doi
stringlengths 14
25
| title
stringlengths 6
470
| authors
stringlengths 5
600
| author_corresponding
stringlengths 0
49
| author_corresponding_institution
stringlengths 0
160
| date
stringlengths 10
10
| version
stringclasses 24
values | type
stringclasses 9
values | license
stringclasses 10
values | category
stringclasses 59
values | jatsxml
stringlengths 66
77
| abstract
stringlengths 0
28.9k
| published
stringlengths 0
59
| server
stringclasses 1
value | __index_level_0__
int64 0
312k
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
10.1101/007914 | A quantitative analysis of objective feather colour assessment: measurements in the lab are more reliable than in the field | Iker Vaquero-Alba;Andrew McGowan;Daniel Pincheira-Donoso;Matthew R. Evans;Sasha R.X. Dall; | Iker Vaquero-Alba | University of Exeter | 2014-08-13 | 2 | New Results | cc_by | Animal Behavior and Cognition | https://www.biorxiv.org/content/early/2014/08/13/007914.source.xml | The evolution of animal colouration is importantly driven by sexual selection operating on traits used to transmit information to rivals and potential mates, which therefore, have major impacts on fitness. Reflectance spectrometry has become a standard colour-measuring tool, especially after the discovery of tetrachromacy in birds and their ability to detect UV. Birds plumage patterns may be invisible to humans, necessitating a reliable and objective way of assessing colouration not dependent on human vision. Plumage colouration measurements can be taken directly on live birds in the field or in the lab (e.g. on collected feathers). Therefore, it is essential to determine which sampling method yields more repeatable and reliable measures, and which of the available quantitative approaches best assess the repeatability of these measures. Using a spectrophotometer, we measured melanin-based colouration in barn swallows (Hirundo rustica) plumage. We assessed the repeatability of measures obtained with both traditional sampling methods separately to quantitatively determine their reliability. We used the ANOVA-based method for calculating the repeatability of measurements from two years separately, and the GLMM-based method to calculate overall adjusted repeatabilities for both years. We repeated the assessment for the whole reflectance spectrum range and only the human-visible part, to assess the influence of the UV component on the reliabilities of sampling methodologies. Our results reveal very high repeatability for lab measurements and a lower, still moderate to high repeatability, for field measurements. Both increased when limited to only the human-visible part, for all plumage patches except the throat, where we observed the opposite trend. Repeatability between sampling methods was quite low including the whole spectrum, but moderate including only the human-visible part. Our results suggest higher reliability for measurements in the lab and higher power and accuracy of the GLMM-based method. They also suggest UV reflectance differences amongst different plumage patches. | NA | biorxiv | 829 |
10.1101/007963 | RNA-Rocket: An RNA-Seq Analysis Resource for Infectious Disease Research | Andrew S. Warren;Cristina Aurrecoechea;Brian Brunk;Prerak Desai;Scott Emrich;Gloria I. Giraldo-Calderón;Omar Harb;Deborah Hix;Daniel Lawson;Dustin Machi;Chunhong Mao;Michael McClelland;Eric Nordberg;Maulik Shukla;Leslie B. Vosshall;Alice R. Wattam;Rebecca Will;Hyun Seung Yoo;Bruno Sobral; | Andrew S. Warren | Virginia Tech | 2014-08-14 | 2 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/14/007963.source.xml | MotivationRNA-Seq is a method for profiling transcription using high-throughput sequencing and is an important component of many research projects that wish to study transcript isoforms, condition specific expression, and transcriptional structure. The methods, tools, and technologies employed to perform RNA-Seq analysis continue to change, creating a bioinformatics challenge for researchers who wish to exploit these data. Resources that bring together genomic data, analysis tools, educational material, and computational infrastructure can minimize the overhead required of life science researchers.\n\nResultsRNA-Rocket is a free service that provides access to RNA-Seq and ChIP-Seq analysis tools for studying infectious diseases. The site makes available thousands of pre-indexed genomes, their annotations, and the ability to stream results to the bioinformatics resources VectorBase, EuPathDB, and PATRIC. The site also provides a combination of experimental data and metadata, examples of pre-computed analysis, step-by-step guides, and a user interface designed to enable both novice and experienced users of RNA-Seq data.\n\nAvailability: RNA-Rocket can be found at rnaseq.pathogenportal.org Source code for this project can be found at github.com/cidvbi/PathogenPortal | 10.1093/bioinformatics/btv002 | biorxiv | 831 |
10.1101/007948 | The importance of study design for detecting differentially abundant features in high-throughput experiments | Huaien Luo;Juntao Li;Kuan Hui Burton Chia;Paul Robson;Niranjan Nagarajan; | Niranjan Nagarajan | Genome Institute of Singapore | 2014-08-14 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/14/007948.source.xml | The use of high-throughput experiments, such as RNA-seq, to simultaneously identify differentially abundant entities across conditions has become widespread, but the systematic planning of such studies is currently hampered by the lack of general-purpose tools to do so. Here we demonstrate that there is substantial variability in performance across statistical tests, normalization techniques and study conditions, potentially leading to significant wastage of resources and/or missing information in the absence of careful study design. We present a broadly applicable experimental design tool called EDDA, and the first for single-cell RNA-seq, Nanostring and Metagenomic studies, that can be used to i) rationally choose from a panel of statistical tests, ii) measure expected performance for a study and iii) plan experiments to minimize mis-utilization of valuable resources. Using case studies from recent single-cell RNA-seq, Nanostring and Metagenomics studies, we highlight its general utility and, in particular, show a) the ability to correctly model single-cell RNA-seq data and do comparisons with 1/5th the amount of sequencing currently used and b) that the selection of suitable statistical tests strongly impacts the ability to detect biomarkers in Metagenomic studies. Furthermore, we demonstrate that a novel mode-based normalization employed in EDDA uniformly improves in robustness over existing approaches (10-20%) and increases precision to detect differential abundance by up to 140%. | 10.1186/s13059-014-0527-7 | biorxiv | 832 |
10.1101/008003 | Assembling Large Genomes with Single-Molecule Sequencing and Locality Sensitive Hashing | Konstantin Berlin;Sergey Koren;Chen-Shan Chin;James Drake;Jane M Landolin;Adam M Phillippy; | Sergey Koren | National Biodefense Analysis and Countermeasures Center | 2014-08-14 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/14/008003.source.xml | We report reference-grade de novo assemblies of four model organisms and the human genome from single-molecule, real-time (SMRT) sequencing. Long-read SMRT sequencing is routinely used to finish microbial genomes, but the available assembly methods have not scaled well to larger genomes. Here we introduce the MinHash Alignment Process (MHAP) for efficient overlapping of noisy, long reads using probabilistic, locality-sensitive hashing. Together with Celera Assembler, MHAP was used to reconstruct the genomes of Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana, Drosophila melanogaster, and human from high-coverage SMRT sequencing. The resulting assemblies include fully resolved chromosome arms and close persistent gaps in these important reference genomes, including heterochromatic and telomeric transition sequences. For D. melanogaster, MHAP achieved a 600-fold speedup relative to prior methods and a cloud computing cost of a few hundred dollars. These results demonstrate that single-molecule sequencing alone can produce near-complete eukaryotic genomes at modest cost. | 10.1038/nbt.3238 | biorxiv | 833 |
10.1101/007930 | How cultural transmission facilitates a long juvenile learning period | Ryan Baldini; | Ryan Baldini | UC Davis | 2014-08-14 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/14/007930.source.xml | The evolution of the long, slow human life history is a major challenge to evolutionary biologists. A compelling theory states that our late age at maturity allows us to acquire the many skills needed to survive in the economically intensive human foraging niche. Cultural transmission may be a crucial part of this process, by exposing learners to a wealth of information and skills that they would otherwise not likely discover. I use mathematical models to show that whether cultural transmission allows a later age at maturity depends on the details of selection and population regulation. In particular, cultural transmission appears to readily allow a later age at maturity under density-dependent fertility, but may not under density-dependent mortality or density-independent population growth. I close with a discussion of possibilities for future theoretical and empirical research. | NA | biorxiv | 834 |
10.1101/007955 | A Distance Method to Reconstruct Species Trees In the Presence of Gene Flow | Lingfei Cui;Laura Kubatko; | Laura Kubatko | The Ohio State University | 2014-08-14 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/14/007955.source.xml | One of the central tasks in evolutionary biology is to reconstruct the evolutionary relationships among species from sequence data, particularly from multilocus data. In the last ten years, many methods have been proposed to use the variance in the gene histories to estimate species trees by explicitly modeling deep coalescence. However, gene flow, another process that may produce gene history variance, has been less studied. In this paper, we propose a simple yet innovative method for species trees estimation in the presence of gene flow. Our method, called STEST (Species Tree Estimation from Speciation Times), constructs species tree estimates from pairwise speciation time or species divergence time estimates. By using methods that estimate speciation times in the presence of gene flow, (for example, M1 (Yang 2010) or SIM3s (Zhu and Yang 2012)), STEST is able to estimate species trees from data subject to gene flow. We develop two methods, called STEST (M1) and STEST (SIM3s), for this purpose. Additionally, we consider the method STEST (M0), which instead uses the M0 method (Yang 2002), a coalescent-based method that does not assume gene flow, to estimate speciation times. It is therefore devised to estimate species trees in the absence of gene flow. Our simulation studies show that STEST (M0) outperforms STEST(M1), STEST (SIM3s) and STEM in terms of estimation accuracy and outperfroms *BEAST in terms of running time when the degree of gene flow is small. STEST (M1) outperforms STEST (M0), STEST (SIM3s), STEM and *BEAST in term of estimation accuracy when the degree of gene flow is large. An empirical data set analyzed by these methods gives species tree estimates that are consistent with the previous results. | NA | biorxiv | 835 |
10.1101/007849 | A codon model of nucleotide substitution with selection on synonymous codon usage | Laura Kubatko;Premal Shah;Radu Herbei;Michael Gilchrist; | Laura Kubatko | The Ohio State University | 2014-08-12 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/12/007849.source.xml | The quality of phylogenetic inference made from protein-coding genes depends, in part, on the realism with which the codon substitution process is modeled. Here we propose a new mechanistic model that combines the standard M0 substitution model of Yang (1997) with a simplified model from Gilchrist (2007) that includes selection on synonymous substitutions as a function of codon-specific nonsense error rates. We tested the newly proposed model by applying it to 104 protein-coding genes in brewer's yeast, and compared the fit of the new model to the standard M0 model and to the mutation-selection model of Yang and Nielsen (2008) using the AIC. Our new model provided significantly better fit in approximately 85% of the cases considered for the basic M0 model and in approximately 25% of the cases for the M0 model with estimated codon frequencies, but only in a few cases when the mutation-selection model was considered. However, our model includes a parameter that can be interpreted as a measure of the rate of protein production, and the estimates of this parameter were highly correlated with an independent measure of protein production for the yeast genes considered here. Finally, we found that in some cases the new model led to the preference of a different phylogeny for a subset of the genes considered, indicating that substitution model choice may have an impact on the estimated phylogeny. | 10.1016/j.ympev.2015.08.026 | biorxiv | 836 |
10.1101/008011 | Estimating strength of polygenic selection with principal components analysis of spatial genetic variation | Davide Piffer; | Davide Piffer | Ulster Institute for Social Research | 2014-08-14 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/08/14/008011.source.xml | Principal components analysis on allele frequencies for 14 and 50 populations (from 1K Genomes and ALFRED databases) produced a factor accounting for over half of the variance, which indicates selection pressure on intelligence or genotypic IQ. Very high correlations between this factor and phenotypic IQ, educational achievement were observed (r>0.9 and r>0.8), also after partialling out GDP and the Human Development Index. Regression analysis was used to estimate a genotypic (predicted) IQ also for populations with missing data for phenotypic IQ. Socio-economic indicators (GDP and Human Development Index) failed to predict residuals, not providing evidence for the effects of environmental factors on intelligence. Another analysis revealed that the relationship between IQ and the genotypic factor was not mediated by race, implying that it exists at a finer resolution, a finding which in turn suggests selective pressures postdating sub-continental population splits.\n\nGenotypic height and IQ were inversely correlated but this correlation was mostly mediated by race. In at least two cases (Native Americans vs East Asians and Africans vs Papuans) genetic distance inferred from evolutionarily neutral genetic markers contrasts markedly with the resemblance observed for IQ and height increasing alleles.\n\nA principal component analysis on a random sample of 20 SNPs revealed two factors representing genetic relatedness due to migrations. However, the correlation between IQ and the intelligence PC was not mediated by them. In fact, the intelligence PC emerged as an even stronger predictor of IQ after entering the \"migratory\" PCs in a regression, indicating that it represents selection pressure instead of migrational effects.\n\nFinally, some observations on the high IQ of Mongoloid people are made which lend support to the \"cold winters theory\" on the evolution of intelligence. | NA | biorxiv | 837 |
10.1101/007898 | Facile semi-automated forensic body fluid identification by multiplex solution hybridization of NanoString® barcode probes to specific mRNA targets | Patrick Danaher;Robin Lynn White;Erin Hanson;Jack Ballantyne; | Jack Ballantyne | University of Central Florida, National Center for Forensic Science | 2014-08-12 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/08/12/007898.source.xml | A DNA profile from the perpetrator does not reveal, per se, the circumstances by which it was transferred. Body fluid identification by mRNA profiling may allow extraction of contextual 'activity level' information from forensic samples. Here we describe the development of a prototype multiplex digital gene expression (DGE) method for forensic body fluid/tissue identification based upon solution hybridization of color-coded NanoString(R) probes to 23 tissue/body fluid specific mRNA targets. The body fluids/tissues targeted were peripheral blood, semen, saliva, vaginal secretions, menstrual blood and skin. We tested and compared a simple 5 minute room temperature cellular lysis protocol against standard RNA isolation from same source material as a means to facilitate ease-of-use in forensic sample processing. We first describe a model for gene expression in a sample from a single body fluid and then extend that model to mixtures of body fluids. We then describe calculation of maximum likelihood estimates (MLEs) of body fluid quantities in a sample, and we describe the use of likelihood ratios to test for the presence of each body fluid in a sample. Known single source blood, semen, vaginal secretions, menstrual blood and skin samples all demonstrated the expected tissue specific gene expression for at least two of the chosen biomarkers. Saliva samples were more problematic, with their previously identified characteristic genes exhibiting poor specificity. Nonetheless the most specific saliva biomarker, HTN3, was expressed at a higher level in saliva than in any of the other tissues. As a preliminary indication of the ability of the method to discern admixtures of body fluids, five mixtures were prepared. Two of the five mixtures were called perfectly using the assay algorithm, and one of the component fluids was identified in the each of the 'false negative' mixtures. Crucially, our algorithm produced zero false positive fluid identifications across this study's 98 samples. Further optimization of the biomarker 'Codeset' will be required before it can be used in casework, particularly with respect to increasing the signal to noise ratio of the saliva biomarkers. With suitable modifications, this simplified protocol with minimal hands on requirement should facilitate routine use of mRNA profiling in casework laboratories. | 10.1016/j.fsigen.2014.09.005 | biorxiv | 838 |
10.1101/007716 | Growth of Primary and Lateral Roots of Vicia faba L. in the Solution of Calcium Sulfate | Michael Pyshnov; | Michael Pyshnov | none | 2014-08-08 | 1 | New Results | cc_by_nc | Plant Biology | https://www.biorxiv.org/content/early/2014/08/08/007716.source.xml | The presence of calcium sulfate in cultivating solution prevents bacterial contamination, browning/lignification and the death of the roots. There is no need for surface sterilization of seeds. No other ingredients, beside calcium sulfate, are needed for the healthy growth of the primary and lateral roots. There is no need to change the solution for several weeks when up to 60 lateral roots per seed can appear.\n\nA modification of the two-stage growing technique where the seeds are first suspended in moist air over the cultivating solution to grow primary roots, and then, the primary roots are covered with the cultivating solution to grow lateral roots, was used.\n\nThe hypothesis is put forward that primary roots actually need water as a liquid to expel air, as the air is probably preventing the appearance of lateral roots. | NA | biorxiv | 839 |
10.1101/008029 | The impact of radio-tags on Ruby-throated Hummingbirds (Archilochus colubris) | Theodore J Zenzal;Robert H Diehl;Frank R Moore; | Theodore J Zenzal | University of Southern Mississippi | 2014-08-14 | 1 | New Results | cc_no | Zoology | https://www.biorxiv.org/content/early/2014/08/14/008029.source.xml | Radio telemetry has advanced the field of wildlife biology, especially with the miniaturization of radio-tags. However, the major limitation faced with radio-tagging birds is the size of the animal to which a radio-tag can be attached. We tested how miniature radio-tags affected flight performance and behavior of Ruby-throated Hummingbirds (Archilochus colubris), possibly the smallest bird species to be fitted with radio-tags. Using eyelash adhesive, we fitted hatch year individuals (n=20 males and 15 females) with faux radio-tags of three sizes varying in mass and antenna length (220mg-12.7cm, 240mg-12.7cm, and 220mg-6.35cm), then filmed the birds in a field aviary to quantify activity budgets. We also estimated flight range using flight simulation models. When the three radio-tag packages were pooled for analysis, the presence of a radio-tag significantly decreased both flight time (-8%) and modeled flight range (-23%) when compared to control birds. However, a multiple comparison analysis between the different packages revealed that there was a significant difference in flight time when the larger radio-tag package (240mg) was attached and no significant difference in flight time when the lighter radio-tag packages (220mg) were attached. Our results are similar to other studies which analyzed the flight time or flight range of birds wearing radio-tags. Therefore, currently available light weight radio-tags ([≤]220mg) may be a new option to aid in the study of hummingbird biology. Future study should focus upon the additional drag created by the radio-tag and the effects of the lightest radio-tag packages on free ranging birds. These studies would provide additional information to determine the feasibility on the use of radio-tags to study hummingbird biology. | 10.1650/CONDOR-13-142.1 | biorxiv | 841 |
10.1101/007971 | Orb prevents autophagy in the Drosophila germline through translational repression of Atg12 mRNA | Isabelle Busseau;Stephanie Pierson;Dany Severac;Christelle Dantec;Martine Simonelig; | Isabelle Busseau | IGH CNRS UPR1142 141 rue de la Cardonille 34396 Montpellier cedex 5 FRANCE | 2014-08-15 | 1 | New Results | cc_by_nc_nd | Developmental Biology | https://www.biorxiv.org/content/early/2014/08/15/007971.source.xml | Drosophila Orb, the homologue of vertebrate CPEB is a key translational regulator involved in oocyte polarity and maturation through poly(A) tail elongation of specific mRNAs. orb has also an essential function during early oogenesis which has not been addressed at the molecular level. Here, we show that orb prevents cell death during early stages of oogenesis, thus allowing oogenesis to progress. It does so through the repression of autophagy, by directly repressing, together with the CCR4 deadenylase, the translation of Autophagy-specific gene 12 (Atg12) mRNA. The uncontrolled autophagy observed in orb mutant ovaries is reduced when Atg12 mRNA levels are decreased. These results reveal a role of Orb in translational repression and identify autophagy as an essential pathway regulated by Orb during early oogenesis. Importantly, they also establish translational regulation as a major mode of control of autophagy, a key process in cell homeostasis in response to environmental cues. | NA | biorxiv | 842 |
