@article{4243, abstract = {We investigate a new model for populations evolving in a spatial continuum. This model can be thought of as a spatial version of the Lambda-Fleming-Viot process. It explicitly incorporates both small scale reproduction events and large scale extinction-recolonisation events. The lineages ancestral to a sample from a population evolving according to this model can be described in terms of a spatial version of the Lambda-coalescent. Using a technique of Evans (1997), we prove existence and uniqueness in law for the model. We then investigate the asymptotic behaviour of the genealogy of a finite number of individuals sampled uniformly at random (or more generally `far enough apart') from a two-dimensional torus of sidelength L as L tends to infinity. Under appropriate conditions (and on a suitable timescale) we can obtain as limiting genealogical processes a Kingman coalescent, a more general Lambda-coalescent or a system of coalescing Brownian motions (with a non-local coalescence mechanism).}, author = {Barton, Nicholas H and Etheridge, Alison and Véber, Amandine}, journal = {Electronic Journal of Probability}, number = {7}, pages = {162 -- 216}, publisher = {Institute of Mathematical Statistics}, title = {{A new model for evolution in a spatial continuum}}, doi = {10.1214/EJP.v15-741}, volume = {15}, year = {2010}, } @article{9452, abstract = {Eukaryotic cytosine methylation represses transcription but also occurs in the bodies of active genes, and the extent of methylation biology conservation is unclear. We quantified DNA methylation in 17 eukaryotic genomes and found that gene body methylation is conserved between plants and animals, whereas selective methylation of transposons is not. We show that methylation of plant transposons in the CHG context extends to green algae and that exclusion of histone H2A.Z from methylated DNA is conserved between plants and animals, and we present evidence for RNA-directed DNA methylation of fungal genes. Our data demonstrate that extant DNA methylation systems are mosaics of conserved and derived features, and indicate that gene body methylation is an ancient property of eukaryotic genomes.}, author = {Zemach, Assaf and McDaniel, Ivy E. and Silva, Pedro and Zilberman, Daniel}, issn = {1095-9203}, journal = {Science}, keywords = {Multidisciplinary}, number = {5980}, pages = {916--919}, publisher = {American Association for the Advancement of Science}, title = {{Genome-wide evolutionary analysis of eukaryotic DNA methylation}}, doi = {10.1126/science.1186366}, volume = {328}, year = {2010}, } @article{9485, abstract = {Cytosine methylation silences transposable elements in plants, vertebrates, and fungi but also regulates gene expression. Plant methylation is catalyzed by three families of enzymes, each with a preferred sequence context: CG, CHG (H = A, C, or T), and CHH, with CHH methylation targeted by the RNAi pathway. Arabidopsis thaliana endosperm, a placenta-like tissue that nourishes the embryo, is globally hypomethylated in the CG context while retaining high non-CG methylation. Global methylation dynamics in seeds of cereal crops that provide the bulk of human nutrition remain unknown. Here, we show that rice endosperm DNA is hypomethylated in all sequence contexts. Non-CG methylation is reduced evenly across the genome, whereas CG hypomethylation is localized. CHH methylation of small transposable elements is increased in embryos, suggesting that endosperm demethylation enhances transposon silencing. Genes preferentially expressed in endosperm, including those coding for major storage proteins and starch synthesizing enzymes, are frequently hypomethylated in endosperm, indicating that DNA methylation is a crucial regulator of rice endosperm biogenesis. Our data show that genome-wide reshaping of seed DNA methylation is conserved among angiosperms and has a profound effect on gene expression in cereal crops.}, author = {Zemach, Assaf and Kim, M. Yvonne and Silva, Pedro and Rodrigues, Jessica A. and Dotson, Bradley and Brooks, Matthew D. and Zilberman, Daniel}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {43}, pages = {18729--18734}, publisher = {National Academy of Sciences}, title = {{Local DNA hypomethylation activates genes in rice endosperm}}, doi = {10.1073/pnas.1009695107}, volume = {107}, year = {2010}, } @article{9489, abstract = {Cytosine methylation is an ancient process with conserved enzymology but diverse biological functions that include defense against transposable elements and regulation of gene expression. Here we will discuss the evolution and biological significance of eukaryotic DNA methylation, the likely drivers of that evolution, and major remaining mysteries.