan Cambrian explosion. Other examples might include explosive variations in mechanisms of photosynthesis and subsequent oxygen metabolisms. Intermediate between Cambrian bauplan and genetic code, variants of both remain today, even after evolutionary pruning, often protected in specialized ecological niches. This suggests that, under less energetic astrobiological ecologies, a spectrum of less complicated reproductive codes may also survive in specialized niches. | NA | biorxiv | 237 |
10.1101/002410 | Broadly tuned and respiration-independent inhibition in the olfactory bulb of awake mice | Brittany N Cazakoff;Billy Y B Lau;Kerensa L Crump;Heike Demmer;Stephen David Shea; | Stephen David Shea | Cold Spring Harbor Laboratory | 2014-02-06 | 1 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/02/06/002410.source.xml | Olfactory representations are shaped by both brain state and respiration; however, the interaction and circuit substrates of these influences are poorly understood. Granule cells (GCs) in the main olfactory bulb (MOB) are presumed to sculpt activity that reaches the olfactory cortex via inhibition of mitral/tufted cells (MTs). GCs may potentially sparsen ensemble activity by facilitating lateral inhibition among MTs, and/or they may enforce temporally-precise activity locked to breathing. Yet, the selectivity and temporal structure of GC activity during wakefulness are unknown. We recorded GCs in the MOB of anesthetized and awake mice and reveal pronounced state-dependent features of odor coding and temporal patterning. Under anesthesia, GCs exhibit sparse activity and are strongly and synchronously coupled to the respiratory cycle. Upon waking, GCs desynchronize, broaden their odor responses, and typically fire without regard for the respiratory rhythm. Thus during wakefulness, GCs exhibit stronger odor responses with less temporal structure. Based on these observations, we propose that during wakefulness GCs likely predominantly shape MT odor responses through broadened lateral interactions rather than respiratory synchronization. | 10.1038/nn.3669 | biorxiv | 238 |
10.1101/002469 | Automated ensemble assembly and validation of microbial genomes | Sergey Koren;Todd J Treangen;Christopher M Hill;Mihai Pop;Adam M Phillippy; | Sergey Koren | National Biodefense Analysis and Countermeasures Center | 2014-02-07 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/07/002469.source.xml | BackgroundThe continued democratization of DNA sequencing has sparked a new wave of development of genome assembly and assembly validation methods. As individual research labs, rather than centralized centers, begin to sequence the majority of new genomes, it is important to establish best practices for genome assembly. However, recent evaluations such as GAGE and the Assemblathon have concluded that there is no single best approach to genome assembly. Instead, it is preferable to generate multiple assemblies and validate them to determine which is most useful for the desired analysis; this is a labor-intensive process that is often impossible or unfeasible.\n\nResultsTo encourage best practices supported by the community, we present iMetAMOS, an automated ensemble assembly pipeline; iMetAMOS encapsulates the process of running, validating, and selecting a single assembly from multiple assemblies. iMetAMOS packages several leading open-source tools into a single binary that automates parameter selection and execution of multiple assemblers, scores the resulting assemblies based on multiple validation metrics, and annotates the assemblies for genes and contaminants. We demonstrate the utility of the ensemble process on 225 previously unassembled Mycobacterium tuberculosis genomes as well as a Rhodobacter sphaeroides benchmark dataset. On these real data, iMetAMOS reliably produces validated assemblies and identifies potential contamination without user intervention. In addition, intelligent parameter selection produces assemblies of R. sphaeroides that exceed the quality of those from the GAGE-B evaluation, affecting the relative ranking of some assemblers.\n\nConclusionsEnsemble assembly with iMetAMOS provides users with multiple, validated assemblies for each genome. Although computationally limited to small or mid-sized genomes, this approach is the most effective and reproducible means for generating high-quality assemblies and enables users to select an assembly best tailored to their specific needs. | 10.1186/1471-2105-15-126 | biorxiv | 239 |
10.1101/002501 | Within the fortress: A specialized parasite of ants is not evicted | Emilia S. Gracia;Charissa de Bekker;Jim Russell;Kezia Manlove;Ephraim Hanks;David P. Hughes; | Emilia S. Gracia | Pennsylvania State University | 2014-02-12 | 2 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/02/12/002501.source.xml | Every level of biological organization from cells to societies require that composing units come together to form parts of a bigger unit (1). Our knowledge of how behavioral manipulating parasites change social interactions between social hosts is limited. Here we use an endoparasite to observe changes in social interactions between infected and healthy ants, using trophallaxis (liquid food exchange) and spatial data as proxies for food sharing and social segregation. We found no change in trophallaxis (p-value = 0.5156). By using K-function and nearest neighbor analyses we did see a significant difference in spatial segregation on day 3 (less than 8 millimeters; p-value < 0.05). These results suggest healthy individuals are unable to detect the parasite within the host. | NA | biorxiv | 241 |
10.1101/002527 | Investigating speciation in face of polyploidization: what can we learn from approximate Bayesian computation approach? | Camille Roux;John Pannell; | Camille Roux | University of Lausanne | 2014-02-09 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/09/002527.source.xml | Despite its importance in the diversification of many eucaryote clades, particularly plants, detailed genomic analysis of polyploid species is still in its infancy, with published analysis of only a handful of model species to date. Fundamental questions concerning the origin of polyploid lineages (e.g., auto- vs. allopolyploidy) and the extent to which polyploid genomes display disomic vs. polysomic vs. heterosomic inheritance are poorly resolved for most polyploids, not least because they have hitherto required detailed karyotypic analysis or the analysis of allele segregation at multiple loci in pedigrees or artificial crosses, which are often not practical for non-model species. However, the increasing availability of sequence data for non-model species now presents an opportunity to apply established approaches for the evolutionary analysis of genomic data to polyploid species complexes. Here, we ask whether approximate Bayesian computation (ABC), applied to sequence data produced by next-generation sequencing technologies from polyploid taxa, allows correct inference of the evolutionary and demographic history of polyploid lineages and their close relatives. We use simulations to investigate how the number of sampled individuals, the number of surveyed loci and their length affect the accuracy and precision of evolutionary and demographic inferences by ABC, including the mode of polyploidisation, mode of inheritance of polyploid taxa, the relative timing of genome duplication and speciation, and effective populations sizes of contributing lineages. We also apply the ABC framework we develop to sequence data from diploid and polyploidy species of the plant genus Capsella, for which we infer an allopolyploid origin for tetra C. bursa-pastoris {approx} 90,000 years ago. In general, our results indicate that ABC is a promising and powerful method for uncovering the origin and subsequent evolution of polyploid species. | NA | biorxiv | 242 |
10.1101/002337 | Metabolic composition of anode community predicts electrical power in microbial fuel cells | Andre Gruning;Nelli J Beecroft;Claudio Avignone-Rossa; | Andre Gruning | University of Surrey | 2014-02-07 | 1 | New Results | cc_by_nc_nd | Microbiology | https://www.biorxiv.org/content/early/2014/02/07/002337.source.xml | Microbial Fuel Cells (MFCs) are a promising technology for organic waste treatment and sustainable bioelectricity production. Inoculated with natural communities, they present a complex microbial ecosystem with syntrophic interactions between microbes with different metabolic capabilities. From this point of view, they are similar to anaerobic digesters, however with methanogenesis replaced by anaerobic respiration with the anode as terminal electron acceptor. Bio-electrochemically they are similar to classical fuel cells where however the electrogenic redox reaction is part of the microbial metabolism rather than mediated by an inorganic catalyst.\n\nIn this paper, we analyse how electric power production in MFCs depends on the composition of the anodic biofilm in terms of metabolic capabilities of identified sets of species. MFCs were started with a natural inoculum and continuously fed with sucrose, a fermentable carbohydrate. The composition of the community, power and other environmental data were sampled over a period of a few weeks during the maturation of the anodic biofilm, and the community composition was determined down to the species level including relevant metabolic capabilities.\n\nOur results support the hypothesis that an MFCs with natural inoculum and fermentable feedstock is essentially a two stage system with fermentation followed by anode-respiration. Our results also show that under identical starting and operating conditions, MFCs with comparable power output can develop different anodic communities with no particular species dominant across all replicas. It is only important for good power production that all cells contain a sufficient fraction of low-potential anaerobic respirators, that is respirators that can use terminal electron acceptors with a low redox potential. We conclude with a number of hypotheses and recommendations for the operation of MFCs to ensure good electric yield. | 10.1007/s00248-014-0518-y | biorxiv | 245 |
10.1101/002576 | Sashimi plots: Quantitative visualization of alternative isoform expression from RNA-seq data | Yarden Katz;Eric T Wang;Jacob Stilterra;Schraga Schwartz;Bang Wong;Helga Thorvaldsdóttir;James T Robinson;Jill P Mesirov;Edoardo M Airoldi;Christopher B Burge; | Christopher B Burge | MIT | 2014-02-11 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/11/002576.source.xml | To the Editor: To the Editor: Software documentation and... References Analysis of RNA sequencing (RNA-Seq) data revealed that the vast majority of human genes express multiple mRNA isoforms, produced by alternative pre-mRNA splicing and other mechanisms, and that most alternative isoforms vary in expression between human tissues (Pan et al., 2008; Wang et al., 2008). As RNA-Seq datasets grow in size, it remains challenging to visualize isoform expression across multiple samples. We present Sashimi plots, a quantitative multi-sample visualization of RNA-Seq reads aligned to gene annotations, which enables quantitative comparison of isoform usage across samples or experimental conditions. Given an input annotation and spliced alignments of reads from a sample, a region of interest is visualized in a Sashimi plot as follows: (i) alignments in ... | 10.1093/bioinformatics/btv034 | biorxiv | 247 |
10.1101/002519 | Social, spatial and temporal segregation in an ant society | Lauren E Quevillon;Ephraim M Hanks;Shweta Bansal;David P Hughes; | Lauren E Quevillon | Penn State University | 2014-02-11 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/02/11/002519.source.xml | Introduction Introduction Results Discussion Methods References Sociality can be risky. A chief cost of social living is increased transmission of infectious diseases, due to higher population densities combined with greater contact between susceptible and infected individuals (1,2,3,4). This greater encounter rate has led to a growing interest in the role of social contact structure in infectious disease transmission (5,6,7,8,9,10,11) To capture the dynamics of disease spread within dense groups, epidemiological models are shifting from the principle of mass action, in which infected and susceptible individuals are assumed to mix randoml ... | NA | biorxiv | 248 |
10.1101/002584 | Estimating the evolution of human life history traits in age-structured populations | Ryan Baldini; | Ryan Baldini | UC Davis | 2014-02-19 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/19/002584.source.xml | I propose a method that estimates the selection response of all vital rates in an age-structured population. I assume that vital rates are determined by the additive genetic contributions of many loci. The method uses all relatedness information in the sample to inform its estimates of genetic parameters, via an MCMC Bayesian framework. One can use the results to estimate the selection response of any life history trait that is a function of the vital rates, including the age at first reproduction, total lifetime fertility, survival to adulthood, and others. This method closely ties the empirical analysis of life history evolution to dynamically complete models of natural selection, and therefore enjoys some theoretical advantages over other methods. I demonstrate the method on a simulated model of evolution with two age classes. Finally I discuss how the method can be extended to more complicated cases. | NA | biorxiv | 250 |