10.1101/008052 | Transposable elements contribute to activation of maize genes in response to abiotic stress | Irina Makarevitch;Amanda J Waters;Patrick T West;Michelle C Stitzer;Jeffrey Ross-Ibarra;Nathan M Springer; | Nathan M Springer | University of Minnesota | 2014-08-15 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/08/15/008052.source.xml | Transposable elements (TEs) account for a large portion of the genome in many eukaryotic species. Despite their reputation as "junk" DNA or genomic parasites deleterious for the host, TEs have complex interactions with host genes and the potential to contribute to regulatory variation in gene expression. It has been hypothesized that TEs and genes they insert near may be transcriptionally activated in response to stress conditions. The maize genome, with many different types of TEs interspersed with genes, provides an ideal system to study the genome-wide influence of TEs on gene regulation. To analyze the magnitude of the TE effect on gene expression response to environmental changes, we profiled gene and TE transcript levels in maize seedlings exposed to a number of abiotic stresses. Many genes exhibit up- or down-regulation in response to these stress conditions. The analysis of TE families inserted within upstream regions of up-regulated genes revealed that between four and nine different TE families are associated with up-regulated gene expression in each of these stress conditions, affecting up to 20% of the genes up-regulated in response to abiotic stress and as many as 33% of genes that are only expressed in response to stress. Expression of many of these same TE families also responds to the same stress conditions. The analysis of the stress- induced transcripts and proximity of the transposon to the gene suggests that these TEs may provide local enhancer activities that stimulate stress-responsive gene expression. Our data on allelic variation for insertions of several of these TEs show strong correlation between the presence of TE insertions and stress-responsive up-regulation of gene expression. Our findings suggest that TEs provide an important source of allelic regulatory variation in gene response to abiotic stress in maize. | 10.1371/journal.pgen.1004915 | biorxiv | 846 |
10.1101/008078 | Understanding Admixture Fractions | Mason Liang;Rasmus Nielsen; | Mason Liang | UC Berkeley | 2014-08-16 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/16/008078.source.xml | Estimation of admixture fractions has become one of the most commonly used computational tools in population genomics. However, there is remarkably little population genetic theory on their statistical properties. We develop theoretical results that can accurately predict means and variances of admixture proportions within a population using models with recombination and genetic drift. Based on established theory on measures of multilocus disequilibrium, we show that there is a set of recurrence relations that can be used to derive expectations for higher moments of the admixture fraction distribution. We obtain closed form solutions for some special cases. Using these results, we develop a method for estimating admixture parameters from estimated admixture proportion obtained from programs such as Structure or Admixture. We apply this method to HapMap data and find that the population history of African Americans, as expected, is not best explained by a single admixture event between people of European and African ancestry. A model of constant gene flow for the past 11 generations until 2 generations ago gives a better fit. | NA | biorxiv | 847 |
10.1101/008128 | Side-binding proteins modulate actin filament dynamics | Alvaro H. Crevenna;Marcelino Arciniega;Aurelie Dupont;Kaja Kowalska;Oliver Lange;Roland Wedlich-Soldner;Don C. Lamb; | Alvaro H. Crevenna | Ludwig-Maximilians Universität München | 2014-08-18 | 1 | New Results | cc_by | Biophysics | https://www.biorxiv.org/content/early/2014/08/18/008128.source.xml | Actin filament dynamics govern many key physiological processes from cell motility to tissue morphogenesis. A central feature of actin dynamics is the capacity of the filament to polymerize and depolymerize at its ends in response to cellular conditions. It is currently thought that filament kinetics can be described by a single rate constant for each end. Here, using direct visualization of single actin filament elongation, we show that actin polymerization kinetics at both filament ends are strongly influenced by proteins that bind to the lateral filament surface. We also show that the less dynamic end, called the pointed-end, has a non-elongating state that dominates the observed filament kinetic asymmetry. Estimates of filament flexibility and Brownian dynamics simulations suggest that the observed kinetic diversity arises from structural alteration. Tuning filament kinetics by exploiting the natural malleability of the actin filament structure may be a ubiquitous mechanism to generate the rich variety of observed cellular actin dynamics. | 10.7554/eLife.04599 | biorxiv | 849 |
10.1101/008193 | An amino acid polymorphism in the Drosophila insulin receptor demonstrates pleiotropic and adaptive function in life history traits | Annalise B. Paaby;Alan O. Bergland;Emily L. Behrman;Paul S. Schmidt; | Annalise B. Paaby | New York University | 2014-08-19 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/19/008193.source.xml | Finding the specific nucleotides that underlie adaptive variation is a major goal in evolutionary biology, but polygenic traits pose a challenge because the complex genotype-phenotype relationship can obscure the effects of individual alleles. However, natural selection working in large wild populations can shift allele frequencies and indicate functional regions of the genome. Previously, we showed that the two most common alleles of a complex amino acid insertion-deletion polymorphism in the Drosophila insulin receptor show independent, parallel clines in frequency across the North American and Australian continents. Here, we report that the cline is stable over at least a five-year period and that the polymorphism also demonstrates temporal shifts in allele frequency concurrent with seasonal change. We tested the alleles for effects on levels of insulin signaling, fecundity, development time, body size, stress tolerance, and lifespan. We find that the alleles are associated with predictable differences in these traits, consistent with patterns of Drosophila life history variation across geography that likely reflect adaptation to the heterogeneous climatic environment. These results implicate insulin signaling as a major mediator of life history adaptation in Drosophila, and suggest that life history tradeoffs can be explained by extensive pleiotropy at a single locus. | 10.1111/evo.12546 | biorxiv | 850 |
10.1101/008151 | Quantitative Genetics and Modularity in cranial and mandibular morphology of Calomys expulsus | Guilherme Garcia;Rui Cerqueira;Erika Hingst-Zaher;Gabriel Marroig; | Guilherme Garcia | University of São Paulo | 2014-08-19 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/19/008151.source.xml | Patterns of genetic covariance between characters (represented by the covariance matrix G) play an important role in morphological evolution, since they interact with the evolutionary forces acting over populations. They are also expected to influence the patterns expressed in their phenotypic counterparts (P), because of limits imposed by multiple developmental and functional restrictions on the genotype/phenotype map. We have investigated genetic covariances in the skull and mandible of the vesper mouse (Calomys expulsus) in order to estimate the degree of similarity between genetic and phenotypic covariances and its potential roots on developmental and functional factors shaping those integration patterns. We use a classic adhoc analysis of morphological integration based on current state of art of developmental/functional factors during mammalian ontogeny and also applied a novel methodology that makes use of simulated evolutionary responses. We have obtained P and G that are strongly similar, for both skull and mandible; their similarity is achieved through the spatial and temporal organization of developmental and functional interactions, which are consistently recognized as hypothesis of trait associations in both matrices. | 10.1007/s11692-014-9293-4 | biorxiv | 851 |
10.1101/008144 | The genomic landscape of polymorphic human nuclear mitochondrial insertions | Gargi Dayama;Sarah B Emery;Jeffrey M Kidd;Ryan E Mills; | Ryan E Mills | University ofMichigan | 2014-08-19 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/08/19/008144.source.xml | The transfer of mitochondrial genetic material into the nuclear genomes of eukaryotes is a well-established phenomenon. Many studies over the past decade have utilized reference genome sequences of numerous species to characterize the prevalence and contribution of nuclear mitochondrial insertions to human diseases. The recent advancement of high throughput sequencing technologies has enabled the interrogation of genomic variation at a much finer scale, and now allows for an exploration into the diversity of polymorphic nuclear mitochondrial insertions (NumtS) in human populations. We have developed an approach to discover and genotype previously undiscovered Numt insertions using whole genome, paired-end sequencing data. We have applied this method to almost a thousand individuals in twenty populations from the 1000 Genomes Project and other data sets and identified 138 novel sites of Numt insertions, extending our current knowledge of existing Numt locations in the human genome by almost 20%. Most of the newly identified NumtS were found in less than 1% of the samples we examined, suggesting that they occur infrequently in nature or have been rapidly removed by purifying selection. We find that recent Numt insertions are derived from throughout the mitochondrial genome, including the D-loop, and have integration biases consistent with previous studies on older, fixed NumtS in the reference genome. We have further determined the complete inserted sequence for a subset of these events to define their age and origin of insertion as well as their potential impact on studies of mitochondrial heteroplasmy. | 10.1093/nar/gku1038 | biorxiv | 852 |
10.1101/008136 | Genome sequencing of the perciform fish Larimichthys crocea provides insights into stress adaptation | Jingqun Ao;Yinnan Mu;Li-Xin Xiang;DingDing Fan;MingJi Feng;Shicui Zhang;Qiong Shi;Lv-Yun Zhu;Ting Li;Yang Ding;Li Nie;Qiuhua Li;Wei-ren Dong;Liang Jiang;Bing Sun;XinHui Zhang;Mingyu Li;Hai-Qi Zhang;ShangBo Xie;YaBing Zhu;XuanTing Jiang;Xianhui Wang;Pengfei Mu;Wei Chen;Zhen Yue;Zhuo Wang;Jun Wang;Jian-Zhong Shao;Xinhua Chen; | Xinhua Chen | Third Institute of Oceanography, State Oceanic Administration | 2014-08-18 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2014/08/18/008136.source.xml | The large yellow croaker Larimichthys crocea (L. crocea) is one of the most economically important marine fish in China and East Asian countries. It also exhibits peculiar behavioral and physiological characteristics, especially sensitive to various environmental stresses, such as hypoxia and air exposure. These traits may render L. crocea a good model for investigating the response mechanisms to environmental stress. To understand the molecular and genetic mechanisms underlying the adaptation and response of L. crocea to environmental stress, we sequenced and assembled the genome of L. crocea using a bacterial artificial chromosome and whole-genome shotgun hierarchical strategy. The final genome assembly was 679 Mb, with a contig N50 of 63.11 kb and a scaffold N50 of 1.03 Mb, containing 25,401 protein-coding genes. Gene families underlying adaptive behaviours, such as vision-related crystallins, olfactory receptors, and auditory sense-related genes, were significantly expanded in the genome of L. crocea relative to those of other vertebrates. Transcriptome analyses of the hypoxia-exposed L. crocea brain revealed new aspects of neuro-endocrine-immune/metabolism regulatory networks that may help the fish to avoid cerebral inflammatory injury and maintain energy balance under hypoxia. Proteomics data demonstrate that skin mucus of the air-exposed L. crocea had a complex composition, with an unexpectedly high number of proteins (3,209), suggesting its multiple protective mechanisms involved in antioxidant functions, oxygen transport, immune defence, and osmotic and ionic regulation. Our results provide novel insights into the mechanisms of fish adaptation and response to hypoxia and air exposure. | 10.1371/journal.pgen.1005118 | biorxiv | 853 |
10.1101/008177 | Statistical mechanics of multistable perception | Gurinder Singh Atwal; | Gurinder Singh Atwal | Cold Spring Harbor | 2014-08-19 | 1 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/08/19/008177.source.xml | The stochastic dynamics of multistable perception poses an enduring challenge to our understanding of neural signal processing in the brain. We show that the emergence of perception switching and stability can be understood using principles of probabilistic Bayesian inference where the prior temporal expectations are matched to a scale-free power spectrum, characteristic of fluctuations in the natural environment. The optimal percept dynamics are inferred by an exact mapping of the statistical estimation problem to the motion of a dissipative quantum particle in a multi-well potential. In the bistable case the problem is further mapped to a long-ranged Ising model. Optimal inference in the presence of a 1/f noise prior leads to critical dynamics, exhibiting a dynamical phase transition from unstable perception to stable perception, as demonstrated in recent experiments. The effect of stimulus fluctuations and perception bias is also discussed. | NA | biorxiv | 854 |
10.1101/008169 | Dual autogenous control of the multiple antibiotic resistance phenotype in Escherichia coli | Guillermo Rodrigo;Djordje Bajic;Ignacio Elola;Juan F Poyatos; | Juan F Poyatos | Spanish National Biotechnology Centre (CNB-CSIC) | 2014-08-19 | 1 | New Results | cc_by | Systems Biology | https://www.biorxiv.org/content/early/2014/08/19/008169.source.xml | Bacteria can defend against diverse antibiotics by mounting a multiple antibiotic resistance (mar) phenotype. The resistance is linked to a chromosomal locus that encodes an activator and a repressor regulating their own expression. Here, we investigated how this dual autogenous control determines the dynamics of the response. We found that the regulatory architecture provides a mechanism to enable rapid induction, generate pulses of activation, and increase the range of sensing. The response is also graded and homogeneous across the population. Moreover, the interaction of a third regulator with the core module fine tunes the previous features, while limiting the cross-talk with metabolic signals. A minimal model accurately anticipates these properties, and emphasizes how specific attributes of the circuit components constrain the appearance of other potential behaviors associated to the regulatory design. Our results integrate both molecular and circuit-level characteristics to fully elucidate the dynamic emergence of the mar phenotype. | NA | biorxiv | 855 |
10.1101/008235 | Coordinated Evolution of Influenza A Surface Proteins | Alexey D. Neverov;Sergey Kryazhimskiy;Joshua B. Plotkin;Georgii A. Bazykin; | Sergey Kryazhimskiy | Harvard University | 2014-08-20 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/20/008235.source.xml | Surface proteins hemagglutinin (HA) and neuraminidase (NA) of the human influenza A virus evolve under selection pressure to escape the human adaptive immune response and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes, that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with substitutions in HA affecting substitutions in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, imply that the evolution of any single protein must be understood within the context of the entire evolving genome. | 10.1371/journal.pgen.1005404 | biorxiv | 858 |
10.1101/008250 | Protein folding and binding can emerge as evolutionary spandrels through structural coupling | Michael Manhart;Alexandre V Morozov; | Alexandre V Morozov | Rutgers University | 2014-08-20 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/20/008250.source.xml | Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and regulation of gene expression. These interactions evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic), or when genes duplicate and diverge. Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between protein folding and binding -- the fact that most proteins can only bind their targets when folded -- gives rise to evolutionary coupling between the traits of folding stability and binding strength. Using biophysical and evolutionary modeling, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutation events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of fundamental evolutionary principles of both natural and engineered proteins. | 10.1073/pnas.1415895112 | biorxiv | 859 |
10.1101/008227 | Dead or just asleep? Variance of microsatellite allele distributions in the human Y-chromosome. | Joe Flood; | Joe Flood | Independent researcher | 2014-08-21 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/08/21/008227.source.xml | Several different methods confirm that a number of micro-satellites on the human Y-chromosome have allele distributions with different variances in different haplogroups, after adjusting for coalescent times. This can be demonstrated through both heteroscedasticity tests and by poor correlation of the variance vectors in different subclades. The most convincing demonstration however is the complete inactivity of some markers in certain subclades - \"microsatellite death\", while they are still active in companion subclades.\n\nMany microsatellites have declined in activity as they proceed down through descendant subclades. This appears to confirm the theory of microsatellite life cycles, in which point mutations cause a steady decay in activity. However, the changes are too fast to be caused by point mutations alone, and slippage events may be implicated.\n\nThe rich microsatellite terrain exposed in our large single-haplotype samples provides new opportunities for genotyping and analysis. | NA | biorxiv | 860 |
10.1101/008219 | Genome-wide Comparative Analysis Reveals Possible Common Ancestors of NBS Domain Containing Genes in Hybrid Citrus sinensis Genome and Original Citrus clementina Genome | Yunsheng Wang;Lijuan Zhou;Dazhi Li;Amy Lawton-Rauh;Pradip K. Srimani;Liangying Dai;Yongping Duan;Feng Luo; | Feng Luo | School of Computing, Clemson University, Clemson, USA | 2014-08-20 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/08/20/008219.source.xml | Background Recently available whole genome sequences of three citrus species: one Citrus clementina and two Citrus sinensis genomes have made it possible to understand the features of candidate disease resistance genes with nucleotide-binding sites (NBS) domain in Citrus and how NBS genes differ between hybrid and original Citrus species. Result We identified and re-annotated NBS genes from three citrus genomes and found similar numbers of NBS genes in those citrus genomes. Phylogenetic analysis of all citrus NBS genes across three genomes showed that there are three approximately evenly numbered groups: one group contains the Toll-Interleukin receptor (TIR) domain and two different groups that contain the Coiled Coil (CC) domain. Motif analysis confirmed that the two groups of CC-containing NBS genes are from different evolutionary origins. We partitioned NBS genes into clades using NBS domain sequence distances and found most clades include NBS genes from all three citrus genomes. This suggests that NBS genes in three citrus genomes may come from shared ancestral origins. We also mapped the re-sequenced reads of three pomelo and three Mandarin orange genomes onto the Citrus sinensis genome. We found that most NBS genes of the hybrid C. sinensis genome have corresponding homologous genes in both pomelo and mandarin genome. The homologous NBS genes in pomelo and mandarin may explain why the NBS genes in their hybrid Citrus sinensis are similar to those in Citrus clementina in this study. Furthermore, sequence variation amongst citrus NBS genes were shaped by multiple independent and shared accelerated mutation accumulation events among different groups of NBS genes and in different citrus genomes. Conclusion Our comparative analyses yield valuable insight into the understanding of the structure, evolution and organization of NBS genes in Citrus genomes. There are significantly more NBS genes in Citrus genomes compared to other plant species. NBS genes in hybrid C. sinensis genomes are very similar to those in progenitor C. clementina genome and they may be derived from possible common ancestral gene copies. Furthermore, our comprehensive analysis showed that there are three groups of plant NBS genes while CC-containing NBS genes can be divided into two groups. | 10.1371/journal.pone.0121893 | biorxiv | 861 |
