{"messages":[{"status":"ok","category":"all","interval":"2013-01-01:2013-12-31","funder":"all","cursor":0,"count":30,"count_new_papers":"109","total":"143"}], "collection":[{"title":"Speciation and introgression between Mimulus nasutus and Mimulus guttatus","authors":"Yaniv Brandvain;Amanda M Kenney;Lex Fagel;Graham Coop;Andrea L Sweigart;","author_corresponding":"Yaniv  Brandvain","author_corresponding_institution":"Department of Evolution and Ecology & Center for Population Biology, University of California -Davis","doi":"10.1101\/000109","date":"2013-11-07","version":"1","type":"New Results","license":"cc_by","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/07\/000109.source.xml","abstract":"Mimulus guttatus and M. nasutus are an evolutionary and ecological model sister species pair differentiated by ecology, mating system, and partial reproductive isolation. Despite extensive research on this system, the history of divergence and differentiation in this sister pair is unclear. We present and analyze a novel population genomic data set which shows that M. nasutus &quot;budded&quot; off of a central Californian M. guttatus population within the last 200 to 500 thousand years. In this time, the M. nasutus genome has accrued numerous genomic signatures of the transition to predominant selfing. Despite clear biological differentiation, we document ongoing, bidirectional introgression. We observe a negative relationship between the recombination rate and divergence between M. nasutus and sympatric M. guttatus samples, suggesting that selection acts against M. nasutus ancestry in M. guttatus.","funder":"NA","published":"10.1371\/journal.pgen.1004410","server":"bioRxiv"},{"title":"A Scalable Formulation for Engineering Combination Therapies for Evolutionary Dynamics of Disease","authors":"Vanessa Jonsson;Anders Rantzer;Richard M Murray;","author_corresponding":"Vanessa  Jonsson","author_corresponding_institution":"Caltech","doi":"10.1101\/000075","date":"2013-11-07","version":"1","type":"New Results","license":"cc_by_nc","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/07\/000075.source.xml","abstract":"It has been shown that optimal controller synthesis for positive systems can be formulated as a linear program. Leveraging these results, we propose a scalable iterative algorithm for the systematic design of sparse, small gain feedback strategies that stabilize the evolutionary dynamics of a generic disease model. We achieve the desired feedback structure by augmenting the optimization problems with {ell}1 and {ell}2 regularization terms, and illustrate our method on an example inspired by an experimental study aimed at finding appropriate HIV neutralizing antibody therapy combinations in the presence of escape mutants.","funder":"NA","published":"10.1109\/ACC.2014.6859452","server":"bioRxiv"},{"title":"Genome-wide targets of selection: female response to experimental removal of sexual selection in Drosophila melanogaster","authors":"Paolo Innocenti;Ilona Flis;Edward H Morrow;","author_corresponding":"Edward H Morrow","author_corresponding_institution":"University of Sussex","doi":"10.1101\/000240","date":"2013-11-12","version":"1","type":"New Results","license":"cc_by","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/12\/000240.source.xml","abstract":"Despite the common assumption that promiscuity should in general be favored in males, but not in females, to date there is no consensus on the general impact of multiple mating on female fitness. Notably, very little is known about the genetic and physiological features underlying the female response to sexual selection pressures. By combining an experimental evolution approach with genomic techniques, we investigated the effects of single and multiple matings on female fecundity and gene expression. We experimentally manipulated the mating system in replicate populations of Drosophila melanogaster by removing sexual selection, with the aim of testing differences in short term post-mating effects of females evolved under different mating strategies. We show that monogamous females suffer decreased fecundity, a decrease that was partially recovered by experimentally reversing the selection pressure back to the ancestral promiscuous state. The post-mating gene expression profiles of monogamous females differ significantly from promiscuous females, involving 9% of the genes tested. These transcripts are active in several tissues, mainly ovaries, neural tissues and midgut, and are involved in metabolic processes, reproduction and signaling pathways. Our results demonstrate how the female post-mating response can evolve under different mating systems, and provide novel insights into the genes targeted by sexual selection in females, by identifying a list of candidate genes responsible for the decrease in female fecundity in the absence of promiscuity.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Population genomics of parallel hybrid zones in the mimetic butterflies, H. melpomene and H. erato","authors":"Nicola Nadeau;Mayte Ruiz;Patricio Salazar;Brian Counterman;Jose Alejandro Medina;Humberto Ortiz-Zuazaga;Anna Morrison;W. Owen McMillan;Chri Jiggins;Riccardo Papa;","author_corresponding":"Chri  Jiggins","author_corresponding_institution":"Cambridge","doi":"10.1101\/000208","date":"2013-11-12","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/12\/000208.source.xml","abstract":"Hybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies of Heliconius butterflies can be very narrow and are maintained by strong selection acting on colour pattern. The co-mimetic species H. erato and H. melpomene have parallel hybrid zones where both species undergo a change from one colour pattern form to another. We use restriction associated DNA sequencing to obtain several thousand