10.1101/002600 | Cell specific eQTL analysis without sorting cells | Harm-Jan Westra;Danny Arends;Tõnu Esko;Marjolein J. Peters;Claudia Schurmann;Katharina Schramm;Johannes Kettunen;Hanieh Yaghootkar;Benjamin Fairfax;Anand Kumar Andiappan;Yang Li;Jingyuan Fu;Juha Karjalainen;Mathieu Platteel;Marijn Visschedijk;Rinse Weersma;Silva Kasela;Lili Milani;Liina Tserel;Pärt Peterson;Eva Reinmaa;Albert Hofman;André G. Uitterlinden;Fernando Rivadeneira;Georg Homuth;Astrid Petersmann;Roberto Lorbeer;Holger Prokisch;Thomas Meitinger;Christian Herder;Michael Roden;Harald Grallert;Samuli Ripatti;Markus Perola;Adrew R. Wood;David Melzer;Luigi Ferrucci;Andrew B. Singleton;Dena | Lude Franke | 2014-02-12 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/02/12/002600.source.xml | Expression quantitative trait locus (eQTL) mapping on tissue, organ or whole organism data can detect associations that are generic across cell types. We describe a new method to focus upon specific cell types without first needing to sort cells. We applied the method to whole blood data from 5,683 samples and demonstrate that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils. | 10.1371/journal.pgen.1005223 | biorxiv | 262 |
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10.1101/002667 | The immunologic V-gene repertoire in mammals | David N Olivieri;Bernardo von Haeften;Christian Sánchez-Espinel;Francisco Gambón-Deza; | David N Olivieri | Universidad de Vigo; School of Computer Science (Spain) | 2014-02-13 | 1 | New Results | cc_no | Immunology | https://www.biorxiv.org/content/early/2014/02/13/002667.source.xml | From recent whole genome shotgun data of 48 mammalian species, we have used our software VgenExtractor to obtain the functional V-gene sequence repertoire in order to conduct comparative phylogenetic studies. These studies reveal a large variation in the number of V-genes across mammalian species, ranging from a mere 36 V-genes in dolphins to nearly 600 V-genes in rats. Monotremes and marsupials are the only mammals possessing an additional locus, the TRMV, apart from the seven common loci found in mammals. Also, we show evidence for the loss of the light chain loci, specifically the V{kappa} chain in one microbat, and the V{lambda} chain in one rodent species. Finally, we suggest different features related to the evolution of immunoglobulin and T cell receptor loci, where frequent sequence duplications are seen in the former, while preserved and undiversified lineages are observed in the latter. All the V-gene sequences described in this study are available in the public database repository vgenerepertoire.org. | NA | biorxiv | 263 |
10.1101/002618 | Genomic V-gene repertoire in reptiles | David N Olivieri;Bernardo von Haeften;Christian Sánchez-Espinel;Jose Faro;Francisco Gambón-Deza; | David N Olivieri | Universidad de Vigo; School of Computer Science (Spain) | 2014-02-12 | 1 | New Results | cc_no | Immunology | https://www.biorxiv.org/content/early/2014/02/12/002618.source.xml | Reptiles and mammals diverged over 300 million years ago, creating two parallel evolutionary lineages amongst terrestrial vertebrates. In reptiles, two main evolutionary lines emerged, one gave rise to Squamata, while the other gave rise to Testudines, Crocodylia and birds. In this study, we determined the genomic variable (V)-gene repertoire in reptiles corresponding to the three main immunoglobulin (Ig) loci and the four main T-cell receptor (TCR) loci. We show that squamata lack the TCR{gamma} /{delta} genes and snakes lack the V{kappa} genes. In representative species of testudines and crocodiles, the seven major Ig and TCR loci are maintained. As in mammals, genes of the Ig loci can be grouped into well-defined clans through a multi-species phylogenetic analysis. We show that the reptile VH and V{lambda} genes are distributed amongst the established mammalian clans, while their V{kappa} genes are found within a single clan, nearly exclusive from the mammalian sequences. The reptile and mammal V-genes of the TRA locus cluster into six common evolutionary clans. In contrast, the reptile V-genes from the TRB locus cluster into three clans, which have few mammalian members. In this locus, the V-gene sequences from mammals appear to have undergone different evolutionary diversification processes that occurred outside these shared reptile clans. | 10.1007/s00251-014-0784-3 | biorxiv | 264 |
10.1101/002691 | Neuroanatomical diversity of corpus callosum and brain volume in the Autism Brain Imaging Data Exchange (Abide) project | Aline Lefebvre;Anita Beggiato;Thomas Bourgeron;Roberto Toro; | Roberto Toro | Institut Pasteur | 2014-02-15 | 2 | Contradictory Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/02/15/002691.source.xml | The corpus callosum - the main pathway for long-distance inter-hemispheric integration in the human brain - has been frequently reported to be smaller among autistic patients compared with non-autistic controls. We conducted a meta-analysis of the literature which suggested a statistically significant difference. However, the studies included were heavily underpowered: on average only 20% power to detect differences of 0.3 standard deviations, which makes it difficult to establish the reality of such a difference. We therefore studied the size of the corpus callosum among 694 subjects (328 patients, 366 controls) from the Abide cohort. Despite having achieved 99% power to detect statistically significant differences of 0.3 standard deviations, we did not observe any. To better understand the neuroanatomical diversity of the corpus callosum, and the possible reasons for the previous findings, we analysed the relationship between its size, the size of the brain, intracranial volume and intelligence scores. The corpus callosum appeared to scale non-linearly with brain size, with large brains having a proportionally smaller corpus callosum. Additionally, intelligence scores correlated with brain volume among controls but the correlation was significantly weaker among patients. We used simulations to determine to which extent these two effects could lead to artefactual differences in corpus callosum size within populations. We observed that, were there a difference in brain volume between cases and controls, normalising corpus callosum size by brain volume would not eliminate the brain volume effect, but adding brain volume as a covariate in a linear model would. Finally, we observed that because of the weaker correlation of intelligence scores and brain volume among patients, matching populations by intelligence scores could result in a bias towards including more patients with large brain volumes, inducing an artificial difference. Overall, our results highlight the necessity for open data sharing efforts such as Abide to provide a more solid ground for the discovery of neuroimaging biomarkers, within the context of the wide human neuroanatomical diversity. | 10.1016/j.biopsych.2015.02.010 | biorxiv | 266 |
10.1101/002766 | A Novel Approach for Multi-Domain and Multi-Gene Family Identification Provides Insights into Evolutionary Dynamics of Disease Resistance Genes in Core Eudicot Plants | Johannes A. Hofberger;Beifei Zhou;Haibao Tang;Jonathan DG Jones;M. Eric Schranz; | M. Eric Schranz | Wageningen University & Research Center | 2014-02-17 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/02/17/002766.source.xml | Recent advances in DNA sequencing techniques resulted in more than forty sequenced plant genomes representing a diverse set of taxa of agricultural, energy, medicinal and ecological importance. However, gene family curation is often only inferred from DNA sequence homology and lacks insights into evolutionary processes contributing to gene family dynamics. In a comparative genomics framework, we integrated multiple lines of evidence provided by gene synteny, sequence homology and protein-based Hidden Markov Modelling to extract homologous super-clusters composed of multi-domain resistance (R)-proteins of the NB-LRR type (for NUCLEOTIDE BINDING/LEUCINE-RICH REPEATS), that are involved in plant innate immunity. To assess the diversity of R-proteins within and between species, we screened twelve eudicot plant genomes including six major crops and found a total of 2,363 NB-LRR genes. Our curated R-proteins set shows a 50% average for tandem duplicates and a 22% fraction of gene copies retained from ancient polyploidy events (ohnologs). We provide evidence for strong positive selection acting on all identified genes and show significant differences in molecular evolution rates (Ka/Ks-ratio) among tandem- (mean = 1.59), ohnolog (mean = 1.36) and singleton (mean = 1.22) R-gene duplicates. To foster the process of gene-edited plant breeding, we report species-specific presence/absence of all 140 NB-LRR genes present in the model plant Arabidopsis and describe four distinct clusters of NB-LRR \"gatekeeper\" loci sharing syntelogs across all analyzed genomes. In summary, we designed and implemented an easy-to-follow computational framework for super-gene family identification, and provide the most curated set of NB-LRR genes whose genetic versatility among twelve lineages can underpin crop improvement. | 10.1186/1471-2164-15-966 | biorxiv | 271 |
10.1101/002741 | Fluorescent sensors for activity and regulation of the nitrate transceptor CHL1/NRT1.1 and oligopeptide transporters | Cheng Hsun Ho;Wolf B. Frommer; | Wolf B. Frommer | Carnegie Institution for Science | 2014-02-18 | 1 | New Results | cc_by_nc | Cell Biology | https://www.biorxiv.org/content/early/2014/02/18/002741.source.xml | To monitor nitrate and peptide transport activity in vivo, we converted the dual-affinity nitrate transceptor CHL1/NRT1.1/NPF6.3 and four related oligopeptide transporters PTR1, 2, 4 and 5 into fluorescence activity sensors (NiTrac1, PepTrac). Substrate addition to yeast expressing transporter fusions with yellow fluorescent protein and mCerulean triggered substrate-dependent donor quenching or resonance energy transfer. Fluorescence changes were nitrate/peptide-specific, respectively. Like CHL1, NiTrac1 had biphasic kinetics. Mutation of T101A eliminated high-affinity transport and blocked the fluorescence response to low nitrate. NiTrac was used for characterizing side chains considered important for substrate interaction, proton coupling, and regulation. We observed a striking correlation between transport activity and sensor output. Coexpression of NiTrac with known calcineurin-like proteins (CBL1, 9; CIPK23) and candidates identified in an interactome screen (CBL1, KT2, WNKinase 8) blocked NiTrac1 responses, demonstrating the suitability for in vivo analysis of activity and regulation. The new technology is applicable in plant and medical research. | 10.7554/eLife.01917.001 | biorxiv | 272 |
10.1101/002790 | ESCRT-0 is not required for ectopic Notch activation and tumor suppression in Drosophila | Emiliana Tognon;Nadine Wollscheid;Katia Cortese;Carlo Tacchetti;thomas vaccari; | thomas vaccari | IFOM, Istituto FIRC di Oncologia Molecolare | 2014-02-18 | 1 | New Results | cc_by_nc_nd | Developmental Biology | https://www.biorxiv.org/content/early/2014/02/18/002790.source.xml | Multivesicular endosome (MVE) sorting depends on proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) family. These are organized in four complexes (ESCRT-0, -I, -II, -III) that act in a sequential fashion to deliver ubiquitylated cargoes into the internal luminal vesicles (ILVs) of the MVE. Drosophila genes encoding ESCRT-I, -II, -III components function in sorting signaling receptors, including Notch and the JAK/STAT signaling receptor Domeless. Loss of ESCRT-I, -II, -III in Drosophila epithelia causes altered signaling and cell polarity, suggesting that ESCRTs genes are tumor suppressors. However, the nature of the tumor suppressive function of ESCRTs, and whether tumor suppression is linked to receptor sorting is unclear. Unexpectedly, a null mutant in Hrs, encoding one of components of the ESCRT-0 complex, which acts upstream of ESCRT-I, -II, -III in MVE sorting is dispensable for tumor suppression. Here, we report that two Drosophila epithelia lacking activity of Stam, the other known components of the ESCRT-0 complex, or of both Hrs and Stam fail to degrade signaling receptors. However, mutant tissue surprisingly maintains normal apico-basal polarity and proliferation control and does not display ectopic Notch signaling activation, unlike cells that lack ESCRT-I, -II, -III activity. Overall, our in vivo data indicate that the ESCRT-0 complex plays no crucial role in regulation of tumor suppression, and suggest re-evaluation of the relationship of signaling modulation in endosomes and tumorigenesis. | 10.1371/journal.pone.0093987 | biorxiv | 273 |
10.1101/002808 | Migration and interaction in a contact zone: mtDNA variation among Bantu-speakers in southern Africa | Chiara Barbieri;Mário Vicente;Sandra Oliveira;Koen Bostoen;Jorge Rocha;Mark Stoneking;Brigitte Pakendorf; | Chiara Barbieri | Department of Evolutionary Genetics, MPI for Evolutionary Anthropology, Leipzig, Germany, 04103 | 2014-02-18 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/18/002808.source.xml | Bantu speech communities expanded over large parts of sub-Saharan Africa within the last 4000-5000 years, reaching different parts of southern Africa 1200-2000 years ago. The Bantu languages subdivide in several major branches, with languages belonging to the Eastern and Western Bantu branches spreading over large parts of Central, Eastern, and Southern Africa. There is still debate whether this linguistic divide is correlated with a genetic distinction between Eastern and Western Bantu speakers. During their expansion, Bantu speakers would have come into contact with diverse local populations, such as the Khoisan hunter-gatherers and pastoralists of southern Africa, with whom they may have intermarried. In this study, we analyze complete mtDNA genome sequences from over 900 Bantu-speaking individuals from Angola, Zambia, Namibia, and Botswana to investigate the demographic processes at play during the last stages of the Bantu expansion. Our results show that most of these Bantu-speaking populations are genetically very homogenous, with no genetic division between speakers of Eastern and Western Bantu languages. Most of the mtDNA diversity in our dataset is due to different degrees of admixture with autochthonous populations. Only the pastoralist Himba and Herero stand out due to high frequencies of particular L3f and L3d lineages; the latter are also found in the neighboring Damara, who speak a Khoisan language and were foragers and small-stock herders. In contrast, the close cultural and linguistic relatives of the Herero and Himba, the Kuvale, are genetically similar to other Bantu-speakers. Nevertheless, as demonstrated by resampling tests, the genetic divergence of Herero, Himba, and Kuvale is compatible with a common shared ancestry with high levels of drift and differential female admixture with local pre-Bantu populations. | 10.1371/journal.pone.0099117 | biorxiv | 274 |