10.1101/008276 | Robust Population Structure Inference and Correction in the Presence of Known or Cryptic Relatedness | Matthew P Conomos;Michael B Miller;Timothy A Thornton; | Timothy A Thornton | University of Washington | 2014-08-21 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/08/21/008276.source.xml | Population structure inference with genetic data has been motivated by a variety of applications in population genetics and genetic association studies. Several approaches have been proposed for the identification of genetic ancestry differences in samples where study participants are assumed to be unrelated, including principal components analysis (PCA), multi-dimensional scaling (MDS), and model-based methods for proportional ancestry estimation. Many genetic studies, however, include individuals with some degree of relatedness, and existing methods for inferring genetic ancestry fail in related samples. We present a method, PC-AiR, for robust population structure inference in the presence of known or cryptic relatedness. PC-AiR utilizes genome-screen data and an efficient algorithm to identify a diverse subset of unrelated individuals that is representative of all ancestries in the sample. The PC-AiR method directly performs PCA on the identified ancestry representative subset and then predicts components of variation for all remaining individuals based on genetic similarities. In simulation studies and in applications to real data from Phase III of the HapMap Project, we demonstrate that PC-AiR provides a substantial improvement over existing approaches for population structure inference in related samples. We also demonstrate significant efficiency gains, where a single axis of variation from PC-AiR provides better prediction of ancestry in a variety of structure settings than using ten (or more) components of variation from widely used PCA and MDS approaches. Finally, we illustrate that PC-AiR can provide improved population stratification correction over existing methods in genetic association studies with population structure and relatedness. | 10.1002/gepi.21896 | biorxiv | 868 |
10.1101/008383 | Omics Pipe: A Computational Framework for Reproducible Multi-Omics Data Analysis | Kathleen M Fisch;Tobias Meißner;Louis Gioia;Jean-Christophe Ducom;Tristan Carland;Salvatore Loguercio;Andrew I. Su; | Andrew I. Su | The Scripps Research Institute | 2014-08-23 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/23/008383.source.xml | Omics Pipe (https://bitbucket.org/sulab/omics_pipe) is a computational platform that automates multi-omics data analysis pipelines on high performance compute clusters and in the cloud. It supports best practice published pipelines for RNA-seq, miRNA-seq, Exome-seq, Whole Genome sequencing, ChIP-seq analyses and automatic processing of data from The Cancer Genome Atlas. Omics Pipe provides researchers with a tool for reproducible, open source and extensible next generation sequencing analysis. | 10.1093/bioinformatics/btv061 | biorxiv | 870 |
10.1101/008284 | Frequent and Transient Acquisition of Pluripotency During Somatic Cell Trans-differentiation with iPSC Reprogramming Factors | Itay Maza;Inbal Casoi;Sergey Viukov;Yoach Rais;Asaf Zviran;Shay Geula;Vladislav Krupalnik;Mirie Zerbib;Rada Massarwa;Noa Novershtern;Jacob Hanna; | Jacob Hanna | Weizmann Institute of Science | 2014-08-23 | 1 | New Results | cc_no | Developmental Biology | https://www.biorxiv.org/content/early/2014/08/23/008284.source.xml | Recent reports have proposed a new paradigm for obtaining mature somatic cell types from fibroblasts without going through a pluripotent state, by briefly expressing canonical iPSC reprogramming factors Oct4, Sox2, Klf4, c-Myc (abbreviated as OSKM) in cells expanded in lineage differentiation promoting conditions. Here we apply genetic lineage tracing for endogenous Nanog locus and X chromosome reactivation during OSKM induced trans-differentiation, as these molecular events mark final stages for acquisition of induced pluripotency. Remarkably, the majority of reprogrammed cardiomyocytes or neural stem cells derived from mouse fibroblasts via OSKM mediated trans-differentiation ([~]>90%), are attained after transient acquisition of pluripotency, and followed by rapid differentiation. Our findings underscore a molecular and functional coupling between inducing pluripotency and obtaining \"trans-differentiated\" somatic cells via OSKM induction, and have implications on defining molecular trajectories assumed during different cell reprogramming methods. | 10.1038/nbt.3270 | biorxiv | 871 |
10.1101/000026 | A Population Genetic Signature of Polygenic Local Adaptation | Jeremy J Berg;Graham Coop; | Graham Coop | University of California, Davis | 2014-09-08 | 2 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/09/08/000026.source.xml | Adaptation in response to selection on polygenic phenotypes occurs via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that have undergone local adaptation. Using GWAS data, we estimate the mean additive genetic value for a give phenotype across many populations as simple weighted sums of allele frequencies. We model the expected differentiation of GWAS loci among populations under neutrality to develop simple tests of selection across an arbitrary number of populations with arbitrary population structure. To find support for the role of specific environmental variables in local adaptation we test for correlations with the estimated genetic values. We also develop a general test of local adaptation to identify overdispersion of the estimated genetic values values among populations. This test is a natural generalization of QST /FST comparisons based on GWAS predictions. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles. We apply our tests to the human genome diversity panel dataset using GWAS data for six different traits. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results. | 10.1371/journal.pgen.1004412 | biorxiv | 873 |
10.1101/001784 | Global Epistasis Makes Adaptation Predictable Despite Sequence-Level Stochasticity | Sergey Kryazhimskiy;Daniel Paul Rice;Elizabeth Jerison;Michael M Desai; | Michael M Desai | Harvard University | 2014-08-25 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/25/001784.source.xml | Epistasis can make adaptation highly unpredictable, rendering evolutionary trajectories contingent on the chance effects of initial mutations. We used experimental evolution in Saccharomyces cerevisiae to quantify this effect, finding dramatic differences in adaptability between 64 closely related genotypes. Despite these differences, sequencing of 105 evolved clones showed no significant effect of initial genotype on future sequence-level evolution. Instead, reconstruction experiments revealed a consistent pattern of diminishing returns epistasis. Our results suggest that many beneficial mutations affecting a variety of biological processes are globally coupled: they interact strongly, but only through their combined effect on fitness. Sequence-level adaptation is thus highly stochastic. Nevertheless, fitness evolution is strikingly predictable because differences in adaptability are determined only by global fitness-mediated epistasis, not by the identity of individual mutations. | 10.1126/science.1250939 | biorxiv | 875 |
10.1101/002964 | T-lex2: genotyping, frequency estimation and re-annotation of transposable elements using single or pooled next-generation sequencing data | Anna-Sophie Fiston-Lavier;Maite G. Barrón;Dmitri A. Petrov;Josefa González; | Anna-Sophie Fiston-Lavier | Institut des Sciences de l'Evolution-UMR5554 CNRS-Université Montpellier 2 | 2014-09-16 | 2 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/16/002964.source.xml | Transposable elements (TEs) are the most active, diverse and ancient component in a broad range of genomes. As such, a complete understanding of genome function and evolution cannot be achieved without a thorough understanding of TE impact and biology. However, in-depth analyses of TEs still represent a challenge due to the repetitive nature of these genomic entities. In this work, we present a broadly applicable and flexible tool: T-lex2. T-lex2 is the only available software that allows routine,automatic, and accurate genotyping of individual TE insertions and estimation of their population frequencies both using individual strain and pooled next-generation sequencing (NGS) data. Furthermore, T-lex2 also assesses the quality of the calls allowing the identification of miss-annotated TEs and providing the necessary information to re-annotate them. Although we tested the fidelity of T-lex2 using the high quality Drosophila melanogaster genome, the flexible and customizable design of T-lex2 allows running it in any genome and for any type of TE insertion. Overall, T-lex2 represents a significant improvement in our ability to analyze the contribution of TEs to genome function and evolution as well as learning about the biology of TEs. T-lex2 is freely available online at http://petrov.stanford.edu/cgi-bin/Tlex.html. | 10.1093/nar/gku1250 | biorxiv | 876 |
10.1101/003319 | Genetic influences on translation in yeast | Frank W. Albert;Dale Muzzey;Jonathan S. Weissman;Leonid Kruglyak; | Frank W. Albert | University of California, Los Angeles | 2014-09-02 | 3 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/09/02/003319.source.xml | Heritable differences in gene expression between individuals are an important source of phenotypic variation. The question of how closely the effects of genetic variation on protein levels mirror those on mRNA levels remains open. Here, we addressed this question by using ribosome profiling to examine how genetic differences between two strains of the yeast S. cerevisiae affect translation. Strain differences in translation were observed for hundreds of genes. Allele specific measurements in the diploid hybrid between the two strains revealed roughly half as many cis-acting effects on translation as were observed for mRNA levels. In both the parents and the hybrid, most effects on translation were of small magnitude, such that the direction of an mRNA difference was typically reflected in a concordant footprint difference. The relative importance of cis and trans acting variation on footprint levels was similar to that for mRNA levels. There was a tendency for translation to cause larger footprint differences than expected given the respective mRNA differences. This is in contrast to translational differences between yeast species that have been reported to more often oppose than reinforce mRNA differences. Finally, we catalogued instances of premature translation termination in the two yeast strains and also found several instances where erroneous reference gene annotations lead to apparent nonsense mutations that in fact reside outside of the translated gene body. Overall, genetic influences on translation subtly modulate gene expression differences, and translation does not create strong discrepancies between genetic influences on mRNA and protein levels.\n\nAuthor summaryIndividuals in a species differ from each other in many ways. For many traits, a fraction of this variation is genetic - it is caused by DNA sequence variants in the genome of each individual. Some of these variants influence traits by altering how much certain genes are expressed, i.e. how many mRNA and protein molecules are made in different individuals. Surprisingly, earlier work has found that the effects of genetic variants on mRNA and protein levels for the same genes appear to be very different. Many variants appeared to influence only mRNA (but not protein) levels, and vice versa. In this paper, we studied this question by using a technique called \"ribosome profiling\" to measure translation (the cellular process of reading mRNA molecules and synthesizing protein molecules) in two yeast strains. We found that the genetic differences between these two strains influence translation for hundreds of genes. Because most of these effects were small in magnitude, they explain at most a small fraction of the discrepancies between the effects of genetic variants on mRNA and protein levels. | 10.1371/journal.pgen.1004692 | biorxiv | 877 |
10.1101/003665 | Flexible analysis of transcriptome assemblies with Ballgown | Alyssa C Frazee;Geo Pertea;Andrew E Jaffe;Ben Langmead;Steven L Salzberg;Jeffrey T Leek; | Jeffrey T Leek | Johns Hopkins Bloomberg School of Public Health | 2014-09-05 | 2 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/05/003665.source.xml | Introduction Introduction Negative control experiment Positive control experiment Confirmation of statistical... Analysis of RNA-seq experiments... Analysis of quantitative... Expression quantitative trait... Computational Efficiency Summary References A key advantage of RNA sequencing (RNA-seq) over hybridization-based technologies such as microarrays is that RNA-seq makes it possible to reconstruct complete gene structures, including multiple splice variants, from raw RNA-seq reads without relying on previously-established annotations [20, 32, 9]. But with this added flexibility, there are increased computational demands on upstream processing tasks such as alignment and ass ... | 10.1038/nbt.3172 | biorxiv | 878 |
10.1101/003657 | Exploring the spatially explicit predictions of the Maximum Entropy Theory of Ecology | Daniel McGlinn;Xiao Xiao;Justin Kitzes;Ethan P White; | Daniel McGlinn | College of Charleston | 2014-09-02 | 2 | New Results | cc_by | Ecology | https://www.biorxiv.org/content/early/2014/09/02/003657.source.xml | AimThe Maximum Entropy Theory of Ecology (METE) is a unified theory of biodiversity that attempts to simultaneously predict patterns of species abundance, size, and spatial structure. The spatial predictions of this theory have repeatedly performed well at predicting diversity patterns across scales. However, the theoretical development and evaluation of METE has focused on predicting patterns that ignore inter-site spatial correlations. As a result the theory has not been evaluated using one of the core components of spatial structure. We develop and test a semi-recursive version of METEs spatially explicit predictions for the distance decay relationship of community similarity and compare METEs performance to the classic random placement model of completely random species distributions. This provides a better understanding and stronger test of METEs spatial community predictions.\n\nLocationNew world tropical and temperate plant communities.\n\nMethodsWe analytically derived and simulated METEs spatially explicit expectations for the Sorensen index of community similarity. We then compared the distance decay of community similarity of 16 mapped plant communities to METE and the random placement model.\n\nResultsThe version of METE we examined was successful at capturing the general functional form of empirical distance decay relationships, a negative power function relationship between community similarity and distance. However, the semi-recursive approach consistently over-predicted the degree and rate of species turnover and yielded worse predictions than the random placement model.\n\nMain conclusionsOur results suggest that while METEs current spatial models accurately predict the spatial scaling of species occupancy, and therefore core ecological patterns like the species-area relationship, its semi-recursive form does not accurately characterize spatially-explicit patterns of correlation. More generally, this suggests that tests of spatial theories based only on the species-area relationship may appear to support the underlying theory despite significant deviations in important aspects of spatial structure. | 10.1111/geb.12295 | biorxiv | 879 |
10.1101/003780 | Protected polymorphisms and evolutionary stability of patch-selection strategies in stochastic environments | Steve Evans;Alexandru Hening;Sebastian Schreiber; | Alexandru Hening | Oxford University | 2014-09-02 | 2 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/02/003780.source.xml | We consider consider a population living in a patchy environment that varies stochastically in space and time. The population is composed of two morphs (that is, individuals of the same species with different genotypes). In terms of survival and reproductive success, the associated phenotypes differ only in their habitat selection strategies. We compute invasion rates corresponding to the rates at which the abundance of an initially rare morph increases in the presence of the other morph established at equilibrium. If both morphs have positive invasion rates when rare, then there is an equilibrium distribution such that the two morphs coexist; that is, there is a protected polymorphism for habitat selection. Alternatively, if one morph has a negative invasion rate when rare, then it is asymptotically displaced by the other morph under all initial conditions where both morphs are present. We refine the characterization of an evolutionary stable strategy for habitat selection from [Schreiber, 2012] in a mathematically rigorous manner. We provide a necessary and sufficient condition for the existence of an ESS that uses all patches and determine when using a single patch is an ESS. We also provide an explicit formula for the ESS when there are two habitat types. We show that adding environmental stochasticity results in an ESS that, when compared to the ESS for the corresponding model without stochasticity, spends less time in patches with larger carrying capacities and possibly makes use of sink patches, thereby practicing a spatial form of bet hedging. | 10.1007/s00285-014-0824-5 | biorxiv | 880 |
10.1101/003871 | Brachyury cooperates with Wnt/β-Catenin signalling to elicit Primitive Streak like behaviour in differentiating mouse ES cells. | David Andrew Turner;Pau Rué;Jonathan P Mackenzie;Eleanor Davies;Alfonso Martinez Arias; | David Andrew Turner | University of Cambridge | 2014-08-27 | 3 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2014/08/27/003871.source.xml | The formation of the Primitive Streak is the first visible sign of gastrulation, the process by which the three germ layers are formed from a single epithelium during early development. Embryonic Stem Cells (ESCs) provide a good system to understand the molecular and cellular events associated with these processes. Previous work, both in embryos and in culture, has shown how converging signals from both Nodal/TGF{beta}R and Wnt/{beta}-Catenin signalling pathways specify cells to adopt a Primitive Streak like fate and direct them to undertake an epithelial to mesenchymal transition (EMT). However, many of these approaches have relied on genetic analyses without taking into account the temporal progression of events within single cells. In addition, it is still unclear as to what extent events in the embryo are able to be reproduced in culture. Here, we combine flow-cytometry and a quantitative live single-cell imaging approach to demonstrate how the controlled differentiation of mouse ESCs (mESCs) towards a Primitive Streak fate in culture results in cells displaying many of the characteristics observed during early mouse development including transient Brachyury expression, EMT and increased motility. We also find that the EMT initiates the process, and this is both fuelled and terminated by the action of Bra, whose expression is dependent on the EMT and {beta}-Catenin activity. As a consequence of our analysis, we propose that a major output of Brachyury expression is in controlling the velocity of the cells that are transiting out of the Primitive Streak. | 10.1186/s12915-014-0063-7 | biorxiv | 882 |
10.1101/004762 | Sequence co-evolution gives 3D contacts and structures of protein complexes | Thomas A. Hopf;Charlotta P.I. Schärfe;João P.G.L.M. Rodrigues;Anna G. Green;Chris Sander;Alexandre M.J.J. Bonvin;Debora S. Marks; | Debora S. Marks | Harvard Medical School | 2014-09-15 | 3 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/15/004762.source.xml | Protein-protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We evaluate prediction performance in blinded tests on 76 complexes of known 3D structure, predict protein-protein contacts in 32 complexes of unknown structure, and demonstrate how evolutionary couplings can be used to distinguish between interacting and non-interacting protein pairs in a large complex. With the current growth of sequence databases, we expect that the method can be generalized to genome-wide elucidation of protein-protein interaction networks and used for interaction predictions at residue resolution. | 10.7554/eLife.03430 | biorxiv | 883 |
10.1101/004887 | Pushed beyond the brink: Allee effects, environmental stochasticity, and extinction | Gregory Roth;Sebastian Schreiber; | Sebastian Schreiber | University of California, Davis | 2014-09-02 | 2 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2014/09/02/004887.source.xml | To understand the interplay between environmental stochasticity and Allee effects, we analyze persistence, asymptotic extinction, and conditional persistence for stochastic difference equations. Our analysis reveals that persistence requires that the geometric mean of fitness at low densities is greater than one. When this geometric mean is less than one, asymptotic extinction occurs with high probability for low initial population densities. Additionally, if the population only experiences positive density-dependent feedbacks, conditional persistence occurs provided the geometric mean of fitness at high population densities is greater than one. However, if the population experiences both positive and negative density-dependent feedbacks, conditional persistence only occurs if environmental fluctuations are sufficiently small. We illustrate counter-intuitively that environmental fluctuations can increase the probability of persistence when populations are initially at low densities, and can cause asymptotic extinction of populations experiencing intermediate predation rates despite conditional persistence occurring at higher predation rates. | 10.1080/17513758.2014.962631 | biorxiv | 884 |
10.1101/005082 | diCal-IBD: demography-aware inference of identity-by-descent tracts in unrelated individuals | Paula Tataru;Jasmine A. Nirody;Yun S. Song; | Paula Tataru | Bioinformatics Research Centre, Aarhus University, Denmark | 2014-09-03 | 3 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/03/005082.source.xml | Summary: We present a tool, diCal-IBD, for detecting identity-by-descent (IBD) tracts between pairs of genomic sequences. Our method builds on a recent demographic inference method based on the coalescent with recombination, and is able to incorporate demographic information as a prior. Simulation study shows that diCal-IBD has significantly higher recall and precision than that of existing IBD detection methods, while retaining reasonable accuracy for IBD tracts as small as 0.1 cM.\n\nAvailability: http://sourceforge.net/p/dical-ibd\n\nContact: [email protected] | 10.1093/bioinformatics/btu563 | biorxiv | 885 |