genome wide sequence markers and use these to analyse patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data; alignment to a reference genome and de novo assembly, and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato, ~15% divergent) related to the reference sequence. Our results confirm that the colour pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to colour pattern differences. We also use association mapping to identify previously unmapped colour pattern loci, in particular the Ro locus. Finally, we identify within our sample a new cryptic population of H. timareta in Ecuador, which occurs at relatively low altitude and is mimetic with H. melpomene malleti.","funder":"NA","published":"10.1101\/gr.169292.113","server":"bioRxiv"},{"title":"The Origin of Human-infecting Avian Influenza A H6N1 Virus","authors":"Liangsheng Zhang;Zhenguo Zhang;","author_corresponding":"Zhenguo  Zhang","author_corresponding_institution":"Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA","doi":"10.1101\/000398","date":"2013-11-14","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/14\/000398.source.xml","abstract":"In this study, we retraced the origin of the reported avian influenza A H6N1 virus infecting a 20-year-old woman in Taiwan. As we know, this is the first reported case of human infection by the H6N1 virus, because this subtype virus usually circulates in birds and poultry. Therefore it is crucial to know how this virus attained the ability to infect humans. Using phylogenetic analysis, we found that this virus was derived from reassortments of multiple lineages of H6N1 viruses and H5N2 viruses. The results deepen our understanding of how the new human-infecting virus originated and based on these we discussed possible explanations for the H6N1 infection of humans. Our results, together with recent studies of H7N9 viruses which result in severe disorders, suggest that reassortments among avian-type viruses are quite often, which may sometimes result in fatal infections in humans. Thus a close watch on the circulation of avian influenza viruses is pretty necessary.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Universality and predictability in molecular quantitative genetics","authors":"Armita Nourmohammad;Torsten Held;Michael Lassig;","author_corresponding":"Michael  Lassig","author_corresponding_institution":"University of Cologne","doi":"10.1101\/000406","date":"2013-11-14","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/14\/000406.source.xml","abstract":"Molecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus on universal evolutionary characteristics: these are largely independent of a traits genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology.","funder":"NA","published":"10.1016\/j.gde.2013.11.001","server":"bioRxiv"},{"title":"Universality and predictability in molecular quantitative genetics","authors":"Armita Nourmohammad;Torsten Held;Michael Lassig;","author_corresponding":"Michael  Lassig","author_corresponding_institution":"University of Cologne","doi":"10.1101\/000406","date":"2013-11-15","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/15\/000406.source.xml","abstract":"Molecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus on universal evolutionary characteristics: these are largely independent of a traits genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology.","funder":"NA","published":"10.1016\/j.gde.2013.11.001","server":"bioRxiv"},{"title":"Pathways to social evolution: reciprocity, relatedness, and synergy","authors":"Jeremy Van Cleve;Erol Akcay;","author_corresponding":"Jeremy  Van Cleve","author_corresponding_institution":"National Evolutionary Synthesis Center","doi":"10.1101\/000521","date":"2013-11-16","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/16\/000521.source.xml","abstract":"Many organisms live in populations structured by space and by class, exhibit plastic responses to their social partners, and are subject to non-additive ecological and fitness effects. Social evolution theory has long recognized that all of these factors can lead to different selection pressures but has only recently attempted to synthesize how these factors interact. Using models for both discrete and continuous phenotypes, we show that analyzing these factors in a consistent framework reveals that they interact with one another in ways previously overlooked. Specifically, behavioral responses (reciprocity), genetic relatedness, and synergy interact in non-trivial ways that cannot be easily captured by simple summary indices of assortment. We demonstrate the importance of these interactions by showing how they have been neglected in previous synthetic models of social behavior both within and between species. These interactions also affect the level of behavioral responses that can evolve in the long run; proximate biological mechanisms are evolutionarily stable when they generate enough responsiveness relative to the level of responsiveness that exactly balances the ecological costs and benefits. Given the richness of social behavior across taxa, these interactions should be a boon for empirical research as they are likely crucial for describing the complex relationship linking ecology, demography, and social behavior.","funder":"NA","published":"10.1111\/evo.12438","server":"bioRxiv"},{"title":"On the concept of biological function, junk DNA and the gospels of ENCODE and Graur et al.","authors":"Claudiu I Bandea;","author_corresponding":"Claudiu I Bandea","author_corresponding_institution":"Centers for Disease Control and Prevention","doi":"10.1101\/000588","date":"2013-11-18","version":"1","type":"Contradictory Results","license":"cc_by_nc","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/18\/000588.source.xml","abstract":"In a recent article