10.1101/002881 | A GWAS platform built on iPlant cyber-infrastructure | Liya Wang;Doreen Ware;Carol Lushbough;Nirav Merchant;Lincoln Stein; | Liya Wang | Cold Spring Harbor Labs | 2014-02-20 | 1 | Confirmatory Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/20/002881.source.xml | We demonstrated a flexible Genome-Wide Association Study (GWAS) platform built upon the iPlant Collaborative Cyber-infrastructure. The platform supports big data management, sharing, and large scale study of both genotype and phenotype data on clusters. End users can add their own analysis tools, and create customized analysis workflows through the graphical user interfaces in both iPlant Discovery Environment and BioExtract server. | 10.1002/cpe.3236 | biorxiv | 277 |
10.1101/002873 | Mapping the structure of drosophilid behavior | Gordon J Berman;Daniel M Choi;William Bialek;Joshua W Shaevitz; | Joshua W Shaevitz | Princeton University | 2014-02-20 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/20/002873.source.xml | Most animals possess the ability to actuate a vast diversity of movements, ostensibly constrained only by morphology and physics. In practice, however, a frequent assumption in behavioral science is that most of an animals activities can be described in terms of a small set of stereotyped motifs. Here we introduce a method for mapping the behavioral space of organisms, relying only upon the underlying structure of postural movement data to organize and classify behaviors. We find that six different drosophilid species each perform a mix of non-stereotyped actions and over one hundred hierarchically-organized, stereotyped behaviors. Moreover, we use this approach to compare these species behavioral spaces, systematically identifying subtle behavioral differences between closely-related species. | 10.1098/rsif.2014.0672 | biorxiv | 281 |
10.1101/002865 | No evidence that natural selection has been less effective at removing deleterious mutations in Europeans than in West Africans | Ron Do;Daniel Balick;Heng Li;Ivan Adzhubei`;Shamil Sunyaev;David Reich; | David Reich | Department of Genetics, Harvard Medical School, Boston, MA 02115 | 2014-02-20 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/20/002865.source.xml | Non-African populations have experienced major bottlenecks in the time since their split from West Africans, which has led to the hypothesis that natural selection to remove weakly deleterious mutations may have been less effective in non-Africans. To directly test this hypothesis, we measure the per-genome accumulation of deleterious mutations across diverse humans. We fail to detect any significant differences, but find that archaic Denisovans accumulated non-synonymous mutations at a higher rate than modern humans, consistent with the longer separation time of modern and archaic humans. We also revisit the empirical patterns that have been interpreted as evidence for less effective removal of deleterious mutations in non-Africans than in West Africans, and show they are not driven by differences in selection after population separation, but by neutral evolution. | 10.1038/ng.3186 | biorxiv | 282 |
10.1101/002956 | Functional normalization of 450k methylation array data improves replication in large cancer studies | Jean-Philippe Fortin;Aurelie Labbe;Mathieu Lemire;Brent W. Zanke;Thomas J. Hudson;Elana J. Fertig;Celia M.T. Greenwood;Kasper D. Hansen; | Kasper D. Hansen | Johns Hopkins University | 2014-02-23 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/23/002956.source.xml | We propose an extension to quantile normalization which removes unwanted technical variation using control probes. We adapt our algorithm, functional normalization, to the Illumina 450k methylation array and address the open problem of normalizing methylation data with global epigenetic changes, such as human cancers. Using datasets from The Cancer Genome Atlas and a large case-control study, we show that our algorithm outperforms all existing normalization methods with respect to replication of results between experiments, and yields robust results even in the presence of batch effects. Functional normalization can be applied to any microarray platform, provided suitable control probes are available. | 10.1186/s13059-014-0503-2 | biorxiv | 283 |
10.1101/002931 | LD Score Regression Distinguishes Confounding from Polygenicity in Genome-Wide Association Studies | Brendan Bulik-Sullivan;Po-Ru Loh;Hilary Finucane;Stephan Ripke;Jian Yang;Schizophrenia Working Group Psychiatric Genomics Consortium;Nick Patterson;Mark J Daly;Alkes L Price;Benjamin M Neale; | Benjamin M Neale | Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital | 2014-02-21 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/02/21/002931.source.xml | Both polygenicity1,2 (i.e. many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification3, can yield inflated distributions of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from bias and true signal from polygenicity. We have developed an approach that quantifies the contributions of each by examining the relationship between test statistics and linkage disequilibrium (LD). We term this approach LD Score regression. LD Score regression provides an upper bound on the contribution of confounding bias to the observed inflation in test statistics and can be used to estimate a more powerful correction factor than genomic control4-14. We find strong evidence that polygenicity accounts for the majority of test statistic inflation in many GWAS of large sample size. | 10.1038/ng.3211 | biorxiv | 284 |
10.1101/002923 | Spatial Information in Large-Scale Neural Recordings | Thaddeus R Cybulski;Joshua I Glaser;Adam H Marblestone;Bradley M Zamft;Edward S Boyden;George M Church;Konrad P Kording; | Thaddeus R Cybulski | Northwestern University | 2014-02-21 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2014/02/21/002923.source.xml | A central issue in neural recording is that of distinguishing the activities of many neurons. Here, we develop a framework, based on Fisher information, to quantify how separable a neurons activity is from the activities of nearby neurons. We (1) apply this framework to model information flow and spatial distinguishability for several electrical and optical neural recording methods, (2) provide analytic expressions for information content, and (3) demonstrate potential applications of the approach. This method generalizes to many recording devices that resolve objects in space and thus may be useful in the design of next-generation scalable neural recording systems. | 10.3389/fncom.2014.00172 | biorxiv | 285 |
10.1101/002907 | Population diversification in a yeast metabolic program promotes anticipation of environmental shifts | Ophelia S Venturelli;Ignacio Zuleta;Richard M Murray;Hana El-Samad; | Hana El-Samad | University of California San Francisco | 2014-02-21 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/02/21/002907.source.xml | Delineating the strategies by which cells contend with combinatorial changing environments is crucial for understanding cellular regulatory organization. When presented with two carbon sources, microorganisms first consume the carbon substrate that supports the highest growth rate (e.g. glucose) and then switch to the secondary carbon source (e.g. galactose), a paradigm known as the Monod model. Sequential sugar utilization has been attributed to transcriptional repression of the secondary metabolic pathway, followed by activation of this pathway upon depletion of the preferred carbon source. In this work, we challenge this notion. Although Saccharomyces cerevisiae cells consume glucose before galactose, we demonstrate that the galactose regulatory pathway is activated in a fraction of the cell population hours before glucose is fully consumed. This early activation reduces the time required for the population to transition between the two metabolic programs and provides a fitness advantage that might be crucial in competitive environments. Importantly, these findings define a new paradigm for the response of microbial populations to combinatorial carbon sources. | 10.1371/journal.pbio.1002042 | biorxiv | 286 |
10.1101/002493 | The roles of standing genetic variation and evolutionary history in determining the evolvability of anti-predator strategies | Jordan Fish;Daniel R O'Donnell;Abhijna Parigi;Ian Dworkin;Aaron P Wagner; | Daniel R O'Donnell | Michigan State University | 2014-02-07 | 1 | New Results | cc_by_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/07/002493.source.xml | Standing genetic variation and the historical environment in which that variation arises (evolutionary history) are both potentially significant determinants of a populations capacity for evolutionary response to a changing environment. We evaluated the relative importance of these two factors in influencing the evolutionary trajectories in the face of sudden environmental change. We used the open-ended digital evolution software Avida to examine how historic exposure to predation pressures, different levels of genetic variation, and combinations of the two, impact anti-predator strategies and competitive abilities evolved in the face of threats from new, invasive, predator populations. We show that while standing genetic variation plays some role in determining evolutionary responses, evolutionary history has the greater influence on a populations capacity to evolve effective anti-predator traits. This adaptability likely reflects the relative ease of repurposing existing, relevant genes and traits, and the broader potential value of the generation and maintenance of adaptively flexible traits in evolving populations. | 10.1371/journal.pone.0100163 | biorxiv | 287 |
10.1101/000752 | Joint analysis of functional genomic data and genome-wide association studies of 18 human traits | Joseph Pickrell; | Joseph Pickrell | New York Genome Center | 2014-02-25 | 4 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/02/25/000752.source.xml | Annotations of gene structures and regulatory elements can inform genome-wide association studies (GWAS). However, choosing the relevant annotations for interpreting an association study of a given trait remains challenging. We describe a statistical model that uses association statistics computed across the genome to identify classes of genomic element that are enriched or depleted for loci that influence a trait. The model naturally incorporates multiple types of annotations. We applied the model to GWAS of 18 human traits, including red blood cell traits, platelet traits, glucose levels, lipid levels, height, BMI, and Crohns disease. For each trait, we evaluated the relevance of 450 different genomic annotations, including protein-coding genes, enhancers, and DNase-I hypersensitive sites in over a hundred tissues and cell lines. We show that the fraction of phenotype-associated SNPs that influence protein sequence ranges from around 2% (for platelet volume) up to around 20% (for LDL cholesterol); that repressed chromatin is significantly depleted for SNPs associated with several traits; and that cell type-specific DNase-I hypersensitive sites are enriched for SNPs associated with several traits (for example, the spleen in platelet volume). Finally, by re-weighting each GWAS using information from functional genomics, we increase the number of loci with high-confidence associations by around 5%. | 10.1016/j.ajhg.2014.03.004 | biorxiv | 288 |
10.1101/000885 | Resource usage and gene circuit performance characterization in a cell-free ?breadboard? | Dan Siegal-Gaskins;Zoltan A. Tuza;Jongmin Kim;Vincent Noireaux;Richard M. Murray; | Dan Siegal-Gaskins | California Institute of Technology | 2014-03-09 | 4 | New Results | cc_by_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2014/03/09/000885.source.xml | The many successes of synthetic biology have come in a manner largely different from those in other engineering disciplines; in particular, without well-characterized and simplified prototyping environments to play a role analogous to wind-tunnels in aerodynamics and breadboards in electrical engineering. However, as the complexity of synthetic circuits increases, the benefits--in cost savings and design cycle time--of a more traditional engineering approach can be significant. We have recently developed an in vitro breadboard prototyping platform based on E. coli cell extract that allows biocircuits to operate in an environment considerably simpler than but functionally similar to in vivo. The simplicity of this system makes it a promising tool for rapid biocircuit design and testing, as well as for probing fundamental aspects of gene circuit operation normally masked by cellular complexity. In this work we characterize the cell-free breadboard using real-time and simultaneous measurements of transcriptional and translational activities of a small set of reporter genes and a transcriptional activation cascade. We determine the effects of promoter strength, gene concentration, and nucleoside triphosphate concentration on biocircuit properties, and we isolate the specific contributions of essential biomolecular resources--core RNA polymerase and ribosomes--to overall performance. Importantly, we show how limits on resources, particularly those involved in translation, are manifested as reduced expression in the presence of orthogonal genes that serve as additional loads on the system. | 10.1021/sb400203p | biorxiv | 289 |