10.1101/005637 | Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia | Simone Ecker;Vera Pancaldi;Daniel Rico;Alfonso Valencia; | Vera Pancaldi | Spanish National Cancer Research Centre (CNIO) | 2014-09-03 | 3 | New Results | cc_by_nc | Cancer Biology | https://www.biorxiv.org/content/early/2014/09/03/005637.source.xml | BackgroundChronic Lymphocytic Leukemia (CLL) presents two subtypes which have drastically different clinical outcomes. So far, these two subtypes are not associated to clear differences in gene expression profiles. Interestingly, recent results have highlighted important roles for heterogeneity, both at the genetic and at the epigenetic level in CLL progression.\n\nResultsWe propose to use gene expression variability across patients to investigate differences between the two CLL subtypes. We find that the most aggressive type of this disease shows higher variability of gene expression across patients and we elaborate on this observation to produce a method that classifies patients into clinical subtypes. Finally, we find that, overall, genes that show higher variability in the aggressive subtype are related to cell cycle, development and inter-cellular communication, probably related to faster progression of this disease subtype.\n\nConclusionsThere are strong relations between disease subtype and gene expression variability linking significantly increased expression variability to phenotypes such as aggressiveness and resistance to therapy in CLL. | 10.1186/s13073-014-0125-z | biorxiv | 886 |
10.1101/005686 | Cancer-associated recurrent mutations in RNase III domains of DICER1 | Bülent Arman Aksoy;Anders Jacobsen;Robert J Fieldhouse;William Lee;Emek Demir;Giovanni Ciriello;Nikolaus Schultz;Debora S Marks;Chris Sander; | Bülent Arman Aksoy | Computational Biology Center, Memorial Sloan-Kettering Cancer Center | 2014-09-12 | 2 | New Results | cc_no | Cancer Biology | https://www.biorxiv.org/content/early/2014/09/12/005686.source.xml | Mutations in the RNase IIIb domain of DICER1 are known to disrupt processing of 5p-strand pre-miRNAs and these mutations have previously been associated with cancer. Using data from the Cancer Genome Atlas project, we show that these mutations are recurrent across four cancer types and that a previously uncharacterized recurrent mutation in the adjacent RNase IIIa domain also disrupts 5p-strand miRNA processing. Analysis of the downstream effects of the resulting imbalance 5p/3p shows a statistically significant effect on the expression of mRNAs targeted by major conserved miRNA families. In summary, these mutations in DICER1 lead to an imbalance in miRNA strands, which has an effect on mRNA transcript levels that appear to contribute to the oncogenesis. | NA | biorxiv | 887 |
10.1101/005819 | Natural variation in teosinte at the domestication locus teosinte branched1 (tb1) | Laura Vann;Thomas Kono;Tanja Pyha ̈j ̈arvi;Matthew B Hufford;Jeffrey Ross-Ibarra; | Jeffrey Ross-Ibarra | University of California, Davis | 2014-09-11 | 2 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/11/005819.source.xml | Premise of the studyThe teosinte branched1 (tb1) gene is a major QTL controlling branching differences between maize and its wild progenitor, teosinte. The insertion of a transposable element (Hopscotch) upstream of tb1 is known to enhance the genes expression, causing reduced tillering in maize. Observations of the maize tb1 allele in teosinte and estimates of an insertion age of the Hopscotch that predates domestication led us to investigate its prevalence and potential role in teosinte.\n\nMethodsPrevalence of the Hopscotch element was assessed across an Americas-wide sample of 837 maize and teosinte individuals using a co-dominant PCR assay. Population genetic summaries were calculated for a subset of individuals from four teosinte populations in central Mexico. Phenotypic data were also collected using seed from a single teosinte population where Hopscotch was found segregating at high frequency.\n\nKey resultsGenotyping results indicate the Hopscotch element is found in a number of teosinte populations and linkage disequilibrium near tb1 does not support recent introgression from maize. Population genetic signatures are consistent with selection on this locus revealing a potential ecological role for Hopscotch in teosinte, but a greenhouse experiment does not detect a strong association between tb1 and tillering in teosinte.\n\nConclusionsOur findings suggest the role of Hopscotch differs between maize and teosinte. Future work should assess tb1 expression levels in teosinte with and without the Hopscotch and more comprehensively phenotype teosinte to assess the ecological significance of the Hopscotch insertion and, more broadly, the tb1 locus in teosinte. | 10.7717/peerj.900 | biorxiv | 888 |
10.1101/005926 | Untangling cross-frequency coupling in neuroscience | Juhan Aru;Jaan Aru;Viola Priesemann;Michael Wibral;Luiz Lana;Gordon Pipa;Wolf Singer;Raul Vicente; | Raul Vicente | Institute of Computer Science, University of Tartu | 2014-08-25 | 2 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/08/25/005926.source.xml | Cross-frequency coupling (CFC) has been proposed to coordinate neural dynamics across spatial and temporal scales. Despite its potential relevance for understanding healthy and pathological brain function, the standard CFC analysis and physiological interpretation come with fundamental problems. For example, apparent CFC can appear because of spectral correlations due to common non-stationarities that may arise in the total absence of interactions between neural frequency components. To provide a road map towards an improved mechanistic understanding of CFC, we organize the available and potential novel statistical/modeling approaches according to their biophysical interpretability. While we do not provide solutions for all the problems described, we provide a list of practical recommendations to avoid common errors and to enhance the interpretability of CFC analysis.\n\nHighlightsFundamental caveats and confounds in the methodology of assessing CFC are discussed.\n\nSignificant CFC can be observed without any underlying physiological coupling.\n\nNon-stationarity of a time-series leads to spectral correlations interpreted as CFC.\n\nWe offer practical recommendations, which can relieve some of the current confounds.\n\nFurther theoretical and experimental work is needed to ground the CFC analysis. | 10.1016/j.conb.2014.08.002 | biorxiv | 889 |
10.1101/006023 | Restriction and recruitment - gene duplication and the origin and evolution of snake venom toxins | Adam D Hargreaves;Martin T Swain;Matthew J Hegarty;Darren W Logan;John F Mulley; | John F Mulley | Bangor University | 2014-08-25 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/25/006023.source.xml | Snake venom has been hypothesised to have originated and diversified via a process that involves duplication of genes encoding body proteins with subsequent recruitment of the copy to the venom gland, where natural selection acts to develop or increase toxicity. However, gene duplication is known to be a rare event in vertebrate genomes and the recruitment of duplicated genes to a novel expression domain (neofunctionalisation) is an even rarer process that requires the evolution of novel combinations of transcription factor binding sites in upstream regulatory regions. Therefore, whilst this hypothesis concerning the evolution of snake venom is therefore very unlikely and should be regarded with caution, it is nonetheless often assumed to be established fact, hindering research into the true origins of snake venom toxins. To critically evaluate this hypothesis we have generated transcriptomic data for body tissues and salivary and venom glands from five species of venomous and non-venomous reptiles. Our comparative transcriptomic analysis of these data reveals that snake venom does not evolve via the hypothesised process of duplication and recruitment of genes encoding body proteins. Indeed, our results show that many proposed venom toxins are in fact expressed in a wide variety of body tissues, including the salivary gland of non-venomous reptiles and that these genes have therefore been restricted to the venom gland following duplication, not recruited. Thus snake venom evolves via the duplication and subfunctionalisation of genes encoding existing salivary proteins. These results highlight the danger of the elegant and intuitive ?just-so story? in evolutionary biology. | 10.1093/gbe/evu166 | biorxiv | 890 |
10.1101/006064 | Recombination impacts damaging and disease mutation accumulation in human populations | Julie Hussin;Alan Hodgkinson;Youssef Idaghdour;Jean-Christophe Grenier;Jean-Philippe Goulet;Elias Gbeha;Elodie Hip-Ki;Philip Awadalla; | Julie Hussin | University of Oxford | 2014-09-10 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/10/006064.source.xml | Many decades of theory have demonstrated that in non-recombining systems, slightly deleterious mutations accumulate non-reversibly1, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion2, however it is not clear the extent to which these processes operate along recombining chromosomes with highly variable rates of crossing over. Using high coverage sequencing data from over 1400 individuals in The 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the genomic distribution of putatively deleterious variants across the entire human genome. We find that exons in regions of low recombination are significantly enriched for deleterious and disease variants, a signature that varies in strength across worldwide human populations with different demographic histories. As low recombining regions are enriched for highly conserved genes with essential cellular functions, and show an excess of mutations with demonstrated effect on health, this phenomenon likely affects disease susceptibility in humans. | 10.1038/ng.3216 | biorxiv | 891 |
10.1101/006148 | Reducing INDEL calling errors in whole-genome and exome sequencing data | Han Fang;Yiyang Wu;Giuseppe Narzisi;Jason A. O'Rawe;Laura T. Jimenez Barrón;Julie Rosenbaum;Michael Ronemus;Ivan Iossifov;Michael C. Schatz;Gholson J. Lyon; | Gholson J. Lyon | Cold Spring Harbor Laboratory | 2014-09-17 | 2 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/17/006148.source.xml | BackgroundINDELs, especially those disrupting protein-coding regions of the genome, have been strongly associated with human diseases. However, there are still many errors with INDEL variant calling, driven by library preparation, sequencing biases, and algorithm artifacts.\n\nMethodsWe characterized whole genome sequencing (WGS), whole exome sequencing (WES), and PCR-free sequencing data from the same samples to investigate the sources of INDEL errors. We also developed a classification scheme based on the coverage and composition to rank high and low quality INDEL calls. We performed a large-scale validation experiment on 600 loci, and find high-quality INDELs to have a substantially lower error rate than low quality INDELs (7% vs. 51%).\n\nResultsSimulation and experimental data show that assembly based callers are significantly more sensitive and robust for detecting large INDELs (>5 bp) than alignment based callers, consistent with published data. The concordance of INDEL detection between WGS and WES is low (52%), and WGS data uniquely identifies 10.8-fold more high-quality INDELs. The validation rate for WGS-specific INDELs is also much higher than that for WES-specific INDELs (85% vs. 54%), and WES misses many large INDELs. In addition, the concordance for INDEL detection between standard WGS and PCR-free sequencing is 71%, and standard WGS data uniquely identifies 6.3-fold more low-quality INDELs. Furthermore, accurate detection with Scalpel of heterozygous INDELs requires 1.2-fold higher coverage than that for homozygous INDELs. Lastly, homopolymer A/T INDELs are a major source of low-quality INDEL calls, and they are highly enriched in the WES data.\n\nConclusionsOverall, we show that accuracy of INDEL detection with WGS is much greater than WES even in the targeted region. We calculated that 60X WGS depth of coverage from the HiSeq platform is needed to recover 95% of INDELs detected by Scalpel. While this is higher than current sequencing practice, the deeper coverage may save total project costs because of the greater accuracy and sensitivity. Finally, we investigate sources of INDEL errors (e.g. capture deficiency, PCR amplification, homopolymers) with various data that will serve as a guideline to effectively reduce INDEL errors in genome sequencing. | 10.1186/s13073-014-0089-z | biorxiv | 892 |
10.1101/006635 | Detecting pairwise correlations in spike trains: an objective comparison of methods and application to the study of retinal waves. | Catherine Sarah Cutts;Stephen J Eglen; | Catherine Sarah Cutts | University of Cambridge | 2014-09-09 | 2 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/09/09/006635.source.xml | Correlations in neuronal spike times are thought to be key to processing in many neural systems. Many measures have been proposed to summarise these correlations and of these the correlation index is widely used and is the standard in studies of spontaneous retinal activity. We show that this measure has two undesirable properties: it is unbounded above and confounded by firing rate. We list properties needed for a measure to fairly quantify and compare correlations and we propose a novel measure of correlation -- the Spike Time Tiling Coefficient. This coefficient, the correlation index and 33 other measures of correlation of spike times are blindly tested for the required properties on synthetic and experimental data. On the basis of this, we propose a measure (the Spike Time Tiling Coefficient) to replace the correlation index. To demonstrate the benefits of this measure, we re-analyse data from seven key studies which previously used the correlation index to investigate the nature of spontaneous activity. We re-analyse data from {beta}2(KO) and {beta}2(TG) mutants, mutants lacking connexin isoforms and also the age-dependent changes in wild type and {beta}2(KO) correlations. Re-analysis of the data using the proposed measure can significantly change the conclusions. It leads to better quantification of correlations and therefore better inference from the data. We hope that the proposed measure will have wide applications, and will help clarify the role of activity in retinotopic map formation. | 10.1523/JNEUROSCI.2767-14.2014 | biorxiv | 893 |
10.1101/005447 | Nuclear stability and transcriptional directionality separate functionally distinct RNA species | Robin Andersson;Peter Refsing Andersen;Eivind Valen;Leighton Core;Jette Bornholdt;Mette Boyd;Torben Heick Jensen;Albin Sandelin; | Albin Sandelin | University of Copenhagen | 2014-08-29 | 2 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/08/29/005447.source.xml | Mammalian genomes are pervasively transcribed, yielding a complex transcriptome with high variability in composition and cellular abundance. While recent efforts have identified thousands of new long non-coding (lnc) RNAs and demonstrated a complex transcriptional repertoire produced by protein-coding (pc) genes, limited progress has been made in distinguishing functional RNA from spurious transcription events. This is partly due to present RNA classification, which is typically based on technical rather than biochemical criteria. Here we devise a strategy to systematically categorize human RNAs by their sensitivity to the ribonucleolytic RNA exosome complex and by the nature of their transcription initiation. These measures are surprisingly effective at correctly classifying annotated transcripts, including lncRNAs of known function. The approach also identifies uncharacterized stable lncRNAs, hidden among a vast majority of unstable transcripts. The predictive power of the approach promises to streamline the functional analysis of known and novel RNAs. | 10.1038/ncomms6336 | biorxiv | 894 |
10.1101/006825 | Probabilities of Fitness Consequences for Point Mutations Across the Human Genome | Brad Gulko;Ilan Gronau;Melissa J Hubisz;Adam Siepel; | Adam Siepel | Cornell University | 2014-09-11 | 3 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/09/11/006825.source.xml | We describe a novel computational method for estimating the probability that a point mutation at each position in a genome will influence fitness. These fitness consequence (fit-Cons) scores serve as evolution-based measures of potential genomic function. Our approach is to cluster genomic positions into groups exhibiting distinct \"fingerprints\" based on high-throughput functional genomic data, then to estimate a probability of fitness consequences for each group from associated patterns of genetic polymorphism and divergence. We have generated fitCons scores for three human cell types based on public data from EN-CODE. Compared with conventional conservation scores, fitCons scores show considerably improved prediction power for cis-regulatory elements. In addition, fitCons scores indicate that 4.2-7.5% of nucleotides in the human genome have influenced fitness since the human-chimpanzee divergence, and, in contrast to several recent studies, they suggest that recent evolutionary turnover has had limited impact on the functional content of the genome. | 10.1038/ng.3196 | biorxiv | 895 |
10.1101/007096 | Stress-Induced Mutagenesis and Complex Adaptation | Yoav Ram;Lilach Hadany; | Lilach Hadany | Tel-Aviv University | 2014-08-25 | 3 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/25/007096.source.xml | Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability - the ability to adapt - and adaptedness - the ability to remain adapted. We model an asexual population crossing a fitness valley and analyze the rate of complex adaptation with and without stress-induced mutagenesis - the increase of mutation rates in response to stress or maladaptation. We show that stress-induced mutagenesis increases the rate of complex adaptation without reducing the population mean fitness, thus breaking the evolutionary trade-off between adaptability and adaptedness. Our theoretical results support the hypothesis that stress-induced mutagenesis promotes adaptation and provide quantitative predictions of the rate of complex adaptation with different mutational strategies. | 10.1098/rspb.2014.1025 | biorxiv | 897 |
10.1101/007047 | Chromosomal distribution of cyto-nuclear genes in a dioecious plant with sex chromosomes | Josh Hough;J Arvid Agren;Spencer CH Barrett;Stephen I Wright; | Stephen I Wright | University of Toronto | 2014-09-05 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/05/007047.source.xml | The coordination between nuclear and organellar genes is essential to many aspects of eukaryotic life, including basic metabolism, energy production, and ultimately, organismal fitness. Whereas nuclear genes are bi-parentally inherited, mitochondrial and chloroplast genes are almost exclusively maternally inherited, and this asymmetry may lead to a bias in the chromosomal distribution of nuclear genes whose products act in the mitochondria or chloroplasts. In particular, because X-linked genes have a higher probability of co-transmission with organellar genes (2/3) compared to autosomal genes (1/2), selection for co-adaptation has been predicted to lead to an over-representation of nuclear-mitochondrial and nuclear-chloroplast genes on the X chromosome relative to autosomes. In contrast, the occurrence of sexually antagonistic organellar mutations might lead to selection for movement of cyto-nuclear genes from the X chromosome to autosomes to reduce male mutation load. Recent broad-scale comparative studies of N-mt distributions in animals have found evidence for these hypotheses in some species, but not others. Here, we use transcriptome sequences to conduct the first study of the chromosomal distribution of cyto-nuclear interacting genes in a plant species with sex chromosomes (Rumex hastatulus; Polygonaceae). We found no evidence of under- or over-representation of either N-mt or N-cp genes on the X chromosome, and thus no support for either the co-adaptation or the sexual-conflict hypothesis. We discuss how our results from a species with recently evolved sex chromosomes fit into an emerging picture of the evolutionary forces governing the chromosomal distribution of nuclear-mitochondrial and nuclear-chloroplast genes. | 10.1093/gbe/evu197 | biorxiv | 898 |
10.1101/007120 | MINI REVIEW: Statistical methods for detecting differentially methylated loci and regions | Mark D Robinson;Abdullah Kahraman;Charity W Law;Helen Lindsay;Malgorzata Nowicka;Lukas M Weber;Xiaobei Zhou; | Mark D Robinson | University of Zurich | 2014-08-29 | 2 | Confirmatory Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/29/007120.source.xml | DNA methylation, the reversible addition of methyl groups at CpG dinucleotides, represents an important regulatory layer associated with gene expression. Changed methylation status has been noted across diverse pathological states, including cancer. The rapid development and uptake of microarrays and large scale DNA sequencing has prompted an explosion of data analytic methods for processing and discovering changes in DNA methylation across varied data types. In this mini-review, we present a compact and accessible discussion of many of the salient challenges, such as experimental design, statistical methods for differential methylation detection, critical considerations such as cell type composition and the potential confounding that can arise from batch effects. From a statistical perspective, our main interests include the use of empirical Bayes or hierarchical models, which have proved immensely powerful in genomics, and the procedures by which false discovery control is achieved. | 10.3389/fgene.2014.00324 | biorxiv | 899 |
10.1101/008326 | Inference of Cancer Progression Models with Biological Noise | Ilya Korsunsky;Daniele Ramazzotti;Giulio Caravagna;Bud Mishra; | Daniele Ramazzotti | Courant Institute of Mathematical Sciences, New York University, New York, USA | 2014-08-25 | 2 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/25/008326.source.xml | MotivationDriver (epi)genomic alterations underlie the positive selection of cancer subpopulations, which promotes drug resistance and relapse. Even though substantial heterogeneity is witnessed in most cancer types, mutation accumulation patterns can be regularly found and can be exploited to reconstruct predictive models of cancer evolution. Yet, available methods cannot infer logical formulas connecting events to represent alternative evolutionary routes or convergent evolution.