}, author = {Zemach, Assaf and Zilberman, Daniel}, issn = {1879-0445}, journal = {Current Biology}, number = {17}, pages = {R780--R785}, publisher = {Elsevier}, title = {{Evolution of eukaryotic DNA methylation and the pursuit of safer sex}}, doi = {10.1016/j.cub.2010.07.007}, volume = {20}, year = {2010}, } @misc{9764, author = {Rosas, Ulises and Barton, Nicholas H and Copsey, Lucy and Barbier De Reuille, Pierre and Coen, Enrico}, publisher = {Public Library of Science}, title = {{Heterosis and the drift load}}, doi = {10.1371/journal.pbio.1000429.s003}, year = {2010}, } @inproceedings{4542, abstract = {Weighted automata are finite automata with numerical weights on transitions. Nondeterministic weighted automata define quantitative languages L that assign to each word w a real number L(w) computed as the maximal value of all runs over w, and the value of a run r is a function of the sequence of weights that appear along r. There are several natural functions to consider such as Sup, LimSup, LimInf, limit average, and discounted sum of transition weights. We introduce alternating weighted automata in which the transitions of the runs are chosen by two players in a turn-based fashion. Each word is assigned the maximal value of a run that the first player can enforce regardless of the choices made by the second player. We survey the results about closure properties, expressiveness, and decision problems for nondeterministic weighted automata, and we extend these results to alternating weighted automata. For quantitative languages L 1 and L 2, we consider the pointwise operations max(L 1,L 2), min(L 1,L 2), 1 − L 1, and the sum L 1 + L 2. We establish the closure properties of all classes of alternating weighted automata with respect to these four operations. We next compare the expressive power of the various classes of alternating and nondeterministic weighted automata over infinite words. In particular, for limit average and discounted sum, we show that alternation brings more expressive power than nondeterminism. Finally, we present decidability results and open questions for the quantitative extension of the classical decision problems in automata theory: emptiness, universality, language inclusion, and language equivalence.}, author = {Chatterjee, Krishnendu and Doyen, Laurent and Henzinger, Thomas A}, location = {Wroclaw, Poland}, pages = {3 -- 13}, publisher = {Springer}, title = {{Alternating weighted automata}}, doi = {10.1007/978-3-642-03409-1_2}, volume = {5699}, year = {2009}, } @inproceedings{4543, abstract = {The synthesis of a reactive system with respect to all omega-regular specification requires the solution of a graph game. Such games have been extended in two natural ways. First, a game graph can be equipped with probabilistic choices between alternative transitions, thus allowing the, modeling of uncertain behaviour. These are called stochastic games. Second, a liveness specification can he strengthened to require satisfaction within all unknown but bounded amount of time. These are called finitary objectives. We study. for the first time, the, combination of Stochastic games and finitary objectives. We characterize the requirements on optimal strategies and provide algorithms for Computing the maximal achievable probability of winning stochastic games with finitary parity or Street, objectives. Most notably the set of state's from which a player can win with probability . for a finitary parity objective can he computed in polynomial time even though no polynomial-time algorithm is known in the nonfinitary case.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Horn, Florian}, location = {High Tatras, Slovakia}, pages = {34 -- 54}, publisher = {Springer}, title = {{Stochastic games with finitary objectives}}, doi = {10.1007/978-3-642-03816-7_4}, volume = {5734}, year = {2009}, } @inproceedings{4545, abstract = {A stochastic game is a two-player game played oil a graph, where in each state the successor is chosen either by One of the players, or according to a probability distribution. We Survey Stochastic games with limsup and liminf objectives. A real-valued re-ward is assigned to each state, and the value of all infinite path is the limsup (resp. liminf) of all rewards along the path. The value of a stochastic game is the maximal expected value of an infinite path that call he achieved by resolving the decisions of the first player. We present the complexity of computing values of Stochastic games and their subclasses, and the complexity, of optimal strategies in such games. }, author = {Chatterjee, Krishnendu and Doyen, Laurent and Henzinger, Thomas A}, location = {Rhodos, Greece}, pages = {1 -- 15}, publisher = {Springer}, title = {{A survey