entitled \\\"On the immortality of television sets: \\\"function\\\" in the human genome according to the evolution-free gospel of ENCODE\\\", Graur et al. dismantle ENCODEs evidence and conclusion that 80% of the human genome is functional. However, the article by Graur et al. contains assumptions and statements that are questionable. Primarily, the authors limit their evaluation of DNAs biological functions to informational roles, sidestepping putative non-informational functions. Here, I bring forward an old hypothesis on the evolution of genome size and on the role of so called  junk DNA (jDNA), which might explain C-value enigma. According to this hypothesis, the jDNA functions as a defense mechanism against insertion mutagenesis by endogenous and exogenous inserting elements such as retroviruses, thereby protecting informational DNA sequences from inactivation or alteration of their expression. Notably, this model couples the mechanisms and the selective forces responsible for the origin of jDNA with its putative protective biological function, which represents a classic example of  fighting fire with fire. One of the key tenets of this theory is that in humans and many other species, jDNAs serves as a protective mechanism against insertional oncogenic transformation. As an adaptive defense mechanism, the amount of protective DNA varies from one species to another based on the rate of its origin, insertional mutagenesis activity, and evolutionary constraints on genome size.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Natural Allelic Variations of Xenobiotic Enzymes Pleiotropically Affect Sexual Dimorphism in Oryzias latipes","authors":"Takafumi Katsumura;Shoji Oda;Shigeki Nakagome;Tsunehiko Hanihara;Hiroshi Kataoka;Hiroshi Mitani;Shoji Kawamura;Hiroki Oota;","author_corresponding":"Hiroki  Oota","author_corresponding_institution":"Kitasato University School of Medicine","doi":"10.1101\/000661","date":"2013-11-19","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/19\/000661.source.xml","abstract":"Summary Summary Highlights Results and Discussion Accession Numbers Reference Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection [1, 2]. Interestingly, sexually selected traits show geographic variations within species despite strong directional selective pressures [3, 4]. However, genetic factors that regulate varied sexual differences remain unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolising enzyme, are associated with local differences of sexual dimorphisms in the anal fin morphology of medaka fish (Oryzias latipes). High and low activity CYP1B1 alleles increased and decreased differences in anal fin sizes ...","funder":"NA","published":"10.1098\/rspb.2014.2259","server":"bioRxiv"},{"title":"Natural Allelic Variations of Xenobiotic Enzymes Pleiotropically Affect Sexual Dimorphism in Oryzias latipes","authors":"Takafumi Katsumura;Shoji Oda;Shigeki Nakagome;Tsunehiko Hanihara;Hiroshi Kataoka;Hiroshi Mitani;Shoji Kawamura;Hiroki Oota;","author_corresponding":"Hiroki  Oota","author_corresponding_institution":"Kitasato University School of Medicine","doi":"10.1101\/000661","date":"2013-11-19","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/19\/000661.source.xml","abstract":"Summary Summary Highlights Results and Discussion Accession Numbers Reference Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection [1, 2]. Interestingly, sexually selected traits show geographic variations within species despite strong directional selective pressures [3, 4]. However, genetic factors that regulate varied sexual differences remain unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolising enzyme, are associated with local differences of sexual dimorphisms in the anal fin morphology of medaka fish (Oryzias latipes). High and low activity CYP1B1 alleles increased and decreased differences in anal fin sizes ...","funder":"NA","published":"10.1098\/rspb.2014.2259","server":"bioRxiv"},{"title":"Natural Allelic Variations of Xenobiotic Enzymes Pleiotropically Affect Sexual Dimorphism in Oryzias latipes","authors":"Takafumi Katsumura;Shoji Oda;Shigeki Nakagome;Tsunehiko Hanihara;Hiroshi Kataoka;Hiroshi Mitani;Shoji Kawamura;Hiroki Oota;","author_corresponding":"Hiroki  Oota","author_corresponding_institution":"Kitasato University School of Medicine","doi":"10.1101\/000661","date":"2013-11-25","version":"3","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/25\/000661.source.xml","abstract":"Summary Summary Highlights Results and Discussion Accession Numbers Reference Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection [1, 2]. Interestingly, sexually selected traits show geographic variations within species despite strong directional selective pressures [3, 4]. However, genetic factors that regulate varied sexual differences remain unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolising enzyme, are associated with local differences of sexual dimorphisms in the anal fin morphology of medaka fish (Oryzias latipes). High and low activity CYP1B1 alleles increased and decreased differences in anal fin sizes ...","funder":"NA","published":"10.1098\/rspb.2014.2259","server":"bioRxiv"},{"title":"Predictability of adaptive evolution under the successive fixation assumption","authors":"Sandeep Venkataram;Diamantis Sellis;Dmitri A Petrov;","author_corresponding":"Dmitri A Petrov","author_corresponding_institution":"Stanford University","doi":"10.1101\/001016","date":"2013-12-02","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/12\/02\/001016.source.xml","abstract":"Predicting the course of evolution is critical for solving current biomedical challenges such as cancer and the evolution of drug resistant pathogens. One approach to studying evolutionary predictability is to observe repeated, independent