ResultsWe introduce PMCE, an expressive framework that leverages mutational profiles from crosssectional sequencing data to infer probabilistic graphical models of cancer evolution including arbitrary logical formulas, and which outperforms the state-of-the-art in terms of accuracy and robustness to noise, on simulations.
The application of PMCE to 7866 samples from the TCGA database allows us to identify a highly significant correlation between the predicted evolutionary paths and the overall survival in 7 tumor types, proving that our approach can effectively stratify cancer patients in reliable risk groups.
AvailabilityPMCE is freely available at https://github.com/BIMIB-DISCo/PMCE, in addition to the code to replicate all the analyses presented in the manuscript.
[email protected], [email protected]. | 10.1093/bioinformatics/btab717 | biorxiv | 903 |
10.1101/008201 | Perturbation biology models predict c-Myc as an effective co-target in RAF inhibitor resistant melanoma cells | Anil Korkut;Weiqing Wang;Emek Demir;B?lent Arman Aksoy;Xiaohong Jing;Evan Molinelli;?zg?n Babur;Debra Bemis;David B Solit;Christine Pratilas;Chris Sander; | Anil Korkut | Memorial Sloan Kettering Cancer Center | 2014-09-11 | 3 | New Results | cc_by_nc_nd | Cancer Biology | https://www.biorxiv.org/content/early/2014/09/11/008201.source.xml | Systematic prediction of cellular response to perturbations is a central challenge in biology, both for mechanistic explanations and for the design of effective therapeutic interventions. We addressed this challenge using a computational/experimental method, termed perturbation biology, which combines high-throughput (phospho)proteomic and phenotypic response profiles to targeted perturbations, prior information from signaling databases and network inference algorithms from statistical physics. The resulting network models are computationally executed to predict the effects of tens of thousands of untested perturbations. We report cell type-specific network models of signaling in RAF-inhibitor resistant melanoma cells based on data from 89 combinatorial perturbation conditions and 143 readouts per condition. Quantitative simulations predicted c-Myc as an effective co-target with BRAF or MEK. Experiments showed that co-targeting c-Myc, using the BET bromodomain inhibitor JQ1, and the RAF/MEK pathway, using kinase inhibitors is both effective and synergistic in this context. We propose these combinations as pre-clinical candidates to prevent or overcome RAF inhibitor resistance in melanoma. | NA | biorxiv | 905 |
10.1101/008425 | DISEASES: Text mining and data integration of disease–gene associations | Sune Pletscher-Frankild;Albert Pallejà;Kalliopi Tsafou;Janos X Binder;Lars Juhl Jensen; | Lars Juhl Jensen | Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark | 2014-08-25 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/25/008425.source.xml | Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases. The DISEASES resource is accessible through a user-friendly web interface at http://diseases.jensenlab.org/, where the text-mining software and all associations are also freely available for download. | 10.1016/j.ymeth.2014.11.020 | biorxiv | 906 |
10.1101/008409 | edgeRun: an R package for sensitive, functionally relevant differential expression discovery using an unconditional exact test | Emmanuel Dimont;Jiantao Shi;Rory Kirchner;Winston Hide; | Emmanuel Dimont | Harvard School of Public Health | 2014-08-25 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/25/008409.source.xml | SummaryNext-generation sequencing platforms for measuring digital expression such as RNA-Seq are displacing traditional microarray-based methods in biological experiments. The detection of differentially expressed genes between groups of biological conditions has led to the development of numerous bioinformatics tools, but so far few, exploit the expanded dynamic range afforded by the new technologies. We present edgeRun, an R package that implements an unconditional exact test that is a more powerful version of the exact test in edgeR. This increase in power is especially pronounced for experiments with as few as 2 replicates per condition, for genes with low total expression and with large biological coefficient of variation. In comparison with a panel of other tools, edgeRun consistently captures functionally similar differentially expressed genes.\n\nAvailabilityThe package is freely available under the MIT license from CRAN (http://cran.r-project.org/web/packages/edgeRun)\n\[email protected] | 10.1093/bioinformatics/btv209 | biorxiv | 907 |
10.1101/008417 | Proportionality: a valid alternative to correlation for relative data | David Lovell;Vera Pawlowsky-Glahn;Juan José Egozcue;Samuel Marguerat;Jürg Bähler; | David Lovell | CSIRO | 2014-08-25 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/25/008417.source.xml | In the life sciences, many measurement methods yield only the relative abundances of different components in a sample. With such relative---or compositional---data, differential expression needs careful interpretation, and correlation---a statistical workhorse for analyzing pairwise relationships---is an inappropriate measure of association. Using yeast gene expression data we show how correlation can be misleading and present proportionality as a valid alternative for relative data. We show how the strength of proportionality between two variables can be meaningfully and interpretably described by a new statistic {varphi} which can be used instead of correlation as the basis of familiar analyses and visualization methods, including co-expression networks and clustered heatmaps. While the main aim of this study is to present proportionality as a means to analyse relative data, it also raises intriguing questions about the molecular mechanisms underlying the proportional regulation of a range of yeast genes. | 10.1371/journal.pcbi.1004075 | biorxiv | 908 |
10.1101/008433 | ReNette: a web-infrastructure for reproducible network analysis | Michele Filosi;Shamar Droghetti;Ernesto Arbitrio;Roberto Visintainer;Samantha Riccadonna;Giuseppe Jurman;Cesare Furlanello; | Cesare Furlanello | Fondazione Bruno Kessler | 2014-08-27 | 2 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/08/27/008433.source.xml | SummaryHere we introduce a novel web-infrastructure for differential network analysis. The aim of the web-site is to provide a comprehensive collection of tools for network inference, network comparison and network reproducibility analysis. Four main processes are available through the web service: the network inference process which include 11 reconstruction algorithms, the network distance process with 3 available metrics, the network stability process which includes all the network reconstruction methods and network distances and the netwok statistic process which computes the most common measures for network characterization. We introduce here a novel infrastructure which allows the user-interface logic to be separated from computing services and the asynchronous task management. Task submission is implemented mimicking the high performance computing queue submission system which allows to run multiple jobs without affecting the front-end server.\n\nAvailability and ImplementationThe web-site is available at https://renette.fbk.eu, the implementation is based on the django framework and Apache, with all major browsers supported. Furthermore, the whole project is Open Source under GPLv2 and the code is available on GitHub at https://github.com/MPBA/renette for local installation.\n\[email protected]; | NA | biorxiv | 910 |
10.1101/008466 | Rational design and adaptive management of combination therapies for Hepatitis C virus infection | Ruian Ke;Claude Loverdo;Hangfei Qi;Ren Sun;James O Lloyd-Smith; | Ruian Ke | Los Alamos National Laboratory | 2014-09-08 | 2 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/08/008466.source.xml | Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. | 10.1371/journal.pcbi.1004040 | biorxiv | 913 |
10.1101/008482 | Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth | Fabien Delahaye;Neil Ari Wijetunga;Hye J Heo;Jessica N Tozour;Yong Mei Zhao;John M Greally;Francine H Einstein; | Francine H Einstein | Albert Einstein College of Medicine | 2014-08-27 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/08/27/008482.source.xml | Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34+ hematopoietic stem/progenitor cells (HSPCs) showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. A sexually dimorphic response was found, intrauterine growth restriction (IUGR) associated with substantially greater epigenetic dysregulation in males but large for gestational age (LGA) growth affecting females predominantly. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular aging and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life. | 10.1038/ncomms6187 | biorxiv | 914 |
10.1101/008474 | Genomic and transcriptomic insights into the regulation of snake venom production | Adam D Hargreaves;Martin T Swain;Matthew J Hegarty;Darren W Logan;John F Mulley; | John F Mulley | Bangor University | 2014-08-27 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/08/27/008474.source.xml | The gene regulatory mechanisms underlying the rapid replenishment of snake venom following expenditure are currently unknown. Using a comparative transcriptomic approach we find that venomous and non-venomous species produce similar numbers of secreted products in their venom or salivary glands and that only one transcription factor (Tbx3) is expressed in venom glands but not salivary glands. We also find evidence for temporal variation in venom production. We have generated a draft genome sequence for the painted saw-scaled viper, Echis coloratus, and identified conserved transcription factor binding sites in the upstream regions of venom genes. We find binding sites to be conserved across members of the same gene family, but not between gene families, indicating that multiple gene regulatory networks are involved in venom production. Finally, we suggest that negative regulation may be important for rapid activation of the venom replenishment cycle. | NA | biorxiv | 915 |
10.1101/008516 | Amino acid and carbohydrate tradeoffs by honey bee nectar foragers and their implications for plant-pollinator interactions | Harmen P. Hendriksma;Karmi L. Oxman;Sharoni Shafir; | Harmen P. Hendriksma | The Hebrew University of Jerusalem | 2014-08-28 | 1 | New Results | cc_by_nc_nd | Animal Behavior and Cognition | https://www.biorxiv.org/content/early/2014/08/28/008516.source.xml | Honey bees are important pollinators, requiring floral pollen and nectar for nutrition. Nectar is rich in sugars, but contains additional nutrients, including amino acids (AAs). We tested the preferences of free-flying foragers between 20 AAs at 0.1% w/w in sucrose solutions in an artificial meadow. We found consistent preferences amongst AAs, with essential AAs preferred over nonessential AAs. The preference of foragers correlated negatively with AA induced deviations in pH values, as compared to the control. Next, we quantified tradeoffs between attractive and deterrent AAs at the expense of carbohydrates in nectar. Bees were attracted by phenylalanine, willing to give up 84 units sucrose for 1 unit AA. They were deterred by glycine, and adding 100 or more units of sucrose could resolve to offset 1 unit AA. In addition, we tested physiological effects of AA nutrition on forager homing performance. In a no-choice context, caged bees showed indifference to 0.1% proline, leucine, glycine or phenylanaline in sucrose solutions. Furthermore, flight tests gave no indication that AA nutrition affected flight capacity directly. In contrast, low carbohydrate nutrition reduced the performance of bees, with important methodological implications for homing studies that evaluate the effect of substances that may affect imbibition of sugar solution. In conclusion, low AA concentrations in nectar relative to pollen suggest a limited role in bee nutrition. Most of the 20 AAs evoked a neutral to a mild deterrent response in bees, thus it seems unlikely that bees respond to AAs in nectar as a cue to assess nutritional quality. Nonetheless, free choice behavior of foraging bees is influenced, for instance by phenylalanine and glycine. Thus, AAs in nectar may affect plant-pollinator interactions and thereby exhibit a selective pressure on the flora in the honey bee habitat.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC=\"FIGDIR/small/008516_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (31K):\[email protected]@138fdd3org.highwire.dtl.DTLVardef@a05775org.highwire.dtl.DTLVardef@cde793_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTS- Amino acids in artificial nectar elicit preferences from honey bee foragers\n- Amino acid identity, pH, and essentiality explain preferences of bees\n- A honey bee forager is willing to pay a premium of carbohydrates for amino acids\n- Carbohydrate nutritional state affects flight performance of foraging bees | 10.1016/j.jinsphys.2014.05.025 | biorxiv | 916 |
10.1101/008524 | Nutritional aspects of honey bee-collected pollen and constraints on colony development in the eastern Mediterranean | Dorit Avni;Harmen P. Hendriksma;Arnon Dag;Zehava Uni;Sharoni Shafir; | Harmen P. Hendriksma | The Hebrew University of Jerusalem | 2014-08-28 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/08/28/008524.source.xml | *Graphical Abstract (for review)\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC=\"FIGDIR/small/008524_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (25K):\[email protected]@9b33e3org.highwire.dtl.DTLVardef@16ba880org.highwire.dtl.DTLVardef@103a08b_HPS_FORMAT_FIGEXP M_FIG C_FIG *Highlights (for review)O_LIHoney bee colonies in Israel collect a mean 7 kg protein and 0.7 kg fat per year\nC_LIO_LIAt maximal colony development, honey bee queens lay up to 3,300 eggs per day\nC_LIO_LIAmount and content of collected pollen differ between sites and seasons\nC_LIO_LIPollen linoleic acid and protein levels best describe bee production cost\nC_LIO_LIColonies seem limited first by climate, then protein and finally specific nutrients\nC_LI\n\nABSTRACTPollen is the main protein and lipid source for honey bees (Apis mellifera), and nutritionally impoverished landscapes pose a threat to colony development. To determine colony nutritional demands, we analyzed a yearly cycle of bee-collected pollen from colonies in the field and compared it to colony worker production and honey bee body composition, for the first time in social insects. We monitored monthly bee production in ten colonies at each of seven sites throughout Israel, and trapped pollen bi-monthly in five additional colonies at each of four of these sites. Pollen mixtures from each sampling date and site were analyzed for weight, total protein, total fatty acids (FAs), and FA composition. Compared to more temperate climates, the eastern Mediterranean allows a relatively high yearly colony growth of ca. 300,000 to 400,000 bees. Colonies at higher elevation above sea level showed lower growth rates. Queen egg-laying rate did not seem to limit growth, as peaks in capped brood areas showed that queens lay a prolific 2,000 eggs a day on average, with up to 3,300 eggs in individual cases. Pollen uptake varied significantly among sites and seasons, with an overall annual mean total 16.8 kg per colony, containing 7.14 kg protein and 677 g fat. Overall mean pollen protein content was high (39.8%), and mean total FA content was 3.8%. Production cost, as expressed by the amount of nutrient used per bee, was least variable for linoleic acid and protein, suggesting these as the best descriptive variables for total number of bees produced. Linolenic acid levels in pollen during the autumn were relatively low, and supplementing colonies with this essential FA may mitigate potential nutritional deficiency. The essentiality of linoleic and linolenic acids was consistent with these FAs tendency to be present at higher levels in collected pollen than in the expected nutrients in bee bodies, demonstrating a well-developed adjustment between pollinator nutritional demands and the nutritional value of food offered by pollinated plants. | 10.1016/j.jinsphys.2014.07.001 | biorxiv | 917 |
10.1101/008540 | Sensitivity of quantitative traits to mutational effects, number of loci, and population history | Joshua G. Schraiber;Michael J. Landis; | Joshua G. Schraiber | University of Washington | 2014-09-04 | 2 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/04/008540.source.xml | When models of quantitative genetic variation are built from population genetic first principles, several assumptions are often made. One of the most important assumptions is that traits are controlled by many genes of small effect. This leads to a prediction of a Gaussian trait distribution in the population, via the Central Limit Theorem. Since these biological assumptions are often unknown or untrue, we characterized how finite numbers of loci or large mutational effects can impact the sampling distribution of a quantitative trait. To do so, we developed a neutral coalescent-based framework, allowing us to experiment freely with the number of loci and the underlying mutational model. Through both analytical theory and simulation we found the normality assumption was highly sensitive to the details of the mutational process, with the greatest discrepancies arising when the number of loci was small or the mutational kernel was heavy-tailed. In particular, fat-tailed mutational kernels result in multimodal sampling distributions for any number of loci. An empirical analysis of 7079 expressed genes in 49 Neurospora crassa strains identified 116 genes with non-normal sampling distributions. Several genes showed evidence of multimodality and/or skewness, suggesting the importance of their genetic architecture. Since selection models and robust neutral models may produce qualitatively similar sampling distributions, we advise extra caution should be taken when interpreting model-based results for poorly understood systems of quantitative traits. | NA | biorxiv | 919 |
10.1101/008532 | C. elegans harbors pervasive cryptic genetic variation for embryogenesis | Annalise Paaby;Amelia White;David Riccardi;Kristin Gunsalus;Fabio Piano;Matthew Rockman; | Annalise Paaby | New York University | 2014-08-28 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/08/28/008532.source.xml | Conditionally functional mutations are an important class of natural genetic variation, yet little is known about their prevalence in natural populations or their contribution to disease risk. Here, we describe a vast reserve of cryptic genetic variation, alleles that are normally silent but which affect phenotype when the function of other genes is perturbed, in the gene networks of C. elegans embryogenesis. We find evidence that cryptic-effect loci are ubiquitous and segregate at intermediate frequencies in the wild. The cryptic alleles demonstrate low developmental pleiotropy, in that specific, rather than general, perturbations are required to reveal them. Our findings underscore the importance of genetic background in characterizing gene function and provide a model for the expression of conditionally functional effects that may be fundamental in basic mechanisms of trait evolution and the genetic basis of disease susceptibility. | 10.7554/eLife.09178 | biorxiv | 920 |