10.1101/001719 | Modeling the functional relationship network at the splice isoform level through heterogeneous data integration | Hongdong Li;Rajasree Menon;Ridvan Eksi;Aysam Guerler;Yang Zhang;Gilbert S. Omenn;Yuanfang Guan; | Yuanfang Guan | University of Michigan, Ann Arbor | 2014-03-07 | 2 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/03/07/001719.source.xml | Functional relationship networks, which reveal the collaborative roles between genes, have significantly accelerated our understanding of gene functions and phenotypic relevance. However, establishing such networks for alternatively spliced isoforms remains a difficult, unaddressed problem due to the lack of systematic functional annotations at the isoform level, which renders most supervised learning methods difficult to be applied to isoforms. Here we describe a novel multiple instance learning-based probabilistic approach that integrates large-scale, heterogeneous genomic datasets, including RNA-seq, exon array, protein docking and pseudo-amino acid composition, for modeling a global functional relationship network at the isoform level in the mouse. Using this approach, we formulate a gene pair as a set of isoform pairs of potentially different properties. Through simulation and cross-validation studies, we showed the superior accuracy of our algorithm in revealing the isoform-level functional relationships. The local networks reveal functional diversity of the isoforms of the same gene, as demonstrated by both large-scale analyses and experimental and literature evidence for the disparate functions revealed for the isoforms of Ptbp1 and Anxa6 by our network. Our work can assist the understanding of the diversity of functions achieved by alternative splicing of a limited set of genes in mammalian genomes, and may shift the current gene-centered network prediction paradigm to the isoform level.\n\nAuthor summaryProteins carry out their functions through interacting with each other. Such interactions can be achieved through direct physical interactions, genetic interactions, or co-regulation. To summarize these interactions, researches have established functional relationship networks, in which each gene is represented as a node and the connections between the nodes represent how likely two genes work in the same biological process. Currently, these networks are established at the gene level only, while each gene, in mammalian systems, can be alternatively spliced into multiple isoforms that may have drastically different interaction partners. This information can be mined through integrating data that provide isoform-level information, such as RNA-seq and protein docking scores predicted from amino acid sequences. In this study, we developed a novel algorithm to integrate such data for predicting isoform-level functional relationship networks, which allows us to investigate the collaborative roles between genes at a high resolution. | NA | biorxiv | 291 |
10.1101/001800 | The Toxoplasma Acto-MyoA Motor Complex Is Important but Not Essential for Gliding Motility and Host Cell Invasion | Saskia Egarter;Nicole Andenmatten;Allison J Jackson;Jamie A Whitelaw;Gurmann Pall;Jennifer A Black;David JP Ferguson;Isabelle Tardieux;Alex Mogilner;Markus Meissner; | Markus Meissner | University of Glasgow | 2014-03-18 | 3 | New Results | cc_by_nc_nd | Cell Biology | https://www.biorxiv.org/content/early/2014/03/18/001800.source.xml | Apicomplexan parasites are thought to actively invade the host cell by gliding motility. This movement is powered by the parasite own actomyosin system and depends on the regulated polymerisation and depolymerisation of actin to generate the force for gliding and host cell penetration. Recent studies demonstrated that Toxoplasma gondii can invade the host cell in the absence of several core components of the invasion machinery, such as the motor protein myosin A (MyoA), the microneme proteins MIC2 and AMA1 and actin, indicating the presence of alternative invasion mechanisms. Here the roles of MyoA, MLC1, GAP45 and Act1, core components of the gliding machinery, are re-dissected in detail. Although important roles of these components for gliding motility and host cell invasion are verified, mutant parasites remain invasive and do not show a block of gliding motility, suggesting that other mechanisms must be in place to enable the parasite to move and invade the host cell. A novel, hypothetical model for parasite gliding motility and invasion is presented based on osmotic forces generated in the cytosol of the parasite that are converted into motility. | 10.1371/journal.pone.0091819 | biorxiv | 292 |
10.1101/001842 | The emergence of the rescue effect from explicit within- and between-patch dynamics in a metapopulation | Anders Eriksson;Federico Elías-Wolff;Bernhard Mehlig;Andrea Manica; | Anders Eriksson | University of Cambridge | 2014-03-05 | 2 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/03/05/001842.source.xml | Immigration can rescue local populations from extinction, helping to stabilise a metapopulation. Local population dynamics is important for determining the strength of this rescue effect, but the mechanistic link between local demographic parameters and the rescue effect at the metapopulation level has received very little attention by modellers. We develop an analytical framework that allows us to describe the emergence of the rescue effect from interacting local stochastic dynamics. We show this framework to be applicable to a wide range of spatial scales, providing a powerful and convenient alternative to individual-based models for making predictions concerning the fate of metapopulations. We show that the rescue effect plays an important role in minimising the increase in local extinction probability associated with high demographic stochasticity, but its role is more limited in the case of high local environmental stochasticity of recruitment or survival. While most models postulate the rescue effect, our framework provides an explicit mechanistic link between local dynamics and the emergence of the rescue effect, and more generally the stability of the whole metapopulation. | 10.1098/rspb.2013.3127 | biorxiv | 293 |
10.1101/002105 | The disruption of trace element homeostasis due to aneuploidy as a unifying theme in the etiology of cancer | Johannes Engelken;Matthias Altmeyer;Renty B Franklin; | Johannes Engelken | 1.Institute of Evolutionary Biology (CSIC Universitat Pompeu Fabra) 08003 Barcelona, Spain. 2. 3. | 2014-03-14 | 5 | New Results | cc_by_nc | Cancer Biology | https://www.biorxiv.org/content/early/2014/03/14/002105.source.xml | #### #### ABSTRACT FOR SCIENTISTS: While decades of cancer research have firmly established multiple hallmarks of cancer 1,2, cancers genomic landscape remains to be fully understood. Particularly, the phenomenon of aneuploidy gains and losses of large genomic regions, i.e. whole chromosomes or chromosome arms and why most cancer cells are aneuploid remains enigmatic 3. Another frequent observation in many different types of cancer is the deregulation of the homeostasis of the trace elements copper, zinc and iron. Concentrations of copper are markedly increased in cancer tissue and the blood plasma of cancer patients, while zinc levels are typically decreased 49. Here we discuss the hypothesis that the disruption of trace element homeostasis and the phenomenon of aneuploidy might be linked. Our tentative analysis of genomic data from diverse tumor types mainly from The Cancer Genome Atlas (TCGA) project suggests that gains and losses of metal transporter genes occur frequently and correlate well with transporter gene expression levels. Hereby they may confer a cancer-driving selective growth advantage at early and possibly also later stages during cancer development. This idea is consistent with recent observations in yeast, which suggest that through chromosomal gains and losses cells can adapt quickly to new carbon sources 10, nutrient starvation 11 as well as to copper toxicity 12. In human cancer development, candidate driving events may include, among others, the gains of zinc transporter genes SLC39A1 and SLC39A4 on chromosome arms 1q and 8q, respectively, and the losses of zinc transporter genes SLC30A5, SLC39A14 and SLC39A6 on 5q, 8p and 18q. The recurrent gain of 3q might be associated with the iron transporter gene TFRC and the loss of 13q with the copper transporter gene ATP7B. By altering cellular trace element homeostasis such events might contribute to the initiation of the malignant transformation. Intriguingly, attenuation or overexpression of several of these metal transporter genes has been shown to lead to malignant cellular behavior in vitro. Consistently, it has been shown that zinc affects a number of the observed hallmarks of cancer characteristics including DNA repair, inflammation and apoptosis, e.g. through its effects on NF-kappa B signaling. We term this model the aneuploidy metal transporter cancer (AMTC) hypothesis and find it compatible with the cancer-promoting role of point mutations and focal copy number alterations in established tumor suppressor genes and oncogenes (e.g. MYC, MYCN, TP53, PIK3CA, BRCA1, ERBB2). We suggest a number of approaches for how this hypothesis could be tested experimentally and briefly touch on possible implications for cancer etiology, metastasis, drug resistance and therapy. #### #### ABSTRACT FOR KIDS: We humans are made up of many very small building blocks, which are called cells. These cells can be seen with a microscope and they know how to grow and what to do from the information on the DNA of their chromosomes. Sometimes, if this information is messed up, a cell can go crazy and start to grow without control, even in places of the body where it should not. This process is called cancer, a terrible disease that makes people very sick. Scientists do not understand exactly what causes cells to go crazy, so it would be good to find out. Many years ago, scientists observed that chromosomes in these cancer cells are missing or doubled but could not find an explanation for it. More recently, scientists have detected that precious metals to our bodies, which are not gold and silver, but zinc, iron and copper, are not found in the right amounts in these crazy cancer cells. There seems to be not enough zinc and iron but too much copper, and again, scientists do not really understand why. So there are many unanswered questions about these crazy cancer cells and in this article, we describe a pretty simple idea on how chromosome numbers and the metals might be connected: we think that the missing or doubled chromosomes produce less or more transporters of zinc, iron and copper. As a result, cancer cells end up with little zinc and too much copper and these changes contribute to their out-of-control growth. If this idea were true, many people would be excited about it. But first this idea needs to be investigated more deeply in the laboratory, on the computer and in the hospitals. Therefore, we put it out on the internet so that other people can also think about and work on our idea. Now there are plenty of ways to do exciting experiments and with the results, we will hopefully understand much better why cancer cells go crazy and how doctors could improve their therapies to help patients in the future. #### #### ABSTRACT FOR ADULTS: One hundred years ago, it was suggested that cancer is a disease of the chromosomes, based on the observations that whole chromosomes or chromosome arms are missing or duplicated in the genomes of cells in a tumor. This phenomenon is called aneuploidy and is observed in most types of cancer, including breast, lung, prostate, brain and other cancers. However, it is not clear which genes could be responsible for this observation or if this phenomenon is only a side effect of cancer without importance, so it is important to find out. A second observation from basic research is that concentrations of several micronutrients, especially of the trace elements zinc, copper and iron are changed in tumor cells. In this article, we speculate that aneuploidy is the reason for these changes and that together, these two phenomena are responsible for some of the famous hallmarks or characteristics that are known from cancer cells: fast growth, escape from destruction by the immune system and poor DNA repair. This idea is new and has not been tested yet. We name it the aneuploidy metal transporter cancer (AMTC) hypothesis. To test our idea we used a wealth of information that was shared by international projects such as the Human Genome Project or the Cancer Genome Atlas Project. Indeed, we find that many zinc, iron and copper transporter genes in the genome are affected by aneuploidy. While a healthy cell has two copies of each gene, some tumor cells have only one or three copies of these genes. Furthermore, the amounts of protein and the activities of these metal transporters seem to correlate with these gene copy numbers, at least we see that the intermediate molecules and protein precursors called messenger RNA correlate well. Hence, we found that the public data is compatible with our suggested link between metal transporters and cancer. Furthermore, we identified hundreds of studies on zinc biology, evolutionary biology, genome and cancer research that also seem compatible. For example, cancer risk increases in the elderly population as well as in obese people, it also increases after certain bacterial or viral infections and through alcohol consumption. Consistent with the AMTC hypothesis and in particular, the idea that external changes in zinc concentrations in an organ or tissue may kick off the earliest steps of tumor development, all of these risk factors have been correlated with changes in zinc or other trace elements. However, since additional experiments to test the AMTC hypothesis have not yet been performed, direct evidence for our hypothesis is still missing. We hope, however, that our idea will promote further research with the goal to better understand cancer as a first step towards its prevention and the development of improved anti-cancer therapies in the future. | NA | biorxiv | 296 |