evolutionary trajectories of similar organisms under similar selection pressures in order to empirically characterize this adaptive fitness landscape. As this approach is infeasible for many natural systems, a number of recent studies have attempted to gain insight into the adaptive fitness landscape by testing the plausibility of different orders of appearance for a specific set of adaptive mutations in a single adaptive trajectory. While this approach is technically feasible for systems with very few available adaptive mutations, the usefulness of this approach for predicting evolution in situations with highly polygenic adaptation is unknown. It is also unclear whether the presence of stable adaptive polymorphisms can influence the predictability of evolution as measured by these methods. In this work, we simulate adaptive evolution under Fishers geometric model to study evolutionary predictability. Remarkably, we find that the predictability estimated by these methods are anti-correlated, and that the presence of stable adaptive polymorphisms can both qualitatively and quantitatively change the predictability of evolution.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Predictability of adaptive evolution under the successive fixation assumption","authors":"Sandeep Venkataram;Diamantis Sellis;Dmitri A Petrov;","author_corresponding":"Dmitri A Petrov","author_corresponding_institution":"Stanford University","doi":"10.1101\/001016","date":"2013-12-04","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Evolutionary Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/12\/04\/001016.source.xml","abstract":"Predicting the course of evolution is critical for solving current biomedical challenges such as cancer and the evolution of drug resistant pathogens. One approach to studying evolutionary predictability is to observe repeated, independent evolutionary trajectories of similar organisms under similar selection pressures in order to empirically characterize this adaptive fitness landscape. As this approach is infeasible for many natural systems, a number of recent studies have attempted to gain insight into the adaptive fitness landscape by testing the plausibility of different orders of appearance for a specific set of adaptive mutations in a single adaptive trajectory. While this approach is technically feasible for systems with very few available adaptive mutations, the usefulness of this approach for predicting evolution in situations with highly polygenic adaptation is unknown. It is also unclear whether the presence of stable adaptive polymorphisms can influence the predictability of evolution as measured by these methods. In this work, we simulate adaptive evolution under Fishers geometric model to study evolutionary predictability. Remarkably, we find that the predictability estimated by these methods are anti-correlated, and that the presence of stable adaptive polymorphisms can both qualitatively and quantitatively change the predictability of evolution.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Designing Robustness to Temperature in a Feedforward Loop Circuit","authors":"Shaunak Sen;Jongmin Kim;Richard M. Murray;","author_corresponding":"Shaunak  Sen","author_corresponding_institution":"Indian Institute of Technology Delhi","doi":"10.1101\/000091","date":"2013-11-07","version":"1","type":"New Results","license":"cc_by_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/07\/000091.source.xml","abstract":"Incoherent feedforward loops represent important biomolecular circuit elements capable of a rich set of dynamic behavior including adaptation and pulsed responses. Temperature can modulate some of these properties through its effect on the underlying reaction rate parameters. It is generally unclear how to design such a circuit where the properties are robust to variations in temperature. Here, we address this issue using a combination of tools from control and dynamical systems theory as well as preliminary experimental measurements towards such a design. We formalize temperature as an uncertainty acting on system dynamics, exploring both structured and unstructured uncertainty representations. Next, we analyze a standard incoherent feedforward loop circuit, noting mechanisms that intrinsically confer temperature robustness to some of its properties. Further, we explore different negative feedback configurations that can enhance the robustness to temperature. Finally, we find that the response of an incoherent feedforward loop circuit in cells can change with temperature. These results present groundwork for the design of a temperature-robust incoherent feedforward loop circuit.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"Negative autoregulation matches production and demand in synthetic transcriptional networks","authors":"Elisa Franco;Giulia Giordano;Per-Ola Forsberg;Richard M Murray;","author_corresponding":"Elisa  Franco","author_corresponding_institution":"University of California at Riverside","doi":"10.1101\/000430","date":"2013-11-14","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/14\/000430.source.xml","abstract":"We propose a negative feedback architecture that regulates activity of artificial genes, or \\\"genelets\\\", to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the \\\"error\\\" between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system, and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.","funder":"NA","published":"10.1021\/sb400157z","server":"bioRxiv"},{"title":"Negative autoregulation matches production and demand in synthetic transcriptional networks","authors":"Elisa Franco;Giulia Giordano;Per-Ola Forsberg;Richard M Murray;","author_corresponding":"Elisa  Franco","author_corresponding_institution":"University of California at