10.1101/008490 | The Genetic Architecture of Gene Expression Levels in Wild Baboons | Jenny Tung;Xiang Zhou;Susan C Alberts;Matthew Stephens;Yoav Gilad; | Yoav Gilad | University of Chicago | 2014-08-28 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/08/28/008490.source.xml | Gene expression variation is well documented in human populations and its genetic architecture has been extensively explored. However, we still know little about the genetic architecture of gene expression variation in other species, particularly our closest living relatives, the nonhuman primates. To address this gap, we performed an RNA sequencing (RNA-seq)-based study of 63 wild baboons, members of the intensively studied Amboseli baboon population in Kenya. Our study design allowed us to measure gene expression levels and identify genetic variants using the same data set, enabling us to perform complementary mapping of putative cis-acting expression quantitative trait loci (eQTL) and measurements of allele-specific expression (ASE) levels. We discovered substantial evidence for genetic effects on gene expression levels in this population. Surprisingly, we found more power to detect individual eQTL in the baboons relative to a HapMap human data set of comparable size, probably as a result of greater genetic variation, enrichment of SNPs with high minor allele frequencies, and longer-range linkage disequilibrium in the baboons. eQTL were most likely to be identified for lineage-specific, rapidly evolving genes. Interestingly, genes with eQTL significantly overlapped between the baboon and human data sets, suggesting that some genes may tolerate more genetic perturbation than others, and that this property may be conserved across species. Finally, we used a Bayesian sparse linear mixed model to partition genetic, demographic, and early environmental contributions to variation in gene expression levels. We found a strong genetic contribution to gene expression levels for almost all genes, while individual demographic and environmental effects tended to be more modest. Together, our results establish the feasibility of eQTL mapping using RNA-seq data alone, and act as an important first step towards understanding the genetic architecture of gene expression variation in nonhuman primates. | 10.7554/eLife.04729 | biorxiv | 921 |
10.1101/008557 | Local Fields of the Hippocampus: More than Meets the Eye | Gautam Agarwal; | Gautam Agarwal | Champalimaud Centre for the Unknown | 2014-08-29 | 1 | New Results | cc_by_nc | Neuroscience | https://www.biorxiv.org/content/early/2014/08/29/008557.source.xml | A standard methodology in systems neuroscience is to establish correlations between the brain and the world. These correlations have been robustly observed when probing the activity of single neurons. For example, there are cells that activate vigorously when subjects are presented with images of certain celebrities (e.g. the \"Jennifer Aniston\" neuron, Quiroga et al., 2005). While single neuron measurements provide remarkable insights into the functional specificity of different brain areas, it remains unclear how single cell activity arises from, and contributes to, the collective activity of brain networks. New technologies allow for the simultaneous recording of spikes from hundreds of cells, yet we are still far from observing entire neuronal circuits in action.\n\nAn alternative approach in monitoring neuronal populations is to measure local field potentials (LFPs). These potentials arise from the coordinated activity of thousands of nearby neurons. LFPs often exhibit oscillations of various frequencies, which correlate with different states of awareness, such as alertness, relaxation, or drowsiness. However, establishing correlations between LFPs and specific behavioral events can be challenging, because the contributions of different neurons to the LFP usually cannot be distinguished. In this chapter, we examine LFPs recorded from the rat hippocampus. At first glance, these LFPs appear to bear little relation to the subjects changing environment. However, through appropriate signal processing, we find that carried in the structure of the LFP is a remarkably precise stream of information (Agarwal et al., 2014). | NA | biorxiv | 922 |
10.1101/008565 | Neuronal control of locomotor handedness in Drosophila | Sean M Buchanan;Jamey S Kain;Benjamin L de Bivort; | Benjamin L de Bivort | Harvard University | 2014-08-29 | 1 | New Results | cc_by | Neuroscience | https://www.biorxiv.org/content/early/2014/08/29/008565.source.xml | Handedness in humans-better performance using either the left or right hand-is personally familiar, moderately heritable, and regulated by many genes, including those involved in general body symmetry. But behavioral handedness, i.e. lateralization, is a multifaceted phenomenon. For example, people display clockwise or counter- clockwise biases in their walking behavior that is uncorrelated to their hand dominance, and lateralized behavioral biases have been shown in species as disparate as mice (paw usage), octopi (eye usage), and tortoises (side rolled on during righting). However, the mechanisms by which asymmetries are instilled in behavior are unknown, and a system for studying behavioral handedness in a genetically tractable model system is needed. Here we show that Drosophila melanogaster flies exhibit striking variability in their left-right choice behavior during locomotion. Very strongly biased \"left-handed\" and \"right-handed\" individuals are common in every line assayed. The handedness of an individual persists for its lifetime, but is not passed on to progeny, suggesting that mechanisms other than genetics determine individual handedness. We use the Drosophila transgenic toolkit to map a specific set of neurons within the central complex that regulates the strength of behavioral handedness within a line. These findings give insights into choice behaviors and laterality in a simple model organism, and demonstrate that individuals from isogenic populations reared under experimentally identical conditions nevertheless display idiosyncratic behaviors. | 10.1073/pnas.1500804112 | biorxiv | 923 |
10.1101/008607 | Mucosal effects of tenofovir 1% gel | Florian Hladik;Adam Burgener;Lamar Ballweber;Raphael Gottardo;Slim Fourati;James Y Dai;Mark J Cameron;Lucia Vojtech;Johanna Strobl;Sean M Hughes;Craig Hoesley;Philip Andrew;Sherri Johnson;Jeanna Piper;David R Friend;T Blake Ball;Ross D. Cranston;Kenneth H Mayer;M Juliana McElrath;Ian McGowan; | Florian Hladik | Fred Hutchinson Cancer Research Center | 2014-09-01 | 1 | New Results | cc_no | Microbiology | https://www.biorxiv.org/content/early/2014/09/01/008607.source.xml | BACKGROUNDTenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa.\n\nMETHODS AND FINDINGSIn MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than--but different from--those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir's presence.\n\nCONCLUSIONSTenofovir's suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations. | 10.7554/eLife.04525 | biorxiv | 926 |
10.1101/008649 | Conditional U1 Gene Silencing in Toxoplasma gondii | Manuela S Pieperhoff;Gurman S Pall;Elena Jimenez-Ruis;Sujaan Das;Eleanor H Wong;Joanne Heng;Sylke Mueller;Michael J Blackman;Markus Meissner; | Markus Meissner | University of Glasgow | 2014-09-01 | 1 | New Results | cc_by_nd | Molecular Biology | https://www.biorxiv.org/content/early/2014/09/01/008649.source.xml | In absence of powerful siRNA approaches, the functional characterisation of essential genes in apicomplexan parasites, such as Toxoplasma gondii or Plasmodium falciparum, relies on conditional mutagenesis systems. Here we present a novel strategy based on U1 snRNP-mediated gene silencing. U1 snRNP is critical in pre-mRNA splicing by defining the exonintron boundaries. When a U1 recognition site is placed into the 3-terminal exon or adjacent to the termination codon, pre-mRNA is cleaved at the 3-end and degraded, leading to an efficient knockdown of the gene of interest (GOI). Here we describe a simple one-step approach that combines endogenous tagging with DiCre-mediated positioning of U1 recognition sites adjacent to the termination codon of the GOI which leads to a conditional knockdown of the GOI in Ku80 knockout and RH T. gondii tachyzoites. Specific knockdown mutants of the reporter gene GFP and several endogenous genes of T. gondii including the clathrin heavy chain gene 1 (chc1), the vacuolar protein sorting gene 26 (vps26), and the dynamin-related protein C gene (drpC) were silenced using this new approach. This new gene silencing tool kit allows protein tracking and functional studies simultaneously. | 10.1371/journal.pone.0130356 | biorxiv | 927 |
10.1101/008656 | BoCluSt: bootstrap clustering stability algorithm for community detection in networks | Carlos Garcia; | Carlos Garcia | Santiago de Compostela University | 2014-09-02 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/02/008656.source.xml | The identification of modules or communities of related variables is a key step in the analysis and modelling of biological systems. Many module identification procedures are available, but few of these can determine the module partitions best fitting a given dataset in the absence of previous information, in an unsupervised way, and when the links between variables have different weights. Here I propose such a procedure, which uses the stability under bootstrap resampling of different alternative module structures as a criterion to identify the structure best fitting to a set of variables. In its present implementation, the procedure uses linear correlations as link weights. Computer simulations show that the procedure is useful for problems involving moderate numbers of variables, such as those commonly found in gene regulation cascades or metabolic pathways, and also that it can detect hierarchical network structures, in which modules are composed of smaller sub modules. The procedure becomes less practical as the number of variables increases, due to increases in processing time.The proposed procedure may be a valuable and robust network analysis tool. Because it is based on comparing the amount of evidence for different module partitions structures, this procedure may detect the existence of hierarchical network structures. | NA | biorxiv | 928 |
10.1101/008698 | ProbAlign: a re-alignment method for long sequencing reads | Feng Zeng;Rui Jiang;Guoli Ji;Ting Chen; | Feng Zeng | Xiamen University | 2014-09-02 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/02/008698.source.xml | The incorrect alignments are a severe problem in variant calling, and remain as a challenge computational issue in Bioinformatics field. Although there have been some methods utilizing the re-alignment approach to tackle the misalignments, a standalone re-alignment tool for long sequencing reads is lacking. Hence, we present a standalone tool to correct the misalignments, called ProbAlign. It can be integrated into the pipelines of not only variant calling but also other genomic applications. We demonstrate the use of re-alignment in two diverse and important genomics fields: variant calling and viral quasispecies reconstruction. First, variant calling results in the Pacific Biosciences SMRT re-sequencing data of NA12878 show that false positives can be reduced by 43.5%, and true positives can be increased by 24.8% averagely, after re-alignment. Second, results in reconstructing a 5-virus-mix show that the viral population can be completely unraveled, and also the estimation of quasispecies frequencies has been improved, after re-alignment. ProbAlign is freely available in the PyroTools toolkit (https://github.com/homopolymer/PyroTools). | NA | biorxiv | 929 |
10.1101/008631 | A Fast 3 x N Matrix Multiply Routine for Calculation of Protein RMSD | Imran S Haque;Kyle A Beauchamp;Vijay S Pande; | Imran S Haque | Stanford University | 2014-09-02 | 1 | New Results | cc_by | Biophysics | https://www.biorxiv.org/content/early/2014/09/02/008631.source.xml | The bottleneck for the rapid calculation of the root-mean-square deviation in atomic coordinates (RMSD) between pairs of protein structures for large numbers of conformations is the evaluation of a 3 x N x N x 3 matrix product over conformation pairs. Here we describe two matrix multiply routines specialized for the 3 x N case that are able to significantly outperform (by up to 3X) off-the-shelf high-performance linear algebra libraries for this computation, reaching machine limits on performance. The routines are implemented in C and Python libraries, and are available at https://github.com/simtk/IRMSD. | NA | biorxiv | 930 |
10.1101/008730 | Dimorphic development in Streblospio benedicti: genetic analysis of morphological differences between larval types | Christina Zakas;Matthew V Rockman; | Matthew V Rockman | New York University | 2014-09-02 | 1 | New Results | cc_no | Developmental Biology | https://www.biorxiv.org/content/early/2014/09/02/008730.source.xml | The marine polychaete Streblospio benedicti exhibits two distinct larval types, making it a model for the study of developmental evolution. Females produce either large eggs or small ones, which develop into distinct lecithotrophic or planktotrophic larvae with concomitant morphological and life-history differences. Here, we investigate the inheritance of key morphological traits that distinguish the larval types. We use genetic crosses to establish the influence of maternal and zygotic differences on larval phenotypes. We find a large maternal effect on larval size and the number of larval chaetae, while the number and length of these chaetae are also strongly influenced by zygotic genotype. Interestingly, the distribution of larval phenotypes produced by these crosses suggests traits intermediate to the two parental types should not be uncommon. Yet, despite gene flow between the types in natural populations, such intermediates are rarely found in nature, suggesting that selection may be maintaining distinct larval modes. | 10.1387/ijdb.140088mr | biorxiv | 931 |
10.1101/008680 | Rate and cost of adaptation in the Drosophila genome | Stephan Schiffels;Michael Lässig;Ville Mustonen; | Stephan Schiffels | Wellcome Trust Sanger Institute | 2014-09-02 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/02/008680.source.xml | Recent studies have consistently inferred high rates of adaptive molecular evolution between Drosophila species. At the same time, the Drosophila genome evolves under different rates of recombination, which results in partial genetic linkage between alleles at neighboring genomic loci. Here we analyze how linkage correlations affect adaptive evolution. We develop a new inference method for adaptation that takes into account the effect on an allele at a focal site caused by neighboring deleterious alleles (background selection) and by neighboring adaptive substitutions (hitchhiking). Using complete genome sequence data and fine-scale recombination maps, we infer a highly heterogeneous scenario of adaptation in Drosophila. In high-recombining regions, about 50% of all amino acid substitutions are adaptive, together with about 20% of all substitutions in proximal intergenic regions. In low-recombining regions, only a small fraction of the amino acid substitutions are adaptive, while hitchhiking accounts for the majority of these changes. Hitchhiking of deleterious alleles generates a substantial collateral cost of adaptation, leading to a fitness decline of about 30/2N per gene and per million years in the lowest-recombining regions. Our results show how recombination shapes rate and efficacy of the adaptive dynamics in eukaryotic genomes. | NA | biorxiv | 934 |
10.1101/008748 | OncoRep: An n-of-1 reporting tool to support genome-guided treatment for breast cancer patients using RNA-sequencing | Tobias Meißner;Kathleen M. Fisch;Louis Gioia;Andrew I. Su; | Andrew I. Su | The Scripps Research Institute | 2014-09-03 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/03/008748.source.xml | Breast cancer comprises multiple tumor entities associated with different biological features and clinical behaviors, making individualized medicine a powerful tool to bring the right drug to the right patient. Next generation sequencing of RNA (RNA-Seq) is a suitable method to detect targets for individualized treatment. Challenges that arise are i) preprocessing and analyzing RNA-Seq data in the n-of-1 setting, ii) extracting clinically relevant and action-able targets from complex data, iii) integrating drug databases, and iv) reporting results to clinicians in a timely and understandable manner. To address these challenges, we present OncoRep, an RNA-Seq based n-of-1 reporting tool for breast cancer patients. It reports molecular classi[fi]cation, altered genes and pathways, gene fusions, clinically actionable mutations and drug recommendations. It visualizes the data in an approachable html-based interactive report and a PDF clinical report, providing the clinician and tumor board with a tool to guide the treatment decision making process. OncoRep is free and open-source, thereby offering a platform for future development and innovation by the community. | 10.1186/s12920-015-0095-z | biorxiv | 937 |
10.1101/008664 | Tracing the genetic origin of Europe’s first farmers reveals insights into their social organization | Anna Szécsényi-Nagy;Guido Brandt;Victoria Keerl;János Jakucs;Wolfgang Haak;Sabine Möller-Rieker;Kitti Köhler;Balázs Mende;Marc Fecher;Krisztián Oross;Tibor Paluch;Anett Osztás;Viktória Kiss;György Pálfi;Erika Molnár;Katalin Sebők;András Czene;Tibor Paluch;Mario Šlaus;Mario Novak;Nives Pećina-Šlaus;Brigitta Ősz;Vanda Voicsek;Krisztina Somogyi;Gábor Tóth;Bernd Kromer;Eszter Bánffy;Kurt Alt; | Anna Szécsényi-Nagy | HAS, Research Centre for the Humanities | 2014-09-03 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/09/03/008664.source.xml | Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis has not been revealed yet. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starevo and LBK sites (7th/6th millennium BC) from the Carpathian Basin and south-eastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early farming south-eastern European and Carpathian Basin cultures on Central European populations of the 6th-4th millennium BC. Our comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through south-eastern Europe and the Carpathian Basin into Central Europe. Our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting patrilineal descent system and patrilocal residential rules among the early farmers. | 10.1098/rspb.2015.0339 | biorxiv | 938 |