of stochastic games with limsup and liminf objectives}}, doi = {10.1007/978-3-642-02930-1_1}, volume = {5556}, year = {2009}, } @inproceedings{4569, abstract = {Most specification languages express only qualitative constraints. However, among two implementations that satisfy a given specification, one may be preferred to another. For example, if a specification asks that every request is followed by a response, one may prefer an implementation that generates responses quickly but does not generate unnecessary responses. We use quantitative properties to measure the “goodness” of an implementation. Using games with corresponding quantitative objectives, we can synthesize “optimal” implementations, which are preferred among the set of possible implementations that satisfy a given specification. In particular, we show how automata with lexicographic mean-payoff conditions can be used to express many interesting quantitative properties for reactive systems. In this framework, the synthesis of optimal implementations requires the solution of lexicographic mean-payoff games (for safety requirements), and the solution of games with both lexicographic mean-payoff and parity objectives (for liveness requirements). We present algorithms for solving both kinds of novel graph games.}, author = {Bloem, Roderick and Chatterjee, Krishnendu and Henzinger, Thomas A and Jobstmann, Barbara}, location = {Grenoble, France}, pages = {140 -- 156}, publisher = {Springer}, title = {{Better quality in synthesis through quantitative objectives}}, doi = {10.1007/978-3-642-02658-4_14}, volume = {5643}, year = {2009}, } @misc{5392, abstract = {We consider probabilistic automata on infinite words with acceptance defined by safety, reachability, Büchi, coBüchi and limit-average conditions. We consider quantitative and qualitative decision problems. We present extensions and adaptations of proofs of [GO09] and present a precise characterization of the decidability and undecidability frontier of the quantitative and qualitative decision problems.}, author = {Chatterjee, Krishnendu}, issn = {2664-1690}, pages = {17}, publisher = {IST Austria}, title = {{Probabilistic automata on infinite words: Decidability and undecidability results}}, doi = {10.15479/AT:IST-2009-0004}, year = {2009}, } @misc{5393, abstract = {Gist is a tool that (a) solves the qualitative analysis problem of turn-based probabilistic games with ω-regular objectives; and (b) synthesizes reasonable environment assumptions for synthesis of unrealizable specifications. Our tool provides efficient implementations of several reduction based techniques to solve turn-based probabilistic games, and uses the analysis of turn-based probabilistic games for synthesizing environment assumptions for unrealizable specifications.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Jobstmann, Barbara and Radhakrishna, Arjun}, issn = {2664-1690}, pages = {12}, publisher = {IST Austria}, title = {{Gist: A solver for probabilistic games}}, doi = {10.15479/AT:IST-2009-0003}, year = {2009}, } @misc{5394, abstract = {We consider two-player games played on graphs with request-response and finitary Streett objectives. We show these games are PSPACE-hard, improving the previous known NP-hardness. We also improve the lower bounds on memory required by the winning strategies for the players.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Horn, Florian}, issn = {2664-1690}, pages = {11}, publisher = {IST Austria}, title = {{Improved lower bounds for request-response and finitary Streett games}}, doi = {10.15479/AT:IST-2009-0002}, year = {2009}, } @misc{5395, abstract = {We study observation-based strategies for partially-observable Markov decision processes (POMDPs) with omega-regular objectives. An observation-based strategy relies on partial information about the history of a play, namely, on the past sequence of observa- tions. We consider the qualitative analysis problem: given a POMDP with an omega-regular objective, whether there is an observation-based strategy to achieve the objective with probability 1 (almost-sure winning), or with positive probability (positive winning). Our main results are twofold. First, we present a complete picture of the computational complexity of the qualitative analysis of POMDPs with parity objectives (a canonical form to express omega-regular objectives) and its subclasses. Our contribution consists in establishing several upper and lower bounds that were not known in literature. Second, we present optimal bounds (matching upper and lower bounds) on the memory required by pure and randomized observation-based strategies for the qualitative analysis of POMDPs with parity objectives and its subclasses.