Riverside","doi":"10.1101\/000430","date":"2013-11-15","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/15\/000430.source.xml","abstract":"We propose a negative feedback architecture that regulates activity of artificial genes, or \\\"genelets\\\", to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the \\\"error\\\" between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system, and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.","funder":"NA","published":"10.1021\/sb400157z","server":"bioRxiv"},{"title":"Efficient Search, Mapping, and Optimization of Multi-protein Genetic Systems in Diverse Bacteria","authors":"Iman Farasat;Manish Kushwaha;Jason Collens;Michael Easterbrook;Matthew Guido;Howard M Salis;","author_corresponding":"Howard M Salis","author_corresponding_institution":"Penn State University","doi":"10.1101\/001008","date":"2013-12-02","version":"1","type":"New Results","license":"cc_no","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/12\/02\/001008.source.xml","abstract":"Engineering multi-protein genetic systems to maximize their performance remains a combinatorial challenge, particularly when measurement throughput is limited. We have developed a computational design and modeling approach to build predictive models and identify optimal expression levels, while circumventing combinatorial explosion. Maximally informative genetic system variants are first designed by the RBS Library Calculator, an algorithm that optimizes the smallest ribosome binding site library to efficiently search the expression space across a >10,000-fold range with tailored search resolutions, sequence constraints, and well-predicted translation rates. We validated the algorithms predictions using a 644 sequence data-set, within single and multi-protein genetic systems, modifying plasmids and genomes, and in Escherichia coli and Bacillus subtilis. We then combined the search algorithm with kinetic modeling to map the mechanistic relationship between sequence, expression, and overall activity for a 3-enzyme biosynthesis pathway, requiring only 73 measurements to forward design highly productive pathway variants. The combination of sequence desi gn and systems modeling accelerates the optimization of many-protein systems, and allow previous measurements to quantitatively inform future designs.","funder":"NA","published":"10.15252\/msb.20134955","server":"bioRxiv"},{"title":"Resource usage and gene circuit performance characterization in a cell-free ?breadboard?","authors":"Dan Siegal-Gaskins;Zoltan A. Tuza;Jongmin Kim;Vincent Noireaux;Richard M. Murray;","author_corresponding":"Dan  Siegal-Gaskins","author_corresponding_institution":"California Institute of Technology","doi":"10.1101\/000885","date":"2013-11-25","version":"1","type":"New Results","license":"cc_by_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/25\/000885.source.xml","abstract":"The many successes of synthetic biology have come in a manner largely different from those in other engineering disciplines; in particular, without well-characterized and simplified prototyping environments to play a role analogous to wind-tunnels in aerodynamics and breadboards in electrical engineering. However, as the complexity of synthetic circuits increases, the benefits--in cost savings and design cycle time--of a more traditional engineering approach can be significant. We have recently developed an in vitro  breadboard prototyping platform based on E. coli cell extract that allows biocircuits to operate in an environment considerably simpler than but functionally similar to in vivo. The simplicity of this system makes it a promising tool for rapid biocircuit design and testing, as well as for probing fundamental aspects of gene circuit operation normally masked by cellular complexity. In this work we characterize the cell-free breadboard using real-time and simultaneous measurements of transcriptional and translational activities of a small set of reporter genes and a transcriptional activation cascade. We determine the effects of promoter strength, gene concentration, and nucleoside triphosphate concentration on biocircuit properties, and we isolate the specific contributions of essential biomolecular resources--core RNA polymerase and ribosomes--to overall performance. Importantly, we show how limits on resources, particularly those involved in translation, are manifested as reduced expression in the presence of orthogonal genes that serve as additional loads on the system.","funder":"NA","published":"10.1021\/sb400203p","server":"bioRxiv"},{"title":"Resource usage and gene circuit performance characterization in a cell-free ?breadboard?","authors":"Dan Siegal-Gaskins;Zoltan A. Tuza;Jongmin Kim;Vincent Noireaux;Richard M. Murray;","author_corresponding":"Dan  Siegal-Gaskins","author_corresponding_institution":"California Institute of Technology","doi":"10.1101\/000885","date":"2013-11-26","version":"2","type":"New Results","license":"cc_by_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/26\/000885.source.xml","abstract":"The many successes of synthetic biology have come in a manner largely different from those in other engineering disciplines; in particular, without well-characterized and simplified prototyping environments to play a role analogous to wind-tunnels in aerodynamics and breadboards in electrical engineering. However, as the complexity of synthetic circuits increases, the benefits--in cost savings and design cycle time--of a more traditional engineering approach can be significant. We have recently developed an in vitro  breadboard prototyping platform based on E. coli cell extract that allows biocircuits to operate in an environment considerably simpler than but functionally similar to in vivo. The simplicity of this system makes it a promising tool for