10.1101/008839 | Glucose-lactate metabolic cooperation in cancer: insights from a spatial mathematical model and implications for targeted therapy | Jessica McGillen;Catherine J Kelly;Alicia Martinez-Gonzalez;Natasha K Martin;Eamonn A Gaffney;Philip K Maini;Victor M Perez-Garcia; | Jessica McGillen | University of Oxford | 2014-09-04 | 1 | New Results | cc_no | Cancer Biology | https://www.biorxiv.org/content/early/2014/09/04/008839.source.xml | A recent hypothesis has proposed a glucose-lactate metabolic symbiosis between adjacent hypoxic and oxygenated regions of a developing tumour, and proposed a treatment strategy to target this symbiosis. However, in vivo experimental support remains inconclusive. Here we develop a minimal spatial mathematical model of glucose-lactate metabolism to examine, in principle, whether metabolic symbiosis is plausible in human tumours, and to assess the potential impact of inhibiting it. We find that symbiosis is a robust feature of our model system--although on the length scale at which oxygen supply is diffusion-limited, its occurrence requires very high cellular metabolic activity--and that necrosis in the tumour core is reduced in the presence of symbiosis. Upon simulating therapeutic inhibition of lactate uptake, we predict that targeted treatment increases the extent of tissue oxygenation without increasing core necrosis. The oxygenation effect is correlated strongly with the extent of wildtype hypoxia and only weakly with wildtype symbiotic behaviour, and therefore may be promising for radiosensitisation of hypoxic, lactate-consuming tumours even if they do not exhibit a spatially well-defined symbiosis. Finally, we conduct a set of in vitro experiments on the U87 glioblastoma cell line to facilitate preliminary speculation as to where highly malignant tumours might fall in our parameter space, and find that these experiments suggest a weakly symbiotic regime for U87 cells, which raises the new question of what relationship exists between symbiosis--if indeed it occurs in vivo--and tumour malignancy. | 10.1016/j.jtbi.2014.09.018 | biorxiv | 940 |
10.1101/008755 | Mixed Model with Correction for Case-Control Ascertainment Increases Association Power | tristan hayeck;Noah Zaitlen;Po-Ru Loh;Bjarni Vilhjalmsson;Samuela Pollack;Alexander Gusev;Jian Yang;Guo-Bo Chen;Michael E. Goddard;Peter M. Visscher;Nick Patterson;Alkes Price; | tristan hayeck | Harvard School of Public Health | 2014-09-04 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/09/04/008755.source.xml | We introduce a Liability Threshold Mixed Linear Model (LTMLM) association statistic for ascertained case-control studies that increases power vs. existing mixed model methods, with a well-controlled false-positive rate. Recent work has shown that existing mixed model methods suffer a loss in power under case-control ascertainment, but no solution has been proposed. Here, we solve this problem using a chi-square score statistic computed from posterior mean liabilities (PML) under the liability threshold model. Each individuals PML is conditional not only on that individuals case-control status, but also on every individuals case-control status and on the genetic relationship matrix obtained from the data. The PML are estimated using a multivariate Gibbs sampler, with the liability-scale phenotypic covariance matrix based on the genetic relationship matrix (GRM) and a heritability parameter estimated via Haseman-Elston regression on case-control phenotypes followed by transformation to liability scale. In simulations of unrelated individuals, the LTMLM statistic was correctly calibrated and achieved higher power than existing mixed model methods in all scenarios tested, with the magnitude of the improvement depending on sample size and severity of case-control ascertainment. In a WTCCC2 multiple sclerosis data set with >10,000 samples, LTMLM was correctly calibrated and attained a 4.1% improvement (P = 0.007) in chi-square statistics (vs. existing mixed model methods) at 75 known associated SNPs, consistent with simulations. Larger increases in power are expected at larger sample sizes. In conclusion, an increase in power over existing mixed model methods is available for ascertained case-control studies of diseases with low prevalence. | 10.1016/j.ajhg.2015.03.004 | biorxiv | 942 |
10.1101/008771 | Synthetic logic circuits using RNA aptamer against T7 RNA polymerase | Jongmin Kim;Juan F Quijano;Enoch Yeung;Richard M Murray; | Jongmin Kim | California Institute of Technology | 2014-09-04 | 1 | New Results | cc_by_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2014/09/04/008771.source.xml | Recent advances in nucleic acids engineering introduced several RNA-based regulatory components for synthetic gene circuits, expanding the toolsets to engineer organisms. In this work, we designed genetic circuits implementing an RNA aptamer previously described to have the capability of binding to the T7 RNA polymerase and inhibiting its activity in vitro. Using in vitro transcription assays, we first demonstrated the utility of the RNA aptamer in combination with programmable synthetic transcription networks. As a step to quickly assess the feasibility of aptamer functions in vivo, a cell-free expression system was used as a breadboard to emulate the in vivo conditions of E. coli. We tested the aptamer and its three sequence variants in the cell-free expression system, verifying the aptamer functionality in the cell-free testbed. In vivo expression of aptamer and its variants demonstrated control over GFP expression driven by T7 RNA polymerase with different response curves, indicating its ability to serve as building blocks for both logic circuits and transcriptional cascades. This work elucidates the potential of RNA-based regulators for cell programming with improved controllability leveraging the fast production and degradation time scales of RNA molecules. | 10.1002/biot.202000449 | biorxiv | 946 |
10.1101/008847 | DiffVar: A new method for detecting differential variability with application to methylation in cancer and aging | Belinda Phipson;Alicia Oshlack; | Belinda Phipson | Murdoch Childrens Research Institute | 2014-09-06 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/06/008847.source.xml | Methylation of DNA is known to be essential to development and dramatically altered in cancers. The Illumina HumanMethylation450 BeadChip has been used extensively as a cost-effective way to profile nearly half a million CpG sites across the human genome. Here we present DiffVar, a novel method to test for differential variability between sample groups. DiffVar employs an empirical Bayes model framework that can take into account any experimental design and is robust to outliers. We applied DiffVar to several datasets from The Cancer Genome Atlas, as well as an aging dataset. DiffVar is available in the missMethyl Bioconductor R package. | 10.1186/s13059-014-0465-4 | biorxiv | 947 |
10.1101/008862 | Generation of a Panel of Induced Pluripotent Stem Cells From Chimpanzees: a Resource for Comparative Functional Genomics | Irene Gallego Romero;Bryan J Pavlovic;Irene Hernando-Herraez;Nicholas E Banovich;Courtney L Kagan;Jonathan E Burnett;Constance H Huang;Amy Mitrano;Claudia I Chavarria;Inbar F Ben-Nun;Yingchun Li;Karen Sabatini;Trevor R Leonardo;Mana Parast;Tomas Marques-Bonet;Louise C Laurent;Jeanne F Loring;Yoav Gilad; | Irene Gallego Romero | University of Chicago | 2014-09-08 | 2 | New Results | cc_by_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/08/008862.source.xml | Comparative genomics studies in primates are extremely restricted because we only have access to a few types of cell lines from non-human apes and to a limited collection of frozen tissues. In order to gain better insight into regulatory processes that underlie variation in complex phenotypes, we must have access to faithful model systems for a wide range of tissues and cell types. To facilitate this, we have generated a panel of 7 fully characterized chimpanzee (Pan troglodytes) induced pluripotent stem cell (iPSC) lines derived from fibroblasts of healthy donors. All lines appear to be free of integration from exogenous reprogramming vectors, can be maintained using standard iPSC culture techniques, and have proliferative and differentiation potential similar to human and mouse lines. To begin demonstrating the utility of comparative iPSC panels, we collected RNA sequencing data and methylation profiles from the chimpanzee iPSCs and their corresponding fibroblast precursors, as well as from 7 human iPSCs and their precursors, which were of multiple cell type and population origins. Overall, we observed much less regulatory variation within species in the iPSCs than in the somatic precursors, indicating that the reprogramming process has erased many of the differences observed between somatic cells of different origins. We identified 4,918 differentially expressed genes and 3,598 differentially methylated regions between iPSCs of the two species, many of which are novel inter-species differences that were not observed between the somatic cells of the two species. Our panel will help realise the potential of iPSCs in primate studies, and in combination with genomic technologies, transform studies of comparative evolution. | NA | biorxiv | 950 |
10.1101/008854 | Myoinhibitory peptide regulates feeding in the marine annelid Platynereis | Elizabeth A Williams;Markus Conzelmann;Gáspár Jékely; | Géspér Jékely | Max Planck Institute for Developmental Biology | 2014-09-08 | 1 | New Results | cc_by | Zoology | https://www.biorxiv.org/content/early/2014/09/08/008854.source.xml | During larval settlement and metamorphosis, marine invertebrates undergo changes in habitat, morphology, behavior and physiology. This change between life-cycle stages is often associated with a change in diet or a transition between a non-feeding and a feeding form. How larvae regulate changes in feeding during this life cycle transition is not well understood. Neuropeptides are known to regulate several aspects of feeding, such as food search, ingestion and digestion. The marine annelid Platynereis dumerilii has a complex life cycle with a pelagic non-feeding larval stage and a benthic feeding postlarval stage, linked by the process of settlement. The conserved neuropeptide myoinhibitory peptide (MIP) is a key regulator of larval settlement behavior in Platynereis. Whether MIP also regulates the initiation of feeding, another aspect of the pelagic-to-benthic transition in Platynereis, is currently unknown. Here, we explore the contribution of MIP to feeding in settled Platynereis postlarvae. We find that MIP is expressed in the gut of developing larvae in sensory neurons that densely innervate the foregut and hindgut. Activating MIP signaling by synthetic neuropeptide addition causes increased gut peristalsis and more frequent pharynx extensions leading to increased food intake. Conversely, morpholino-mediated knockdown of MIP expression inhibits feeding. In the long-term, treatment of Platynereis postlarvae with synthetic MIP increases growth rate and results in earlier cephalic metamorphosis. Our results show that MIP activates ingestion and digestion in Platynereis postlarvae. MIP is expressed in sensory-neurosecretory cells of the digestive system indicating that following larval settlement, feeding is initiated by a direct sensory mechanism. This is similar to the mechanism by which MIP induces larval settlement. The pleiotropic roles of MIP may thus have evolved by redeploying the same signaling mechanism in different aspects of a life cycle transition. | 10.1186/s12983-014-0093-6 | biorxiv | 951 |
10.1101/008896 | MDTraj: a modern, open library for the analysis of molecular dynamics trajectories | Robert T McGibbon;Kyle A Beauchamp;Christian R Schwantes;Lee-Ping Wang;Carlos X Hernández;Matthew P Harrigan;Thomas J Lane;Jason M Swails;Vijay S Pande; | Robert T McGibbon | Stanford University | 2014-09-09 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/09/008896.source.xml | Summary: MDTraj is a modern, lightweight and efficient software package for analyzing molecular dynamics simulations. MDTraj reads trajectory data from a wide variety of commonly used formats. It provides a large number of trajectory analysis capabilities including RMSD, DSSP secondary structure assignment and the extraction of common order parameters. The package has a strong focus on interoperability with the wider scientific Python ecosystem, bridging the gap between molecular dynamics data and the rapidly-growing collection of industry-standard statistical analysis and visualization tools in Python. Availability: Package downloads, detailed examples and full documentation are available at http://mdtraj.org. The source code is distributed under the GNU Lesser General Public License at https://github.com/simtk/mdtraj. | 10.1016/j.bpj.2015.08.015 | biorxiv | 952 |
10.1101/008904 | SPOILS OF WAR AND PEACE: ENEMY ADOPTION AND QUEEN-RIGHT COLONY FUSION FOLLOW COSTLY INTRASPECIFIC CONFLICT IN ACACIA ANTS | Kathleen P. Rudolph;Jay P. McEntee; | Kathleen P. Rudolph | University of Florida | 2014-09-08 | 1 | New Results | cc_no | Animal Behavior and Cognition | https://www.biorxiv.org/content/early/2014/09/08/008904.source.xml | Intraspecific conflict over vital limited resources can lead to costly fights. How winners compensate for costs and minimize the threat of Pyrrhic victory is not well known. This study tracked the outcomes of experimentally induced field conflicts between highly territorial Acacia ant Crematogaster mimosae colonies using molecular genetics, and discovered that fatal fights significantly decrease within-colony worker relatedness. We find that reduced relatedness can be explained by colonies increasing worker number via 1) non-kin enemy adoption or 2) queen-right colony fusion. We hypothesize that incorporating non-kin enemies can speed recovery from conflict when resource defense is paramount. In the case of queen-right colony fusion, territorial defense benefits could outweigh fitness costs. We provide evidence that winners of colony fights have reduced worker forces to defend larger territories. Field assays indicate that post-fight colonies are more vulnerable to heavy browsing of host trees by mega-herbivores and takeover by competitors following conflict. We discuss the implications of our findings for ant colony cohesion and recognition systems. | NA | biorxiv | 953 |
10.1101/008912 | Genome-wide characterization of RNA editing in chicken: lack of evidence for non-A-to-I events | Laure Frésard;Sophie Leroux;Pierre-François Roux;C Klopp;Stéphane Fabre;Diane Esquerré;Patrice Dehais;Anis Djari;David Gourichon;Sandrine Lagarrigue;Frédérique Pitel; | Frédérique Pitel | UMR INRA / INPT ENSAT / INPT ENVT, GenPhySE, INRA, 31326 Castanet Tolosan, France | 2014-09-09 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/09/09/008912.source.xml | RNA editing corresponds to a post-transcriptional nucleotide change in the RNA sequence, creating an alternative nucleotide, not present in the DNA sequence. This leads to a diversification of transcription products with potential functional consequences. Two nucleotide substitutions are mainly described in animals, from adenosine to inosine (A-to-I) and from cytidine to uridine (C-to-U). This phenomenon is more and more described in mammals, notably since the availability of next generation sequencing technologies allowing a whole genome screening of RNA-DNA differences. The number of studies recording RNA editing in other vertebrates like chicken are still limited. We chose to use high throughput sequencing technologies to search for RNA editing in chicken, to understand to what extent this phenomenon is conserved in vertebrates. We performed RNA and DNA sequencing from 8 embryos. Being aware of common pitfalls inherent to sequence analyses leading to false positive discovery, we stringently filtered our datasets and found less than 40 reliable candidates. Conservation of particular sites of RNA editing was attested by the presence of 3 edited sites previously detected in mammals. We then characterized editing levels for selected candidates in several tissues and at different time points, from 4.5 days of embryonic development to adults, and observed a clear tissue-specificity and a gradual editing level increase with time. By characterizing the RNA editing landscape in chicken, our results highlight the extent of evolutionary conservation of this phenomenon within vertebrates, and provide support of an absence of non A-to-I events from the chicken transcriptome. | 10.1371/journal.pone.0126776 | biorxiv | 955 |
10.1101/008920 | Mechanisms for multiple activity modes of VTA dopamine neurons | Andrew M. Oster;Philippe Faure;Boris S. Gutkin; | Andrew M. Oster | Department of Mathematics, Eastern Washington University, Cheney, WA, USA | 2014-09-09 | 1 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/09/09/008920.source.xml | Midbrain ventral segmental area (VTA) dopaminergic neurons send numerous projections to cortical and sub-cortical areas, and diffusely release dopamine (DA) to their targets. DA neurons display a range of activity modes that vary in frequency and degree of burst firing. Importantly, DA neuronal bursting is associated with a significantly greater degree of DA release than an equivalent tonic activity pattern. Here, we introduce a single compartmental, conductance-based computational model for DA cell activity that captures the behavior of DA neuronal dynamics and examine the multiple factors that underlie DA firing modes: the strength of the SK conductance, the amount of drive, and GABA inhibition. Our results suggest that neurons with low SK conductance fire in a fast firing mode, are correlated with burst firing, and require higher levels of applied current before undergoing depolarization block. We go on to consider the role of GABAergic inhibition on an ensemble of dynamical classes of DA neurons and find that strong GABA inhibition suppresses burst firing. Our studies suggest differences in the distribution of the SK conductance and GABA inhibition levels may indicate subclasses of DA neurons within the VTA. We further identify, that by considering alternate potassium dynamics, the dynamics display burst patterns that terminate via depolarization block, akin to those observed in vivo in VTA DA neurons and in substantia nigra pars compacta DA cell preparations under apamin application. In addition, we consider the generation of transient burst firing events that are NMDA-initiated or elicited by a sudden decrease of GABA inhibition, that is, disinhibition. | 10.3389/fncom.2015.00095 | biorxiv | 956 |
10.1101/008946 | Extensive Decoupling of Metabolic Genes in Cancer | Ed Reznik;Chris Sander; | Ed Reznik | Computational Biology Center, Sloan-Kettering Institute | 2014-09-09 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/09/09/008946.source.xml | Tumorigenesis involves, among other factors, the alteration of metabolic gene expression to support malignant, unrestrained proliferation. Here, we examine how the altered metabolism of cancer cells is reflected in changes in co-expression patterns of metabolic genes between normal and tumor tissues. Our emphasis on changes in the interactions of pairs of genes, rather than on the expression levels of individual genes, exposes changes in the activity of metabolic pathways which do not necessarily show clear patterns of over- or under-expression. We report the existence of key metabolic genes which act as hubs of differential co-expression, showing significantly different co-regulation patterns between normal and tumor states. Notably, we find that the extent of differential co-expression of a gene is only weakly correlated with its differential expression, suggesting that the two measures probe different features of metabolism. By leveraging our findings against existing pathway knowledge, we extract networks of functionally connected differentially co-expressed genes and the transcription factors which regulate them. Doing so, we identify a previously unreported network of dysregulated metabolic genes in clear cell renal cell carcinoma transcriptionally controlled by the transcription factor HNF4A. While HNF4A shows no significant differential expression, the co-expression HNF4A and several of its regulated target genes in normal tissue is completely abrogated in tumor tissue. Finally, we aggregate the results of differential co-expression analysis across seven distinct cancer types to identify pairs of metabolic genes which may be recurrently dysregulated. Among our results is a cluster of four genes, all located in the mitochondrial electron transport chain, which show significant loss of co-expression in tumor tissue, pointing to potential mitochondrial dysfunction in these tumor types. | 10.1371/journal.pcbi.1004176 | biorxiv | 957 |