10.1101/002238 | Fast Principal Component Analysis of Large-Scale Genome-Wide Data | Gad Abraham;Michael Inouye; | Gad Abraham | University of Melbourne | 2014-03-11 | 2 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/03/11/002238.source.xml | Principal component analysis (PCA) is routinely used to analyze genome-wide single-nucleotide polymorphism (SNP) data, for detecting population structure and potential outliers. However, the size of SNP datasets has increased immensely in recent years and PCA of large datasets has become a time consuming task. We have developed flashpca, a highly efficient PCA implementation based on randomized algorithms, which delivers identical accuracy in extracting the top principal components compared with existing tools, in substantially less time. We demonstrate the utility of flashpca on both HapMap3 and on a large Immunochip dataset. For the latter, flashpca performed PCA of 15,000 individuals up to 125 times faster than existing tools, with identical results, and PCA of 150,000 individuals using flashpca completed in 4 hours. The increasing size of SNP datasets will make tools such as flashpca essential as traditional approaches will not adequately scale. This approach will also help to scale other applications that leverage PCA or eigen-decomposition to substantially larger datasets. | 10.1371/journal.pone.0093766 | biorxiv | 297 |
10.1101/002725 | Spectacle: Faster and more accurate chromatin state annotation using spectral learning | Jimin Song;Kevin C Chen; | Kevin C Chen | Rutgers University | 2014-03-09 | 2 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/03/09/002725.source.xml | Recently, a wealth of epigenomic data has been generated by biochemical assays and next-generation sequencing (NGS) technologies. In particular, histone modification data generated by the ENCODE project and other large-scale projects show specific patterns associated with regulatory elements in the human genome. It is important to build a unified statistical model to decipher the patterns of multiple histone modifications in a cell type to annotate chromatin states such as transcription start sites, enhancers and transcribed regions rather than to map histone modifications individually to regulatory elements.\n\nSeveral genome-wide statistical models have been developed based on hidden Markov models (HMMs). These methods typically use the Expectation-Maximization (EM) algorithm to estimate the parameters of the model. Here we used spectral learning, a state-of-the-art parameter estimation algorithm in machine learning. We found that spectral learning plus a few (up to five) iterations of local optimization of the likelihood outper-forms the standard EM algorithm. We also evaluated our software implementation called Spectacle on independent biological datasets and found that Spectacle annotated experimentally defined functional elements such as enhancers significantly better than a previous state-of-the-art method.\n\nSpectacle can be downloaded from https://github.com/jiminsong/Spectacle. | NA | biorxiv | 298 |
10.1101/002642 | A reassessment of consensus clustering for class discovery | Yasin Şenbabaoğlu;George Michailidis;Jun Z Li; | Jun Z Li | University of Michigan Ann Arbor | 2014-03-11 | 3 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/03/11/002642.source.xml | Consensus clustering (CC) is an unsupervised class discovery method widely used to study sample heterogeneity in high-dimensional datasets. It calculates \"consensus rate\" between any two samples as how frequently they are grouped together in repeated clustering runs under a certain degree of random perturbation. The pairwise consensus rates form a between-sample similarity matrix, which has been used (1) as a visual proof that clusters exist, (2) for comparing stability among clusters, and (3) for estimating the optimal number (K) of clusters. However, the sensitivity and specificity of CC have not been systemically studied. To assess its performance, we investigated the most common implementations of CC; and compared CC with other popular methods that also focus on cluster stability and estimation of K. We evaluated these methods using simulated datasets with either known structure or known absence of structure. Our results showed that (1) CC was able to divide randomly generated unimodal data into pre-specified numbers of clusters, and was able to show apparent stability of these chance partitions of known cluster-less data; (2) for data with known structure, the proportion of ambiguously clustered (PAC) pairs infers the known number of clusters more reliably than several commonly used K estimating methods; and (3) validation of the optimal K by choosing the most discriminant genes from the discovery cohort and applying them in an independent cohort often exaggerates the confidence in K due to inherent gene-gene correlations among the selected genes. While these results do not yet prove that any of the published studies using CC has generated false positive findings, they show that datasets with subtle or no structure are fully capable of producing strong evidence of consensus clustering. We therefore recommend caution is using CC in class discovery and validation. | 10.1038/srep06207 | biorxiv | 299 |
10.1101/002717 | Immune stimulation reduces sleep and memory ability in Drosophila melanogaster | Eamonn Mallon;Akram Alghamdi;Robert Holdbrook;Ezio Rosato; | Eamonn Mallon | University of Leicester | 2014-03-12 | 2 | New Results | cc_by_nc | Zoology | https://www.biorxiv.org/content/early/2014/03/12/002717.source.xml | Psychoneuroimmunology studies the increasing number of connections between neurobiology and immunology. We establish Drosophila melanogaster as a tractable model in this field by demonstrating the effects of the immune response on two fundamental behaviours: sleep and memory ability.\n\nWe used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. Importantly, by stimulating the immune system of adult flies in the absence of infection we have avoided the added complications of developmental and disease effects that have confounded other studies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep.\n\nImmune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. The effects on sleep were more pronounced for day compared to night sleep. Immune stimulated flies also showed a reduction in memory abilities.\n\nThese are important results as they establish Drosophila as a model for immune-neural interactions and provide a possible role for sleep in the interplay between the immune response and memory. | 10.7717/peerj.434 | biorxiv | 301 |
10.1101/002972 | Efficient synergistic single-cell genome assembly | Narjes S. Movahedi;Zeinab Taghavi;Mallory Embree;Harish Nagarajan;Karsten Zengler;Hamidreza Chitsaz; | Hamidreza Chitsaz | Wayne State University | 2014-02-24 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/24/002972.source.xml | As the vast majority of all microbes are unculturable, single-cell sequencing has become a significant method to gain insight into microbial physiology. Single-cell sequencing methods, currently powered by multiple displacement genome amplification (MDA), have passed important milestones such as finishing and closing the genome of a prokaryote. However, the quality and reliability of genome assemblies from single cells are still unsatisfactory due to uneven coverage depth and the absence of scattered chunks of the genome in the final collection of reads caused by MDA bias. In this work, our new algorithm Hybrid De novo Assembler (HyDA) demonstrates the power of co-assembly of multiple single-cell genomic data sets through significant improvement of the assembly quality in terms of predicted functional elements and length statistics. Co-assemblies contain significantly more base pairs and protein coding genes, cover more subsystems, and consist of longer contigs compared to individual assemblies by the same algorithm as well as state-of-the-art single-cell assemblers SPAdes and IDBA-UD. Hybrid De novo Assembler (HyDA) is also able to avoid chimeric assemblies by detecting and separating shared and exclusive pieces of sequence for input data sets. By replacing one deep single-cell sequencing experiment with a few single-cell sequencing experiments of lower depth, the co-assembly method can hedge against the risk of failure and loss of the sample, without significantly increasing sequencing cost. Application of the single-cell coassembler HyDA to the study of three uncultured members of an alkane-degrading methanogenic community validated the usefulness of the co-assembly concept. | 10.3389/fbioe.2016.00042 | biorxiv | 304 |
10.1101/002980 | Genetic drift suppresses bacterial conjugation in spatially structured populations | Peter D. Freese;Kirill S. Korolev;Jose I Jimenez;Irene A. Chen; | Irene A. Chen | Univ. of California - Santa Barbara | 2014-02-24 | 1 | New Results | cc_by_nc | Biophysics | https://www.biorxiv.org/content/early/2014/02/24/002980.source.xml | Conjugation is the primary mechanism of horizontal gene transfer that spreads antibiotic resistance among bacteria. Although conjugation normally occurs in surface-associated growth (e.g., biofilms), it has been traditionally studied in well-mixed liquid cultures lacking spatial structure, which is known to affect many evolutionary and ecological processes. Here we visualize spatial patterns of gene transfer mediated by F plasmid conjugation in a colony of Escherichia coli growing on solid agar, and we develop a quantitative understanding by spatial extension of traditional mass-action models. We found that spatial structure suppresses conjugation in surface-associated growth because strong genetic drift leads to spatial isolation of donor and recipient cells, restricting conjugation to rare boundaries between donor and recipient strains. These results suggest that ecological strategies, such as enforcement of spatial structure and enhancement of genetic drift, could complement molecular strategies in slowing the spread of antibiotic resistance genes. | 10.1016/j.bpj.2014.01.012 | biorxiv | 306 |
10.1101/002998 | Extensive translation of small ORFs revealed by polysomal ribo-Seq | Julie L Aspden;Ying Chen Eyre-Walker;Rose J. Phillips;Michele Brocard;Unum Amin;Juan Couso; | Juan Couso | University of Sussex | 2014-02-24 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/02/24/002998.source.xml | Thousands of small Open Reading Frames (smORFs) encoding small peptides of fewer than 100 amino acids exist in our genomes. Examples of functional smORFs have been characterised in a few species but the actual number of translated smORFs, and their molecular, functional and evolutionary features are not known. Here we present a genome-wide assessment of smORF translation by ribosomal profiling of polysomal fractions. This polysomal ribo-Seq suggests that smORFs are translated at the same level and in the same relative numbers (80%) as normal proteins. The smORF peptides appear widely conserved, show activity in cells, and display a putative amino acid signature. These findings reinforce the idea that smORFs are an abundant and fundamental genome component, displaying features usually attributed to canonical proteins, including high translation levels, biological function, amino acid sequence specificity and cross-species conservation. | NA | biorxiv | 307 |
10.1101/003053 | A tug-of-war between driver and passenger mutations in cancer and other adaptive processes | Christopher Dennis McFarland;Leonid A Mirny;Kirill S Korolev; | Leonid A Mirny | Massachusetts Institute of Technology | 2014-02-26 | 1 | New Results | cc_by | Cancer Biology | https://www.biorxiv.org/content/early/2014/02/26/003053.source.xml | Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations--a natural consequence of cancers elevated mutation rate. Some passengers can be deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression that is described by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers meltdown. We find support for the model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to rationalize successes and failures of different treatment strategies. We find that a tumors load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by both current and future therapies. | 10.1073/pnas.1404341111 | biorxiv | 308 |
10.1101/003004 | Neanderthals had our de novo genes. | John Stewart Taylor; | John Stewart Taylor | Department of Biology, University of Victoria, Victoria, BC, Canada | 2014-02-25 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/25/003004.source.xml | Gene duplication provides a profusion of raw material for evolutionary innovation (Lynch and Conery, 2000). While most duplicates rapidly become unrecognizable some, e.g., those that are immediately useful or those that after a period of relaxed selection gain unique roles, are retained and thereby expand a genomes protein-coding repertoire. Ohno (1970) famously remarked that without gene duplication, the creation of metazoans, vertebrates, and mammals from unicellular organisms would have been impossible. Such big leaps in evolution, he argued, required the creation of new gene loci with previously nonexistent functions (Taylor and Raes, 2004). Recently, another source of new genes has been recognized: Though rare, it seems clear that new genes can emerge from formerly non-coding DNA, the de novo protein coding genes (Zhao et al., 2014, and references therein).\n\nIn 2009 Knowles ... | 10.1007/s00239-014-9628-x | biorxiv | 309 |