rapid biocircuit design and testing, as well as for probing fundamental aspects of gene circuit operation normally masked by cellular complexity. In this work we characterize the cell-free breadboard using real-time and simultaneous measurements of transcriptional and translational activities of a small set of reporter genes and a transcriptional activation cascade. We determine the effects of promoter strength, gene concentration, and nucleoside triphosphate concentration on biocircuit properties, and we isolate the specific contributions of essential biomolecular resources--core RNA polymerase and ribosomes--to overall performance. Importantly, we show how limits on resources, particularly those involved in translation, are manifested as reduced expression in the presence of orthogonal genes that serve as additional loads on the system.","funder":"NA","published":"10.1021\/sb400203p","server":"bioRxiv"},{"title":"Resource usage and gene circuit performance characterization in a cell-free ?breadboard?","authors":"Dan Siegal-Gaskins;Zoltan A. Tuza;Jongmin Kim;Vincent Noireaux;Richard M. Murray;","author_corresponding":"Dan  Siegal-Gaskins","author_corresponding_institution":"California Institute of Technology","doi":"10.1101\/000885","date":"2013-12-10","version":"3","type":"New Results","license":"cc_by_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/12\/10\/000885.source.xml","abstract":"The many successes of synthetic biology have come in a manner largely different from those in other engineering disciplines; in particular, without well-characterized and simplified prototyping environments to play a role analogous to wind-tunnels in aerodynamics and breadboards in electrical engineering. However, as the complexity of synthetic circuits increases, the benefits--in cost savings and design cycle time--of a more traditional engineering approach can be significant. We have recently developed an in vitro  breadboard prototyping platform based on E. coli cell extract that allows biocircuits to operate in an environment considerably simpler than but functionally similar to in vivo. The simplicity of this system makes it a promising tool for rapid biocircuit design and testing, as well as for probing fundamental aspects of gene circuit operation normally masked by cellular complexity. In this work we characterize the cell-free breadboard using real-time and simultaneous measurements of transcriptional and translational activities of a small set of reporter genes and a transcriptional activation cascade. We determine the effects of promoter strength, gene concentration, and nucleoside triphosphate concentration on biocircuit properties, and we isolate the specific contributions of essential biomolecular resources--core RNA polymerase and ribosomes--to overall performance. Importantly, we show how limits on resources, particularly those involved in translation, are manifested as reduced expression in the presence of orthogonal genes that serve as additional loads on the system.","funder":"NA","published":"10.1021\/sb400203p","server":"bioRxiv"},{"title":"Design and implementation of a synthetic biomolecular concentration tracker","authors":"Victoria Hsiao;Emmanuel LC de los Santos;Weston R Whitaker;John E Dueber;Richard M Murray;","author_corresponding":"Victoria  Hsiao","author_corresponding_institution":"California Institute of Technology","doi":"10.1101\/000448","date":"2013-11-15","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/15\/000448.source.xml","abstract":"As a field, synthetic biology strives to engineer increasingly complex artificial systems in living cells. Active feedback in closed loop systems offers a dynamic and adaptive way to ensure constant relative activity independent of intrinsic and extrinsic noise. In this work, we design, model, and implement a biomolecular concentration tracker, in which an output protein tracks the concentration of an input protein. Synthetic modular protein scaffold domains are used to colocalize a two-component system, and a single negative feedback loop modulates the production of the output protein. Using a combination of model and experimental work, we show that the circuit achieves real-time protein concentration tracking in Escherichia coli and that steady state outputs can be tuned.","funder":"NA","published":"10.1021\/sb500024b","server":"bioRxiv"},{"title":"Design and implementation of a synthetic biomolecular concentration tracker","authors":"Victoria Hsiao;Emmanuel LC de los Santos;Weston R Whitaker;John E Dueber;Richard M Murray;","author_corresponding":"Victoria  Hsiao","author_corresponding_institution":"California Institute of Technology","doi":"10.1101\/000448","date":"2013-12-10","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Synthetic Biology ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/12\/10\/000448.source.xml","abstract":"As a field, synthetic biology strives to engineer increasingly complex artificial systems in living cells. Active feedback in closed loop systems offers a dynamic and adaptive way to ensure constant relative activity independent of intrinsic and extrinsic noise. In this work, we design, model, and implement a biomolecular concentration tracker, in which an output protein tracks the concentration of an input protein. Synthetic modular protein scaffold domains are used to colocalize a two-component system, and a single negative feedback loop modulates the production of the output protein. Using a combination of model and experimental work, we show that the circuit achieves real-time protein concentration tracking in Escherichia coli and that steady state outputs can be tuned.","funder":"NA","published":"10.1021\/sb500024b","server":"bioRxiv"},{"title":"A data repository and analysis framework for spontaneous neural activity recordings in developing retina","authors":"Stephen Eglen;Michael Weeks;Mark Jessop;Jennifer Simonotto;Tom Jackson;Evelyne Sernagor;","author_corresponding":"Stephen  Eglen","author_corresponding_institution":"University of Cambridge","doi":"10.1101\/000455","date":"2013-11-15","version":"1","type":"New Results","license":"cc_by_nc_nd","category":"Neuroscience ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/15\/000455.source.xml","abstract":"BackgroundDuring early development, neural circuits fire spontaneously, generating activity episodes with complex spatiotemporal patterns. Recordings of spontaneous activity have been made in many parts of the nervous system over the last 25 years, reporting developmental changes in activity patterns and the effects of various genetic perturbations.