}, author = {Chatterjee, Krishnendu and Doyen, Laurent and Henzinger, Thomas A}, issn = {2664-1690}, pages = {20}, publisher = {IST Austria}, title = {{Qualitative analysis of partially-observable Markov decision processes}}, doi = {10.15479/AT:IST-2009-0001}, year = {2009}, } @inbook{3675, abstract = {Sex and recombination have long been seen as adaptations that facilitate natural selection by generating favorable variations. If recombination is to aid selection, there must be negative linkage disequilibria—favorable alleles must be found together less often than expected by chance. These negative linkage disequilibria can be generated directly by selection, but this must involve negative epistasis of just the right strength, which is not expected, from either experiment or theory. Random drift provides a more general source of negative associations: Favorable mutations almost always arise on different genomes, and negative associations tend to persist, precisely because they shield variation from selection. We can understand how recombination aids adaptation by determining the maximum possible rate of adaptation. With unlinked loci, this rate increases only logarithmically with the influx of favorable mutations. With a linear genome, a scaling argument shows that in a large population, the rate of adaptive substitution depends only on the expected rate in the absence of interference, divided by the total rate of recombination. A two-locus approximation predicts an upper bound on the rate of substitution, proportional to recombination rate. If associations between linked loci do impede adaptation, there can be substantial selection for modifiers that increase recombination. Whether this can account for the maintenance of high rates of sex and recombination depends on the extent of selection. It is clear that the rate of species-wide substitutions is typically far too low to generate appreciable selection for recombination. However, local sweeps within a subdivided population may be effective.}, author = {Barton, Nicholas H}, booktitle = {Cold Spring Harbor Symposia on Quantitative Biology}, pages = {187 -- 195}, publisher = {Cold Spring Harbor Laboratory Press}, title = {{Why sex and recombination?}}, doi = {10.1101/sqb.2009.74.030}, volume = {74}, year = {2009}, } @article{3775, abstract = {There is a close analogy between statistical thermodynamics and the evolution of allele frequencies under mutation, selection and random drift. Wright's formula for the stationary distribution of allele frequencies is analogous to the Boltzmann distribution in statistical physics. Population size, 2N, plays the role of the inverse temperature, 1/kT, and determines the magnitude of random fluctuations. Log mean fitness, View the MathML source, tends to increase under selection, and is analogous to a (negative) energy; a potential function, U, increases under mutation in a similar way. An entropy, SH, can be defined which measures the deviation from the distribution of allele frequencies expected under random drift alone; the sum View the MathML source gives a free fitness that increases as the population evolves towards its stationary distribution. Usually, we observe the distribution of a few quantitative traits that depend on the frequencies of very many alleles. The mean and variance of such traits are analogous to observable quantities in statistical thermodynamics. Thus, we can define an entropy, SΩ, which measures the volume of allele frequency space that is consistent with the observed trait distribution. The stationary distribution of the traits is View the MathML source; this applies with arbitrary epistasis and dominance. The entropies SΩ, SH are distinct, but converge when there are so many alleles that traits fluctuate close to their expectations. Populations tend to evolve towards states that can be realised in many ways (i.e., large SΩ), which may lead to a substantial drop below the adaptive peak; we illustrate this point with a simple model of genetic redundancy. This analogy with statistical thermodynamics brings together previous ideas in a general framework, and justifies a maximum entropy approximation to the dynamics of quantitative traits.