10.1101/003012 | Genetic drift opposes mutualism during spatial population expansion | Melanie JI Mueller;Beverly I Neugeboren;David R Nelson;Andrew W Murray; | Melanie JI Mueller | Harvard University | 2014-02-25 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/02/25/003012.source.xml | Mutualistic interactions benefit both partners, promoting coexistence and genetic diversity. Spatial structure can promote cooperation, but spatial expansions may also make it hard for mutualistic partners to stay together, since genetic drift at the expansion front creates regions of low genetic and species diversity. To explore the antagonism between mutualism and genetic drift, we grew cross-feeding strains of the budding yeast S. cerevisiae on agar surfaces as a model for mutualists undergoing spatial expansions. By supplying varying amounts of the exchanged nutrients, we tuned strength and symmetry of the mutualistic interaction. Strong mutualism suppresses genetic demixing during spatial expansions and thereby maintains diversity, but weak or asymmetric mutualism is overwhelmed by genetic drift even when mutualism is still beneficial, slowing growth and reducing diversity. Theoretical modeling using experimentally measured parameters predicts the size of demixed regions and how strong mutualism must be to survive a spatial expansion. | 10.1073/pnas.1313285111 | biorxiv | 310 |
10.1101/003095 | On a solution of the biodiversity paradox and a competitive coexistence principle | Lev V. Kalmykov;Vyacheslav L. Kalmykov; | Vyacheslav L. Kalmykov | Institute of Cell Biophysics of the Russian Academy of Sciences | 2014-02-27 | 1 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/02/27/003095.source.xml | The biodiversity paradox is the central problem in theoretical ecology. The paradox consists in the contradiction between the competitive exclusion principle and the observed biodiversity. This contradiction is the key subject of the long-standing and continuing biodiversity debates. The paradox impedes our insights into biodiversity conservation. Previously we proved that due to a soliton-like behaviour of population waves complete competitors can indefinitely coexist in one closed homogeneous habitat on one and the same limiting resource under constant conditions of environment, without any trade-offs and cooperations. As this fact violates the known formulations of the competitive exclusion principle we have reformulated the principle. Here we explain why this reformulation of the principle results in a solution of the biodiversity paradox. In addition, we generalize the competitive exclusion principle. Reasoning by contradiction, we formulate a generalized principle of competitive coexistence. These principles expand theoretical basis for biodiversity conservation and sustainable development. | NA | biorxiv | 312 |
10.1101/003061 | DNA methylation modulates transcription factor occupancy chiefly at sites of high intrinsic cell-type variability | Matthew Maurano;Hao Wang;Sam John;Anthony Shafer;Theresa Canfield;Kristen Lee;John A Stamatoyannopoulos; | Matthew Maurano | University of Washington | 2014-02-27 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/02/27/003061.source.xml | The nuclear genome of every cell harbors millions of unoccupied transcription factor (TF) recognition sequences that harbor methylated cytosines. Although DNA methylation is commonly invoked as a repressive mechanism, the extent to which it actively silences specific TF occupancy sites is unknown. To define the role of DNA methylation in modulating TF binding, we quantified the effect of DNA methyltransferase abrogation on the occupancy patterns of a ubiquitous TF capable of autonomous binding to its target sites in chromatin (CTCF). Here we show that the vast majority of unoccupied, methylated CTCF recognition sequences remain unbound upon depletion of DNA methylation. Rather, methylation-regulated binding is restricted to a small fraction of elements that exhibit high intrinsic variability in CTCF occupancy across cell types. Our results suggest that DNA methylation is not a major groundskeeper of genomic transcription factor occupancy landscapes, but rather a specialized mechanism for stabilizing epigenetically labile sites. | NA | biorxiv | 313 |
10.1101/003111 | Genomic Repeat Element Analyzer for Mammals (GREAM) | Darshan S Chandrashekar;Poulami Dey;Kshitish K Acharya; | Kshitish K Acharya | Institute of Bioinformatics and Applied Biotechnology (IBAB) | 2014-02-28 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/02/28/003111.source.xml | Background: Understanding the mechanism behind the transcriptional regulation of genes is still a challenge. Recent findings indicate that the genomic repeat elements (such as LINES, SINES and LTRs) could play an important role in the transcription control. Hence, it is important to further explore the role of genomic repeat elements in the gene expression regulation, and perhaps in other molecular processes. Although many computational tools exists for repeat element analysis, almost all of them simply identify and/or classifying the genomic repeat elements within query sequence(s); none of them facilitate identification of repeat elements that are likely to have a functional significance, particularly in the context of transcriptional regulation.\n\nResult: We developed the Genomic Repeat Element Analyzer for Mammals (GREAM) to allow gene-centric analysis of genomic repeat elements in 17 mammalian species, and validated it by comparing with some of the existing experimental data. The output provides a categorized list of the specific type of transposons, retro-transposons and other genome-wide repeat elements that are statistically over-represented across specific neighborhood regions of query genes. The position and frequency of these elements, within the specified regions, are displayed as well. The tool also offers queries for position-specific distribution of repeat elements within chromosomes. In addition, GREAM facilitates the analysis of repeat element distribution across the neighborhood of orthologous genes.\n\nConclusion: GREAM allows researchers to short-list the potentially important repeat elements, from the genomic neighborhood of genes, for further experimental analysis. GREAM is free and available for all at http://resource.ibab.ac.in/GREAM/ | NA | biorxiv | 314 |
10.1101/003137 | A novel inference of the fundamental biodiversity number for multiple immigration-limited communities | Champak Beeravolu Reddy;François Munoz;Pierre Couteron; | Champak Beeravolu Reddy | Centre de Biologie pour la Gestion des Populations | 2014-02-28 | 1 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/02/28/003137.source.xml | Neutral community theory postulates a fundamental quantity, {theta}, which reflects the species diversity on a regional scale. While the recent genealogical formulation of community dynamics has considerably enhanced quantitative neutral ecology, its inferential aspects have remained computationally prohibitive. Here, we make use of a generalized version of the original two-level hierarchical framework in order to define a novel estimator for{theta} ;, which proves to be computationally efficient and robust when tested on a wide range of simulated neutral communities. Estimating{theta} ; from field data is also illustrated using two tropical forest datasets consisting of spatially separated permanent field plots. Preliminary results also reveal that our inferred regional diversity parameter based on community dynamics may be linked to widely used ordination techniques in ecology. This paper essentially paves the way for future work dealing with the parameter inference of neutral communities with respect to their spatial scale and structure. | NA | biorxiv | 315 |
10.1101/003145 | High Bacterial Load Predicts Poor Outcomes in Patients with Idiopathic Pulmonary Fibrosis | Philip Molyneaux;Michael Cox;Saffron Willis-Owen;Kirsty Russell;Patrick Mallia;Anne-Marie Russell;Sebastian Johnston;Athol Wells;William Cookson;Toby Maher;Miriam Moffatt; | Philip Molyneaux | Imperial College | 2014-02-28 | 1 | New Results | cc_no | Microbiology | https://www.biorxiv.org/content/early/2014/02/28/003145.source.xml | BackgroundRepetitive alveolar damage and aberrant repair may be important in the development of the fatal condition Idiopathic Pulmonary Fibrosis (IPF). The role played by microorganisms in this cycle is unknown.\n\nMethodsWe consecutively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, non-smokers and subjects with moderate Chronic Obstructive Pulmonary Disease (COPD) as controls. Subjects underwent bronchoalveolar lavage (BAL) from which genomic DNA was isolated. The V3-V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA qPCR and pyrosequencing.\n\nResultsOur 65 IPF patients had 3.9x109 copies of the 16S rRNA gene per ml of BAL, two-fold more than the 1.8x109 copies in 44 sex- and smoking-matched controls (P<0.0001). Baseline BAL bacterial burden predicted Forced Vital Capacity (FVC) decline (P=0.02). Patients in the highest tertile of bacterial burden were at a higher risk of mortality compared to subjects in the lowest tertile (hazard ratio 4.59 (95% CI, 1.05-20); P=0.04).\n\nSequencing yielded 912,883 high quality reads from all subjects. Operational Taxonomic Units (OTUs) representing Haemophilus, Streptococcus, Neisseria and Veillonella were 1.5 to 3.5 fold more abundant in cases than controls (P<0.05). Regression analyses indicated that these specific OTUs as well as bacterial burden associated independently with IPF.\n\nConclusionsIPF is characterised by an increased bacterial burden in BAL that predicts decline in lung function and death. Clinical trials of antimicrobial therapy may determine if microbial burden is causal or not in IPF progression. | NA | biorxiv | 316 |
10.1101/003129 | A Genetic Screen Identifies Two Novel Rice Cysteine-rich Receptor-like Kinases That Are Required for the Rice NH1-mediated Immune Response | Mawsheng Chern;Rebecca Bart;Wei Bai;Deling Ruan;Wing Hoi Sze-To;Canlas Patrick;Rashmi Jain;Xuewei Chen;Pamela Ronald; | Pamela Ronald | UC Davis | 2014-02-28 | 1 | New Results | cc_no | Plant Biology | https://www.biorxiv.org/content/early/2014/02/28/003129.source.xml | Over-expression of rice NH1 (NH1ox), the ortholog of Arabidopsis NPR1, confers immunity to bacterial and fungal pathogens and induces the appearance of necrotic lesions due to activation of defense genes at the pre-flowering stage. This lesion-mimic phenotype can be enhanced by the application of benzothiadiazole (BTH). To identify genes regulating these responses, we screened a fast neutron-irradiated NH1ox rice population. We identified one mutant, called sn11 (suppressor of NH1-mediated lesion-mimic 1), which is impaired both in BTH-induced necrotic lesion formation and in the immune response. Using a comparative genome hybridization approach employing rice whole genome tiling array, we identified 11 genes associated with the sn11 phenotype. Transgenic analysis revealed that RNA interference of two of the genes, encoding previously uncharacterized cysteine-rich receptor-like kinases (CRK6 and CRK10), re-created the sn11 phenotype. Elevated expression of CRK10 using an inducible expression system resulted in enhanced immunity. Quantitative PCR revealed that BTH treatment and elevated levels of rice NH1 and its paralog NH3 induced expression of CRK10 and CRK6 RNA. These results indicate that CRK6 and CRK10 are required for the BTH-activated immune response mediated by NH1. | NA | biorxiv | 317 |
10.1101/003103 | Effect of alternating red and blue light irradiation generated by light emitting diodes on the growth of leaf lettuce | Akihiro Shimokawa;Yuki Tonooka;Misato Matsumoto;Hironori Ara;Hiroshi Suzuki;Naoki Yamauchi;Masayoshi Shigyo; | Masayoshi Shigyo | Faculty of Agriculture, Yamaguchi University | 2014-02-28 | 1 | New Results | cc_no | Plant Biology | https://www.biorxiv.org/content/early/2014/02/28/003103.source.xml | Because global climate change has made agricultural supply unstable, plant factories are expected to be a safe and stable means of food production. As the light source of a plant factory or controlled greenhouse, the light emitting diode (LED) is expected to solve cost problems and promote plant growth efficiently. In this study, we examined the light condition created by using monochromatic red and blue LEDs, to provide both simultaneous and alternating irradiation to leaf lettuce. The result was that simultaneous red and blue irradiation promoted plant growth more effectively than monochromatic and fluorescent light irradiation. Moreover, alternating red and blue light accelerated plant growth significantly even when the total light intensity per day was the same as with simultaneous irradiation. The fresh weight in altering irradiation was almost two times higher than with fluorescent light and about 1.6 times higher than with simultaneous irradiation. The growth-promoting effect of alternating irradiation of red and blue light was observed in different cultivars. From the results of experiments, we offer a novel plant growth method named \"Shigyo Method\", the core concept of which is the alternating irradiation of red and blue light. | NA | biorxiv | 318 |
10.1101/003152 | Complementation of a temperature sensitive Escherichia coli rpoD mutation using Lactobacillus sigma factors | James Winkler;Katy Kao; | Katy Kao | Texas A&M University | 2014-03-02 | 1 | New Results | cc_by_nc | Synthetic Biology | https://www.biorxiv.org/content/early/2014/03/02/003152.source.xml | Housekeeping sigma factors in the{sigma} 70 family, as components of the RNA polymerase holoenzyme, are responsible for regulating transcription of genes related to vegetative growth. While these factors are well understood in model organisms such as Escherichia coli and Bacillus subtilis, little experimental work has focused on the sigma factors in members of the Lactobacillus genus such as Lactobacillus brevis and Lactobacillus plantarum. This study evaluates the ability of putative{sigma} 70 proteins from L. brevis ([Formula]) and L. plantarum ([Formula]) to complement a temperature sensitive mutation in the E. coli 285c{sigma} 70 protein. This report is the first to show that these heterologous sigma factors were capable of restoring the viability of E. coli 285c for growth at 40-43.5 {degrees}C, indicating the [Formula] and [Formula] are capable of initiating transcription in a complex with the E. coli 285c RNA polymerase. These heterologous sigma factors may therefore be useful for improving biochemical knowledge of the sigma factor family or for use in the expression of hetereologous genomic libraries. | NA | biorxiv | 319 |