\\n\\nResultsWe present a curated repository of multielectrode array recordings of spontaneous activity in developing mouse and ferret retina. The data have been annotated with minimal metadata and converted into HDF5. This paper describes the structure of the data, along with examples of reproducible research using these data files. We also demonstrate how these data can be analysed in the CARMEN workflow system. This article is written as a literate programming document; all programs and data described here are freely available.\\n\\nConclusions1. We hope this repository will lead to novel analysis of spontaneous activity recorded in different laboratories. 2. We encourage published data to be added to the repository. 3. This repository serves as an example of how multielectrode array recordings can be stored for long-term reuse.","funder":"NA","published":"10.1186\/2047-217X-3-3","server":"bioRxiv"},{"title":"A data repository and analysis framework for spontaneous neural activity recordings in developing retina","authors":"Stephen Eglen;Michael Weeks;Mark Jessop;Jennifer Simonotto;Tom Jackson;Evelyne Sernagor;","author_corresponding":"Stephen  Eglen","author_corresponding_institution":"University of Cambridge","doi":"10.1101\/000455","date":"2013-11-27","version":"2","type":"New Results","license":"cc_by_nc_nd","category":"Neuroscience ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/27\/000455.source.xml","abstract":"BackgroundDuring early development, neural circuits fire spontaneously, generating activity episodes with complex spatiotemporal patterns. Recordings of spontaneous activity have been made in many parts of the nervous system over the last 25 years, reporting developmental changes in activity patterns and the effects of various genetic perturbations.\\n\\nResultsWe present a curated repository of multielectrode array recordings of spontaneous activity in developing mouse and ferret retina. The data have been annotated with minimal metadata and converted into HDF5. This paper describes the structure of the data, along with examples of reproducible research using these data files. We also demonstrate how these data can be analysed in the CARMEN workflow system. This article is written as a literate programming document; all programs and data described here are freely available.\\n\\nConclusions1. We hope this repository will lead to novel analysis of spontaneous activity recorded in different laboratories. 2. We encourage published data to be added to the repository. 3. This repository serves as an example of how multielectrode array recordings can be stored for long-term reuse.","funder":"NA","published":"10.1186\/2047-217X-3-3","server":"bioRxiv"},{"title":"Genetics of single-cell protein abundance variation in large yeast populations","authors":"Frank Albert;Sebastian Treusch;Arthur H Shockley;Joshua S Bloom;Leonid Kruglyak;","author_corresponding":"Leonid  Kruglyak","author_corresponding_institution":"UCLA","doi":"10.1101\/000067","date":"2013-11-07","version":"1","type":"New Results","license":"cc_no","category":"Genomics ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/07\/000067.source.xml","abstract":"Many DNA sequence variants influence phenotypes by altering gene expression. Our understanding of these variants is limited by sample sizes of current studies and by measurements of mRNA rather than protein abundance. We developed a powerful method for identifying genetic loci that influence protein expression in very large populations of the yeast Saccharomyes cerevisiae. The method measures single-cell protein abundance through the use of green-fluorescent-protein tags. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci cluster at hotspot locations that influence multiple proteins--in some cases, more than half of those examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell physiology between yeast strains.","funder":"NA","published":"10.1038\/nature12904","server":"bioRxiv"},{"title":"A genome wide dosage suppressor network reveals genetic robustness and a novel mechanism for Huntington&amp;#146;s disease","authors":"Biranchi Patra;Yoshiko Kon;Gitanjali Yadav;Anthony Sevold;Jesse P Frumkin;Ravishankar R Vallabhajosyula;Arend Hintze;Bj\u00f8rn \u00d8stman;Jory Schossau;Ashish Bhan;Bruz Marzolf;Jenna K Tamashiro;Amardeep Kaur;Nitin S Baliga;Elizabeth J Grayhack;Christoph Adami;David J Galas;Alpan Raval;Eric M Phizicky;Animesh Ray;","author_corresponding":"Animesh  Ray","author_corresponding_institution":"Keck Graduate Institute","doi":"10.1101\/000265","date":"2013-11-12","version":"1","type":"New Results","license":"cc_by_nd","category":"Genomics ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/12\/000265.source.xml","abstract":"Mutational robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of mutational robustness in the budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs, and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggest a surprising degree of functional plasticity of macromolecular