10.1101/008953 | The Sea Lamprey Meiotic Map Resolves Ancient Vertebrate Genome Duplications | Jeramiah Smith; | Jeramiah Smith | University of Kentucky | 2014-09-10 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2014/09/10/008953.source.xml | Gene and genome duplications serve as an important reservoir of material for the evolution of new biological functions. It is generally accepted that many genes present in vertebrate genomes owe their origin to two whole genome duplications that occurred deep in the ancestry of the vertebrate lineage. However, details regarding the timing and outcome of these duplications are not well resolved. We present high-density meiotic and comparative genomic maps for the sea lamprey, a representative of an ancient lineage that diverged from all other vertebrates approximately 550 million years ago. Linkage analyses yielded a total of 95 linkage groups, similar to the estimated number of germline chromosomes (1N [~] 99), spanning a total of 5,570.25 cM. Comparative mapping data yield strong support for one ancient whole genome duplication but do not strongly support a hypothetical second event. Rather, these comparative maps reveal several evolutionary independent segmental duplications occurring over the last 600+ million years of chordate evolution. This refined history of vertebrate genome duplication should permit more precise investigations into the evolution of vertebrate gene functions. | 10.1101/gr.184135.114 | biorxiv | 958 |
10.1101/008961 | Intrinsic cortical dynamics dominate population responses to natural images across human visual cortex | Linda Henriksson;Seyed-Mahdi Khaligh-Razavi;Kendrick Kay;Nikolaus Kriegeskorte; | Linda Henriksson | Aalto University | 2014-09-12 | 1 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/09/12/008961.source.xml | Intrinsic cortical dynamics are thought to underlie trial-to-trial variability of visually evoked responses in animal models. Understanding their function in the context of sensory processing and representation is a major current challenge. Here we report that intrinsic cortical dynamics strongly affect the representational geometry of a brain region, as reflected in response-pattern dissimilarities, and exaggerate the similarity of representations between brain regions. We characterized the representations in several human visual areas by representational dissimilarity matrices (RDMs) constructed from fMRI response-patterns for natural image stimuli. The RDMs of different visual areas were highly similar when the response-patterns were estimated on the basis of the same trials (sharing intrinsic cortical dynamics), and quite distinct when patterns were estimated on the basis of separate trials (sharing only the stimulus-driven component). We show that the greater similarity of the representational geometries can be explained by the coherent fluctuations of regional-mean activation within visual cortex, reflecting intrinsic dynamics. Using separate trials to study stimulus-driven representations revealed clearer distinctions between the representational geometries: a Gabor wavelet pyramid model explained representational geometry in visual areas V1-3 and a categorical animate- inanimate model in the object-responsive lateral occipital cortex. | 10.1016/j.neuroimage.2015.04.026 | biorxiv | 960 |
10.1101/008995 | General markers of conscious visual perception and their timing | Renate Rutiku;Jaan Aru;Annika Tallinn;Talis Bachmann; | Renate Rutiku | Institute of Psychology, University of Tartu | 2014-09-11 | 1 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/09/11/008995.source.xml | The goal of the present investigation was to identify reliable markers of conscious visual perception and to characterize their onset latency and its variability. To that end many visual stimuli from different categories were presented at near-threshold contrast and contrastive analyses were carried out on 100 balanced subsets of the data. N200 and P300 were the two reliable markers of conscious perception common to all perceived stimuli and absent for all non-perceived stimuli. The estimated mean onset latency for both markers was shortly after 200 ms. However, the onset latency of both of these markers of conscious perception showed considerable variability depending on which subsets of the data were considered. Some of this variability could be attributed to noise, but it was first and foremost the amplitude fluctuation in the condition without conscious perception that explained the variability in onset latencies of the markers of conscious perception. The present results help to understand why different studies have observed different onset times for the neural correlates of conscious perception. Moreover, the consciousness markers explored here have more generality as stimulus specificity was reduced. | 10.3389/fnhum.2016.00023 | biorxiv | 961 |
10.1101/009001 | Average genome size estimation enables accurate quantification of gene family abundance and sheds light on the functional ecology of the human microbiome | Stephen Nayfach;Katherine S Pollard; | Katherine S Pollard | Gladstone Institutes, University of California San Francisco | 2014-09-11 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/11/009001.source.xml | Average genome size (AGS) is an important, yet often overlooked property of microbial communities. We developed MicrobeCensus to rapidly and accurately estimate AGS from short-read metagenomics data and applied our tool to over 1,300 human microbiome samples. We found that AGS differs significantly within and between body sites and tracks with major functional and taxonomic differences. For example, in the gut, AGS ranges from 2.5 to 5.8 megabases and is positively correlated with the abundance of Bacteroides and polysaccharide metabolism. Furthermore, we found that AGS variation can bias comparative analyses, and that normalization improves detection of differentially abundant genes. | 10.1186/s13059-015-0611-7 | biorxiv | 962 |
10.1101/009100 | Conservation and structural analysis of the Xenopus laevis phospho-proteome | Jeffrey R Johnson;Silvia D Santos;Tasha Johnson;Ursula Pieper;Andrej Sali;Nevan J Krogan;Pedro Beltrao; | Pedro Beltrao | EMBL-EBI | 2014-09-14 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/14/009100.source.xml | The African clawed frog Xenopus laevis is an important model organism for studies in developmental and cell biology, including cell-signaling. However, our knowledge of X. laevis protein post-translational modifications remains scarce. Here, we used a mass spectrometry-based approach to survey the phosphoproteome of this species, compiling a list of 3225 phosphosites. We used this resource to study the conservation between the phosphoproteomes of X. laevis and 13 other species. We found that the degree of conservation of phosphorylation across species is predictive of sites with known molecular function, kinase interactions and functionally relevant phospho-regulatory interactions. In addition, using comparative protein structure models, we find that phosphosites within structured domains tend to be located at positions with high conformational flexibility. A fraction of sites appear to occur in inaccessible positions and have the potential to regulate protein conformation. | NA | biorxiv | 963 |
10.1101/009092 | Population genomic analysis uncovers African and European admixture in Drosophila melanogaster populations from the southeastern United States and Caribbean Islands | Joyce Y Kao;Asif Zubair;Matthew P Salomon;Sergey V Nuzhdin;Daniel Campo; | Joyce Y Kao | University of Southern California | 2014-09-13 | 1 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/09/13/009092.source.xml | Genome sequences from North American Drosophila melanogaster populations have become available to the scientific community. Deciphering the underlying population structure of these resources is crucial to make the most of these population genomic resources. Accepted models of North American colonization generally purport that several hundred years ago, flies from Africa and Europe were transported to the east coast United States and the Caribbean Islands respectively and thus current east coast US and Caribbean populations are an admixture of African and European ancestry. Theses models have been constructed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the southeast US and Caribbean Islands and examined these populations in conjunction with population sequences from Winters, CA, (USA); Raleigh, NC (USA); Cameroon (Africa); and Montpellier (France) to uncover the underlying population structure of North American populations. We find that west coast US populations are most like European populations likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in east coast US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude further supporting the proposed demographic model of Caribbean flies being established by African ancestors. Our genomic analysis of Caribbean flies is the first study that exposes the source of previously reported novel African alleles found in east coast US populations. | 10.1111/mec.13137 | biorxiv | 965 |
10.1101/009027 | Behavioral individuality reveals genetic control of phenotypic variability | Julien F Ayroles;Sean M Buchanan;Chelsea Jenney;Kyobi Skutt-Kakaria;Jennifer Grenier;Andrew G Clark;Daniel L Hartl;Benjamin L de Bivort; | Benjamin L de Bivort | Harvard University | 2014-09-12 | 2 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2014/09/12/009027.source.xml | Variability is ubiquitous in nature and a fundamental feature of complex systems. Few studies, however, have investigated variance itself as a trait under genetic control. By focusing primarily on trait means and ignoring the effect of alternative alleles on trait variability, we may be missing an important axis of genetic variation contributing to phenotypic differences among individuals1,2. To study genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used a panel of Drosophila inbred lines3 and focused on locomotor handedness4, in an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals while others had low levels. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicated a neuropil in the central complex5 of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination6. We have validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. This study reveals the constellation of phenotypes that can arise from a single genotype and it shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variability. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.\n\nAbbreviationsDGRP: Drosophila Genome Reference Panel; ANOMV: Analysis of means for variance; QTL: quantitative trait loci, GWAS: genome wide association study, MAD: median absolute deviation. GWAS: genome wide association study, CI: confidence interval. | 10.1073/pnas.1503830112 | biorxiv | 967 |
10.1101/008185 | Interpretable per Case Weighted Ensemble Method for Cancer Associations | Adrin Jalali;Nico Pfeifer; | Adrin Jalali | Max Planck Institute for Informatics | 2014-09-15 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2014/09/15/008185.source.xml | Motivation: Molecular measurements from cancer patients such as gene expression and DNA methylation are usually very noisy. Furthermore, cancer types can be very heterogeneous. Therefore, one of the main assumptions for machine learning, that the underlying unknown distribution is the same for all samples, might not be completely fullfilled. We introduce a method, that can estimate this bias on a per-feature level and incorporate calculated feature confidences into a weighted combination of classifiers with disjoint feature sets. Results: The new method achieves state-of-the-art performance on many different cancer data sets with measured DNA methylation or gene expression. Moreover, we show how to visualize the learned classifiers to find interesting associations with the target label. Applied to a leukemia data set we find several ribosomal proteins associated with leukemia's risk group that might be interesting targets for follow-up studies and support the hypothesis that the ribosomes are a new frontier in gene regulation. Availability: The method is available under GPLv3+ License at https: //github.com/adrinjalali/Network-Classifier. | 10.1186/s12864-016-2647-9 | biorxiv | 969 |
10.1101/009068 | Oncogenic mutations of the EGF-Receptor ectodomain reveal an unexpected mechanism for ligand-independent activation | LAURA ORELLANA;ADAM HOSPITAL;MODESTO OROZCO; | Laura Orellana | SCIENCE FOR LIFE LABORATORY | 2014-09-16 | 1 | New Results | cc_no | Biophysics | https://www.biorxiv.org/content/early/2014/09/16/009068.source.xml | Epidermal Growth Factor Receptor (EGFR) signaling is supposed to be triggered by a dramatic ligand-induced conformational change of the extracellular domain from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for dimerization and activation. The ectodomain also untethers spontaneously, but the molecular mechanism is still unknown. Experiments with the mAb806 antibody have suggested the existence of a third untethered state, still uncharacterized, appearing transiently during the tethered to untethered transition, and which exposes a cryptic epitope hidden in the known structures. Here, molecular dynamics simulations of two ectodomain mutants (R84K and G39R) targeting a hinge at domain I-II interface highlight the possibility of such additional intermediate conformer. The new conformation is untethered but surprisingly compact, and originates from a large rotation of domain I that exposes the mAb806 epitope, in a similar way as the EGFRvIII deletion does. The present findings not only point to different molecular processes for ligand-dependent and spontaneous untethering, but also suggest that domain I-II mutation clusters and the EGFRvIII deletion may share a common structural mechanism, based on the removal of an steric hindrance from domain I that restricts dimerization. | 10.1073/pnas.1821442116 | biorxiv | 970 |
10.1101/009183 | Functional Antagonism Between CELF and Mbnl Proteins in the Cytoplasm | Eric T. Wang;Amanda J. Ward;Jennifer Cherone;Thomas T. Wang;Jimena Giudice;Thomas A. Cooper;Christopher B. Burge; | Christopher B. Burge | MIT | 2014-09-16 | 1 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/09/16/009183.source.xml | The conserved CUGBP1, Elav-like (CELF) family of RNA binding proteins contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand genome-wide functions of CELF proteins, we analyzed transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart or CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. Analysis of expression and mRNA binding data revealed hundreds of mRNAs bound in their 3' UTRs by both CELF1 and and the developmentally induced Mbnl1 protein, 3-fold more than expected. The relative extent of CELF1 and Mbnl1 binding in 3' UTRs predicted the extent of repression or stabilization, respectively, following CELF induction. These findings support a ?Cytoplasmic Competition? model in which CELF and Mbnl proteins compete to specify degradation or membrane localization/stabilization, respectively, of an overlapping set of targets. Several hundred messages contained proximal CELF1 and Mbnl1 binding sites (within 50 bases), and were more strongly repressed by CELF1 than messages with distal sites. Messages with different spacing of CELF and Mbnl sites in their 3' UTRs exhibited different developmental dynamics, suggesting that spacing is used to tune cytoplasmic competition between these factors to specify the timing of developmental induction. CELF1 also shared dozens of splicing targets with Mbnl1, most regulated oppositely, confirming a phenomenon observed in smaller scale studies but not previously supported by genome-wide methods, which also appears to enhance developmental transitions. | NA | biorxiv | 974 |
10.1101/007823 | Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes | John Beaulaurier;Shijia Zhu;Robert Sebra;Xue-Song Zhang;Chaggai Rosenbluh;Gintaras Deikus;Nan Shen;Diana Munera;Matthew K Waldor;Martin Blaser;Andrew Chess;Eric Schadt;Gang Fang; | Gang Fang | Icahn School of Medicine at Mount Sinai | 2014-09-17 | 1 | New Results | cc_no | Microbiology | https://www.biorxiv.org/content/early/2014/09/17/007823.source.xml | Comprehensive genome-wide analyses of bacterial DNA methylation have not been possible until the recent advent of single molecule, real-time (SMRT) sequencing. This technology enables the direct detection of N6-methyladenine (6mA) and 4-methylcytosine (4mC) at single nucleotide resolution on a genome-wide scale. The distributions of these two major types of DNA methylation, along with 5-methylcytosine (5mC), comprise the bacterial methylome, some rare exceptions notwithstanding. SMRT sequencing has already revealed marked diversity in bacterial methylomes as well as the existence of heterogeneity of methylation in cells in single bacterial colonies, where such epigenetic variation can enable bacterial populations to rapidly adapt to changing conditions. However, current methods for studying bacterial methylomes using SMRT sequencing mainly rely on population-level summaries that do not provide the single-cell resolution necessary for dissecting the epigenetic heterogeneity in bacterial populations. Here, we present a novel SMRT sequencing-based framework, consisting of two complementary methods, for single molecule-level detection of DNA methylation and assessment of methyltransferase activity through single molecule-level long read-based epigenetic phasing. Using seven bacterial strains and integrating data from SMRT and Illumina sequencing, we show that our method yields significantly improved resolution compared to existing population-level methods, and reveals several distinct types of epigenetic heterogeneity. Our approach enables new investigations of the complex architecture and dynamics of bacterial methylomes and provides a powerful new tool for the study of bacterial epigenetic control. | 10.1038/ncomms8438 | biorxiv | 976 |
10.1101/009191 | Inference of Gorilla demographic and selective history from whole genome sequence data | Kimberly F. McManus;Joanna L. Kelley;Shiya Song;Krishna Veeramah;August E. Woerner;Laurie S. Stevison;Oliver A. Ryder;Great Ape Genome Project;Jeffrey M. Kidd;Jeffrey D. Wall;Carlos D. Bustamante;Michael F. Hammer; | Michael F. Hammer | University of Arizona | 2014-09-17 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2014/09/17/009191.source.xml | While population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor [~]261 thousand years ago (kya), and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage [~]68 kya. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of [~]1.4-fold around [~]970 kya and a recent [~]5.6-fold contraction in population size [~]23 kya. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection. | 10.1093/molbev/msu394 | biorxiv | 977 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.