10.1101/003160 | Conditions for the validity of SNP-based heritability estimation | James J Lee;Carson C Chow; | Carson C Chow | NIDDK, NIH | 2014-03-04 | 2 | New Results | cc_by_nd | Genetics | https://www.biorxiv.org/content/early/2014/03/04/003160.source.xml | The heritability of a trait (h2) is the proportion of its population variance caused by genetic differences, and estimates of this parameter are important for interpreting the results of genome-wide association studies (GWAS). In recent years, researchers have adopted a novel method for estimating a lower bound on heritability directly from GWAS data that uses realized genetic similarities between nominally unrelated individuals. The quantity estimated by this method is purported to be the contribution to heritability that could in principle be recovered from association studies employing the given panel of SNPs [Formula] Thus far the validity of this approach has mostly been tested empirically. Here, we provide a mathematical explication and show that the method should remain a robust means of obtaining [Formula] under circumstances wider than those under which it has so far been derived. | 10.1007/s00439-014-1441-5 | biorxiv | 322 |
10.1101/003186 | Does ‘information control the living state’? | Rodrick Wallace; | Rodrick Wallace | The New York State Psychiatric Institute | 2014-03-04 | 1 | New Results | cc_by_nc_nd | Biophysics | https://www.biorxiv.org/content/early/2014/03/04/003186.source.xml | We generalize the recently-uncovered Data Rate Theorem in the context of cognitive systems having a dual information source, including those of the living state that is particularly characterized by cognition at every scale and level of organization. The unification of information theory and control theory via the Data Rate Theorem is not additive, but synergistic, generating new statistical tools that greatly constrain the possible dynamics of that state. Thus, in addition to providing novel conceptual approaches, this emerging body of theory permits construction of models that, like those of regression analysis, can provide benchmarks against which to compare experimental or observational data. | NA | biorxiv | 323 |
10.1101/003210 | Detecting translational regulation by change point analysis of ribosome profiling datasets | Anze Zupanic;Catherine Meplan;Sushma N Grellscheid;John C Mathers;Tom BL Kirkwood;John E Hesketh;Daryl P Shanley; | Daryl P Shanley | Institute for Ageing and Health, Newcastle University | 2014-03-05 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/03/05/003210.source.xml | Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While ribosome density is constant along the length of the mRNA coding region, it can be altered by translational regulatory events. In this study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modelling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq dataset obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artefacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g. premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new gene isoforms. | 10.1261/rna.045286.114 | biorxiv | 324 |
10.1101/003228 | Meteorological conditions influence short-term survival and dispersal in a reinforced long-lived bird population. | Loïc A Hardouin;Alexandre Robert;Marie Nevoux;Olivier Gimenez;Frederic Lacroix;Yves Hingrat; | Lo?c A Hardouin | Centre d?Ecologie et des Sciences de la COnservation | 2014-03-05 | 1 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/03/05/003228.source.xml | O_LIA high immediate mortality rate of released animals is an important cause of translocation failure (\"release cost\"). Post-release dispersal (i.e. the movements from the release site to the first breeding site) has recently been identified as another source of local translocation failure. In spite of their potential effects on conservation program outcomes, little is known about the quantitative effects of these two sources of translocation failure and their interactions with environmental factors and management designs.\nC_LIO_LIBased on long-term monitoring data of captive-bred North African houbara bustards (hereafter, houbaras) over large spatial scales, we investigated the relative effects of release (e.g., release group size, period of release), individual (e.g., sex and body condition) and meteorological (e.g., temperature and rainfall) conditions on post-release survival (N = 957 houbaras) and dispersal (N = 436 houbaras).\nC_LIO_LIWe found that (i) rainfall and ambient air temperature had respectively a negative and a positive effect on houbara post-release dispersal distance, (ii) in interaction with the release period, harsh meteorological conditions had negative impact on the survival of houbaras, (iii) density dependent processes influenced the pattern of departure from the release site and (iv) post-release dispersal distance was male-biased, as natal dispersal of wild birds (although the dispersal patterns and movements may be influenced by different processes in captive-bred and in wild birds).\nC_LIO_LISynthesis and applications. Overall, our results demonstrate that post-release dispersal and mortality costs in translocated species may be mediated by meteorological factors, which in turn can be buffered by the release method. As the consequences of translocation programs on population dynamics depend primarily upon release costs and colonisation process, we suggest that their potential interactions with meteorological conditions be carefully addressed in future programs.\nC_LI | 10.1111/1365-2664.12302 | biorxiv | 325 |
10.1101/003202 | TCF7L2 is a master regulator of insulin production and processing | Yuedan Zhou;Soo-Young Park;Jing Su;Kathleen Bailey;Emilia Ottosson-Laakso;Liliya Shcerbina;Nikolay Oskolkov;Enming Zhang;Thomas Thevenin;Jo?o Fadista;Hedvig Bennet;Petter Vikman;Nils Wierup;Malin Fex;Johan Rung;Claes Wollheim;Marcelo Nobrega;Erik Renstr?m;Leif Groop;Ola Hansson; | Ola Hansson | Lund University | 2014-03-05 | 1 | New Results | cc_no | Cell Biology | https://www.biorxiv.org/content/early/2014/03/05/003202.source.xml | Although variants in the T-cell factor 7-like 2 gene (TCF7L2) confer the strongest risk of type 2 diabetes (T2D) by presumed effects on islet function, the underlying mechanisms are not well understood. We have identified TCF7L2-target genes and described the regulatory network downstream of TCF7L2 responsible for its effect on insulin secretion in rodents and human pancreatic islets. ISL1 is a direct target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1 and PCSK2 and possibly clearance of proinsulin via SLC30A8. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2, but also processing and possibly clearance of proinsulin and insulin in a genotype dependent manner. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing the strongest association with T2D. | 10.1093/hmg/ddu359 | biorxiv | 327 |
10.1101/003236 | Characterization of directed differentiation by high-throughput single-cell RNA-Seq | Magali Soumillon;Davide Cacchiarelli;Stefan Semrau;Alexander van Oudenaarden;Tarjei S Mikkelsen; | Tarjei S Mikkelsen | Broad Institute | 2014-03-05 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/03/05/003236.source.xml | Directed differentiation of cells in vitro is a powerful approach for dissection of developmental pathways, disease modeling and regenerative medicine, but analysis of such systems is complicated by heterogeneous and asynchronous cellular responses to differentiation-inducing stimuli. To enable deep characterization of heterogeneous cell populations, we developed an efficient digital gene expression profiling protocol that enables surveying of mRNA in thousands of single cells at a time. We then applied this protocol to profile 12,832 cells collected at multiple time points during directed adipogenic differentiation of human adipose-derived stem/stromal cells in vitro. The resulting data reveal the major axes of cell-to-cell variation within and between time points, and an inverse relationship between inflammatory gene expression and lipid accumulation across cells from a single donor. | NA | biorxiv | 328 |
10.1101/003244 | An Analysis of Cochlear Implant Distortion from a User's Perspective | Barry David Jacobson; | Barry David Jacobson | Massachusetts Institute of Technology | 2014-03-09 | 2 | New Results | cc_by_nc_nd | Bioengineering | https://www.biorxiv.org/content/early/2014/03/09/003244.source.xml | We describe our first-hand experience with a cochlear implant (CI), being both a recent recipient and a hearing researcher. We note the promising loudness, but very unpleasant distortion, which makes understanding speech difficult in many environments, including in noise, on the phone or through the radio. We also discuss the extreme unpleasantness of music, which makes recognizing familiar melodies very difficult. We investigate the causes of the above problems through mathematical analysis and computer simulations of sound mixtures, and find that surprisingly, the culprit appears to be non-biological in origin, but primarily due to the envelope-based signal processing algorithms currently used. This distortion is generated before the signal even enters the cochlea. Hence, the long-held belief that inter-electrode interference or current spreading is the cause, appears incorrect. We explain that envelope processing may have been originally instituted based on an inaccurate understanding of the role of place coding vs. temporal coding, or alternatively, because of an incorrect analogy to radio modulation theory. On the basis of our analysis, we suggest immediate concrete steps, some possibly in firmware alone, that may lead to a much improved experience. | NA | biorxiv | 330 |
10.1101/003244 | An Analysis of Cochlear Implant Distortion from a User’s Perspective | Barry David Jacobson; | Barry David Jacobson | Massachusetts Institute of Technology | 2014-03-11 | 3 | New Results | cc_by_nc_nd | Bioengineering | https://www.biorxiv.org/content/early/2014/03/11/003244.source.xml | We describe our first-hand experience with a cochlear implant (CI), being both a recent recipient and a hearing researcher. We note the promising loudness, but very unpleasant distortion, which makes understanding speech difficult in many environments, including in noise, on the phone or through the radio. We also discuss the extreme unpleasantness of music, which makes recognizing familiar melodies very difficult. We investigate the causes of the above problems through mathematical analysis and computer simulations of sound mixtures, and find that surprisingly, the culprit appears to be non-biological in origin, but primarily due to the envelope-based signal processing algorithms currently used. This distortion is generated before the signal even enters the cochlea. Hence, the long-held belief that inter-electrode interference or current spreading is the cause, appears incorrect. We explain that envelope processing may have been originally instituted based on an inaccurate understanding of the role of place coding vs. temporal coding, or alternatively, because of an incorrect analogy to radio modulation theory. On the basis of our analysis, we suggest immediate concrete steps, some possibly in firmware alone, that may lead to a much improved experience. | NA | biorxiv | 331 |
10.1101/003285 | Alignathon: A competitive assessment of whole genome alignment methods. | Dent Earl;Ngan K Nguyen;Glenn Hickey;Robert S. Harris;Stephen Fitzgerald;Kathryn Beal;Igor Seledtsov;Vladimir Molodtsov;Brian Raney;Hiram Clawson;Jaebum Kim;Carsten Kemena;Jia-Ming Chang;Ionas Erb;Alexander Poliakov;Minmei Hou;Javier Herrero;Victor Solovyev;Aaron E. Darling;Jian Ma;Cedric Notredame;Michael Brudno;Inna Dubchak;David Haussler;Benedict Paten; | Benedict Paten | University of California, Santa Cruz | 2014-03-10 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/03/10/003285.source.xml | BackgroundMultiple sequence alignments (MSAs) are a prerequisite for a wide variety of evolutionary analyses. Published assessments and benchmark datasets for protein and, to a lesser extent, global nucleotide MSAs are available, but less effort has been made to establish benchmarks in the more general problem of whole genome alignment (WGA).\n\nResultsUsing the same model as the successful Assemblathon competitions, we organized a competitive evaluation in which teams submitted their alignments, and assessments were performed collectively after all the submissions were received. Three datasets were used: two of simulated primate and mammalian phylogenies, and one of 20 real fly genomes. In total 35 submissions were assessed, submitted by ten teams using 12 different alignment pipelines.\n\nConclusionsWe found agreement between independent simulation-based and statistical assessments, indicating that there are substantial accuracy differences between contemporary alignment tools. We saw considerable difference in the alignment quality of differently annotated regions, and found few tools aligned the duplications analysed. We found many tools worked well at shorter evolutionary distances, but fewer performed competitively at longer distances. We provide all datasets, submissions and assessment programs for further study, and provide, as a resource for future benchmarking, a convenient repository of code and data for reproducing the simulation assessments. | 10.1101/gr.174920.114 | biorxiv | 333 |