complexes and the existence of degenerate pathways for circumventing potentially lethal mutations. The utility of dosage-suppressor networks is illustrated by the discovery of a novel connection between chromosome cohesion-condensation pathways involving homologous recombination, and Huntingtons disease.","funder":"NA","published":"10.1093\/nar\/gkw1148","server":"bioRxiv"},{"title":"A Complete Public Domain Family Genomics Dataset","authors":"Manuel Corpas;Mike Cariaso;Alain Coletta;David Weiss;Andrew P Harrison;Federico Moran;Huanming Yang;","author_corresponding":"Manuel  Corpas","author_corresponding_institution":"Independent","doi":"10.1101\/000216","date":"2013-11-12","version":"1","type":"New Results","license":"cc_by","category":"Genomics ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/12\/000216.source.xml","abstract":"BackgroundThe availability of open access genomic data is essential for the personal genomics field. Public genomic data allow comparative analyses, testing of new tools and genotype-phenotype association studies. Personal genomics data of unrelated individuals are available in the public domain, notably the Personal Genome Project; however, to date genomics family data and metadata are severely lacking, mainly due to cost, privacy concerns or restricted access to Next Generation Sequencing (NGS) technology. Family data have a lot to offer as they allow the study of heritability, something which is impossible to do just by using unrelated individuals.\\n\\nFindingsA whole family from Southern Spain decided to genotype, sequence and analyse their personal genomes making them publicly available under a Creative Commons 0 license (CC0; commonly denominated as public domain). These data include a) five 23andMe SNP chip genotype bed files, b) four raw exomes with their assorted bam files and VCF files, c) a metagenomic raw sequencing data file and d) derived data of likely phenotypes using SNPedia-derived tools.\\n\\nConclusionsTo our knowledge this is the first CC0 released set of genomic, phenotypic and metagenomic data for a whole family. This dataset is also unique in that it was obtained through direct-to-consumer genetic tests. Hence any ordinary citizen with enough budget and samples should be able to reproduce this experiment. We envisage this dataset to be a useful resource for a variety of applications in the personal genomics field as a) negative control data for trait association discovery, b) testing data for development of new software and c) sample data for heritability studies. We encourage prospective users to share with us derived results so that they can be added to our existing collection.","funder":"NA","published":"NA","server":"bioRxiv"},{"title":"On the Reproducibility of TCGA Ovarian Cancer MicroRNA Profiles","authors":"Ying-Wooi Wan;Claire Mach;Genevera I. Allen;Matthew Anderson;Zhandong Liu;","author_corresponding":"Zhandong  Liu","author_corresponding_institution":"Baylor College of Medicine","doi":"10.1101\/000315","date":"2013-11-13","version":"1","type":"Contradictory Results","license":"cc_by_nc_nd","category":"Genomics ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/13\/000315.source.xml","abstract":"Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p<0.01). We also identified 12 miRNAs that are associated with survival when miRNAs were profiled in the same specimens using Next Generation Sequencing (miRNA-Seq) (p<0.01). Surprisingly, only 1 miRNA transcript is associated with ovarian cancer survival in both datasets. Our analyses indicate that this discrepancy is due to the fact that miRNA levels reported by the two platforms correlate poorly, even after correcting for potential issues inherent to signal detection algorithms. Further investigation is warranted.","funder":"NA","published":"10.1371\/journal.pone.0087782","server":"bioRxiv"},{"title":"Joint analysis of functional genomic data and genome-wide association studies of 18 human traits","authors":"Joseph Pickrell;","author_corresponding":"Joseph  Pickrell","author_corresponding_institution":"New York Genome Center","doi":"10.1101\/000752","date":"2013-11-19","version":"1","type":"New Results","license":"cc_by","category":"Genomics ","jatsxml":"https:\/\/www.biorxiv.org\/content\/early\/2013\/11\/19\/000752.source.xml","abstract":"Annotations of gene structures and regulatory elements can inform genome-wide association studies (GWAS). However, choosing the relevant annotations for interpreting an association study of a given trait remains challenging. We describe a statistical model that uses association statistics computed across the genome to identify classes of genomic element that are enriched or depleted for loci that influence a trait. The model naturally incorporates multiple types of annotations. We applied the model to GWAS of 18 human traits, including red blood cell traits, platelet traits, glucose levels, lipid levels, height, BMI, and Crohns disease. For each trait, we evaluated the relevance of 450 different genomic annotations, including protein-coding genes, enhancers, and DNase-I hypersensitive sites in over a hundred tissues and cell lines. We show that the fraction of phenotype-associated SNPs that influence protein sequence ranges from around 2% (for platelet volume) up to around 20% (for LDL cholesterol); that repressed chromatin is significantly depleted for SNPs associated with several traits; and that cell type-specific DNase-I hypersensitive sites are enriched for SNPs associated with several traits (for example, the spleen in platelet volume). Finally, by re-weighting each GWAS using information from functional genomics, we increase the number of loci with high-confidence associations by around 5%.","funder":"NA","published":"10.1016\/j.ajhg.2014.03.004","server":"bioRxiv"}]}