10.1101/003293 | Distinct structural transitions of chromatin topological domains coordinate hormone-induced gene regulation | François Le Dily;Davide Baù;Andy Pohl;Guillermo P. Vicent;Daniel Soronellas;Giancarlo Castellano;François Serra;Roni H. G. Wright;Cecilia J. Ballare;Guillaume Filion;Marc A. Marti-Renom;Miguel Beato; | Miguel Beato | Centre de Regulaci? Gen?mica (CRG) | 2014-03-13 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/03/13/003293.source.xml | The human genome is segmented into Topologically Associating Domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we described the distribution of Progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-Seq, Hi-C and 3D modelling techniques, we found that the borders of the [~]2,000 TADs in these cells are largely maintained after hormone treatment but that some TADs operate as discrete regulatory units in which the majority of the genes are either transcriptionally activated or repressed upon hormone stimulus. The epigenetic signatures of the TADs are coordinately modified by hormone in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs. In response to hormone activated TADs exhibit higher density of internal contacts, while repressed TADs show less intra-TAD contacts. Integrative 3D modelling revealed that TADs structurally expanded if activated and compacted when repressed, and that this is accompanied by differential changes in their global accessibility. We thus propose that TADs function as \"regulons\" to enable spatially proximal genes to be coordinately transcribed in response to hormones. | 10.1101/gad.241422.114 | biorxiv | 335 |
10.1101/003335 | Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems | Melissa K Takahashi;James Chappell;Clarmyra A Hayes;Zachary Z Sun;Vipul Singhal;Kevin J Spring;Shaima Al-Khabouri;Christopher P Fall;Vincent Noireaux;Richard M Murray;Julius B Lucks; | Julius B Lucks | Cornell University | 2014-03-18 | 2 | New Results | cc_by_nc_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2014/03/18/003335.source.xml | RNA regulators are emerging as powerful tools to engineer synthetic genetic networks or rewire existing ones. A potential strength of RNA networks is that they may be able to propagate signals on timescales that are set by the fast degradation rates of RNAs. However, a current bottleneck to verifying this potential is the slow design-build-test cycle of evaluating these networks in vivo. Here we adapt an Escherichia coli-based cell-free transcription-translation (TX-TL) system for rapidly prototyping RNA networks. We used this system to measure the response time of an RNA transcription cascade to be approximately five minutes per step of the cascade. We also show that this response time can be adjusted with temperature and regulator threshold response tuning. Finally we use TX-TL to prototype a new RNA network, an RNA single input module, and show that this network temporally stages the expression of two genes in vivo. | 10.1021/sb400206c | biorxiv | 338 |
10.1101/003327 | Measuring error rates in genomic perturbation screens: gold standards for human functional genomics | Traver Hart;Kevin R Brown;Fabrice Sircoulomb;Robert Rottapel;Jason Moffat; | Jason Moffat | University of Toronto | 2014-03-17 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/03/17/003327.source.xml | Technological advancement has opened the door to systematic genetics in mammalian cells. Genome-scale loss-of-function screens can assay fitness defects induced by partial gene knockdown, using RNA interference, or complete gene knockout, using new CRISPR techniques. These screens can reveal the basic blueprint required for cellular proliferation. Moreover, comparing healthy to cancerous tissue can uncover genes that are essential only in the tumor; these genes are targets for the development of specific anticancer therapies. Unfortunately, progress in this field has been hampered by offtarget effects of perturbation reagents and poorly quantified error rates in large-scale screens. To improve the quality of information derived from these screens, and to provide a framework for understanding the capabilities and limitations of CRISPR technology, we derive gold-standard reference sets of essential and nonessential genes, and provide a Bayesian classifier of gene essentiality that outperforms current methods on both RNAi and CRISPR screens. Our results indicate that CRISPR technology is more sensitive than RNAi, and that both techniques have nontrivial false discovery rates that can be mitigated by rigorous analytical methods. | 10.15252/msb.20145216 | biorxiv | 339 |
10.1101/003376 | Analysis of stop-gain and frameshift variants in human innate immunity genes | Antonio Rausell;Pejman Mohammadi;Paul J McLaren;Ioannis Xenarios;Jacques Fellay;Amalio Telenti; | Amalio Telenti | University Hospital of Lausanne and University of Lausanne | 2014-03-17 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/03/17/003376.source.xml | Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to the innate immunity genes we first evaluated 17764 stop-gain and 13915 frameshift variants from the NHLBI Exome Sequencing Project and 1000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and non-sense mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. | 10.1371/journal.pcbi.1003757 | biorxiv | 340 |
10.1101/003350 | Horizontal Transfers and Gene Losses in the phospholipid pathway of Bartonella reveal clues about early ecological niches | Qiyun Zhu;Michael Kosoy;Kevin J Olival;Katharina Dittmar; | Katharina Dittmar | University at Buffalo, State University of New York | 2014-03-17 | 1 | New Results | cc_by_nc_nd | Microbiology | https://www.biorxiv.org/content/early/2014/03/17/003350.source.xml | Bartonellae are mammalian pathogens vectored by blood-feeding arthropods. Although of increasing medical importance, little is known about their ecological past, and host associations are underexplored. Previous studies suggest an influence of horizontal gene transfers in ecological niche colonization by acquisition of host pathogenicity genes. We here expand these analyses to metabolic pathways of 28 Bartonella genomes, and experimentally explore the distribution of bartonellae in 21 species of blood-feeding arthropods. Across genomes, repeated gene losses and horizontal gains in the phospholipid pathway were found. The evolutionary timing of these patterns suggests functional consequences likely leading to an early intracellular lifestyle for stem bartonellae. Comparative phylogenomic analyses discover three independent lineage-specific reacquisitions of a core metabolic gene - NAD(P)H-dependent glycerol-3-phosphate dehydrogenase (gpsA) - from Gammaproteobacteria and Epsilonproteobacteria. Transferred genes are significantly closely related to invertebrate Arsenophonus-, and Serratia-like endosymbionts, and mammalian Helicobacter-like pathogens, supporting a cellular association with arthropods and mammals at the base of extant bartonellae. Our studies suggest that the horizontal re-aquisitions had a key impact on bartonellae lineage specific ecological and functional evolution. | 10.1093/gbe/evu169 | biorxiv | 341 |
10.1101/003368 | Hydrogen peroxide thermochemical oscillator as driver for primordial RNA replication | Rowena Ball;John Brindley; | Rowena Ball | The Australian National University | 2014-03-17 | 1 | New Results | cc_by_nc_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2014/03/17/003368.source.xml | This paper presents and tests a previously unrecognised mechanism for driving a replicating molecular system on the prebiotic earth. It is proposed that cell-free RNA replication in the primordial soup may have been driven by self-sustained oscillatory thermochemical reactions. To test this hypothesis a well-characterised hydrogen peroxide oscillator was chosen as the driver and complementary RNA strands with known association and melting kinetics were used as the substrate. An open flow system model for the self-consistent, coupled evolution of the temperature and concentrations in a simple autocatalytic scheme is solved numerically, and it is shown that thermochemical cycling drives replication of the RNA strands. For the (justifiably realistic) values of parameters chosen for the simulated example system, the mean amount of replicant produced at steady state is 6.56 times the input amount, given a constant supply of substrate species. The spontaneous onset of sustained thermochemical oscillations via slowly drifting parameters is demonstrated, and a scheme is given for prebiotic production of complementary RNA strands on rock surfaces. | 10.1098/rsif.2013.1052 | biorxiv | 347 |
10.1101/003384 | Metabolic free energy and deterministic-but-for-error biological codes: a ‘Data Rate Theorem’ aging model | Rodrick Wallace; | Rodrick Wallace | New York State Psychiatric Institute | 2014-03-17 | 1 | New Results | cc_by_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/03/17/003384.source.xml | The living state is cognitive at every scale and level of organization. Since it is possible to associate a broad class of cognitive processes with dual information sources, many pathologies can be addressed using statistical models based on the Shannon Coding, the Shannon-McMillan Source Coding, the Rate Distortion, and the Data Rate Theorems, as these impose powerful necessary condition constraints on information generation and exchange, and on system control. Deterministic-but-for-error biological codes do not directly invoke cognition, although they may be essential subcomponents within larger cognitive processes. A formal argument, however, places such codes within a similar framework, with metabolic free energy serving as a control signal stabilizing biochemical code-and-translator dynamics in the presence of noise. Demand beyond available energy supply then expresses itself in punctuated destabilization of the coding channel, affecting a spectrum of essential biological functions. Aging, normal or prematurely driven by psychosocial or environmental stressors, must eventually interfere with the routine operation of such mechanisms, triggering chronic diseases associated with senescence. Amyloid fibril formation, intrinsically disordered protein logic gates, and cell surface glycan/lectin kelp bed logic gates are reviewed from this perspective. The results, however, generalize beyond coding systems having easily recognizable symmetry modes. | 10.1007/s11538-014-0013-0 | biorxiv | 348 |
10.1101/003459 | Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation | Ashley P Ng;Maria Kauppi;Donald Metcalf;Craig D Hyland;Emma C Josefsson;Marion Lebois;Jian-Guo Zhang;Ladina Di Rago;Tracey Baldwin;Douglas J Hilton;Warren S Alexander; | Ashley P Ng | The Walter and Eliza Hall Institute of Medical Research | 2014-03-19 | 1 | New Results | cc_no | Cell Biology | https://www.biorxiv.org/content/early/2014/03/19/003459.source.xml | Thrombopoietin (TPO) acting via its receptor Mpl is the major cytokine regulator of platelet number. To precisely define the role of specific hematopoietic cells in TPO dependent hematopoiesis, we generated mice that express the Mpl receptor normally on stem/progenitor cells but lack expression on megakaryocytes and platelets (MplPF4cre/PF4cre). MplPF4cre/PF4cre mice displayed profound megakaryocytosis and thrombocytosis with a remarkable expansion of megakaryocyte-committed and multipotential progenitor cells, the latter displaying biological responses and a gene expression signature indicative of chronic TPO over-stimulation as the underlying causative mechanism, despite a normal circulating TPO level. Thus, TPO signaling in megakaryocytes is dispensable for platelet production; its key role in control of platelet number is via generation and stimulation of the bipotential megakaryocyte precursors. Nevertheless, Mpl expression on megakaryocytes and platelets is essential to prevent megakaryocytosis and myeloproliferation by restricting the amount of TPO available to stimulate the production of megakaryocytes from the progenitor cell pool.\n\nSignificance statementBlood platelets, the small circulating cells that co-ordinate hemostasis, are produced by specialized bone marrow cells called megakaryocytes. The cytokine thrombopoietin (TPO) is a key regulator of platelet production acting via its specific cell receptor, Mpl. Via genetic modification of the Mpl allele in mice, we precisely define the bone marrow cells that express Mpl and, by genetically removing Mpl from megakaryocytes and platelets, we show TPO signaling via Mpl is not required in megakaryocytes for their expansion, maturation or platelet production. Rather, Mpl expression on megakaryocytes is essential for regulating TPO availability in the bone marrow microenvironment to prevent myeloproliferation, a model we suggest is important for human disease. | 10.1073/pnas.1404354111 | biorxiv | 349 |
10.1101/003442 | The Role of Migration in the Evolution of Phenotypic Switching | Oana Carja;Robert E Furrow;Marc W Feldman; | Oana Carja | Stanford University | 2014-03-19 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/03/19/003442.source.xml | Stochastic switching is an example of phenotypic bet-hedging, where an individual can switch between different phenotypic states in a fluctuating environment. Although the evolution of stochastic switching has been studied when the environment varies temporally, there has been little theoretical work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here we use a population genetic model to explore the interaction of temporal and spatial variation in the evolutionary dynamics of phenotypic switching. We find that spatial variation in selection is important; when selection pressures are similar across space, migration can decrease the rate of switching, but when selection pressures differ spatially, increasing migration between demes can facilitate the evolution of higher rates of switching. These results may help explain the diverse array of non-genetic contributions to phenotypic variability and phenotypic inheritance observed in both wild and experimental populations. | 10.1098/rspb.2014.1677 | biorxiv | 350 |
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