}, author = {Barton, Nicholas H and Coe, Jason}, journal = {Journal of Theoretical Biology}, number = {2}, pages = {317 -- 324}, publisher = {Elsevier}, title = {{On the application of statistical physics to evolutionary biology}}, doi = {10.1016/j.jtbi.2009.03.019}, volume = {259}, year = {2009}, } @article{3780, abstract = {Why are sinistral snails so rare? Two main hypotheses are that selection acts against the establishment of new coiling morphs, because dextral and sinistral snails have trouble mating, or else a developmental constraint prevents the establishment of sinistrals. We therefore used an isolate of the snail Lymnaea stagnalis, in which sinistrals are rare, and populations of Partula suturalis, in which sinistrals are common, as well as a mathematical model, to understand the circumstances by which new morphs evolve. The main finding is that the sinistral genotype is associated with reduced egg viability in L. stagnalis, but in P. suturalis individuals of sinistral and dextral genotype appear equally fecund, implying a lack of a constraint. As positive frequency-dependent selection against the rare chiral morph in P. suturalis also operates over a narrow range (< 3%), the results suggest a model for chiral evolution in snails in which weak positive frequency-dependent selection may be overcome by a negative frequency-dependent selection, such as reproductive character displacement. In snails, there is not always a developmental constraint. As the direction of cleavage, and thus the directional asymmetry of the entire body, does not generally vary in other Spiralia (annelids, echiurans, vestimentiferans, sipunculids and nemerteans), it remains an open question as to whether this is because of a constraint and/or because most taxa do not have a conspicuous external asymmetry (like a shell) upon which selection can act.}, author = {Davison, Angus and Barton, Nicholas H and Clarke, Bryan}, journal = {Journal of Evolutionary Biology}, number = {8}, pages = {1624 -- 1635}, publisher = {Wiley}, title = {{The effect of chirality phenotype and genotype on the fecundity and viability of Partula suturalis and Lymnaea stagnalis: Implications for the evolution of sinistral snails}}, doi = {10.1111/j.1420-9101.2009.01770.x}, volume = {22}, year = {2009}, } @inproceedings{3837, abstract = {In this paper we extend the work of Alfaro, Henzinger et al. on interface theories for component-based design. Existing interface theories often fail to capture functional relations between the inputs and outputs of an interface. For example, a simple synchronous interface that takes as input a number n ≥ 0 and returns, at the same time, as output n + 1, cannot be expressed in existing theories. In this paper we provide a theory of relational interfaces, where such input-output relations can be captured. Our theory supports synchronous interfaces, both stateless and stateful. It includes explicit notions of environments and pluggability, and satisfies fundamental properties such as preservation of refinement by composition, and characterization of pluggability by refinement. We achieve these properties by making reasonable restrictions on feedback loops in interface compositions.}, author = {Tripakis, Stavros and Lickly, Ben and Henzinger, Thomas A and Lee, Edward}, booktitle = {EMSOFT '09 Proceedings of the seventh ACM international conference on Embedded software}, location = {Grenoble, France}, pages = {67 -- 76}, publisher = {ACM}, title = {{On relational interfaces}}, doi = {10.1145/1629335.1629346}, year = {2009}, } @inproceedings{3841, abstract = {We compare several languages for specifying Markovian population models such as queuing networks and chemical reaction networks. These languages —matrix descriptions, stochastic Petri nets, stoichiometric equations, stochastic process algebras, and guarded command models— all describe continuous-time Markov chains, but they differ according to important properties, such as compositionality, expressiveness and succinctness, executability, ease of use, and the support they provide for checking the well-formedness of a model and for analyzing a model. }, author = {Henzinger, Thomas A and Jobstmann, Barbara and Wolf, Verena}, location = {Palaiseau, France}, pages = {3 -- 23}, publisher = {Springer}, title = {{Formalisms for specifying Markovian population models}}, doi = {10.1007/978-3-642-04420-5_2}, volume = {5797}, year = {2009}, } @inproceedings{3843, abstract = {Within systems biology there is an increasing interest in the stochastic behavior of biochemical reaction networks. An appropriate stochastic description is provided by the chemical master equation, which represents a continuous- time Markov chain (CTMC). Standard Uniformization (SU) is an efficient method for the transient analysis of CTMCs. For systems with very different time scales, such as biochemical reaction networks, SU is computationally expensive. In these cases, a variant of SU, called adaptive uniformization (AU), is known to reduce the large number of iterations needed by SU. The additional difficulty of AU is that it requires the solution of a birth process. In this paper we present an on-the-fly variant of AU, where we improve the original algorithm for AU at the cost of a small approximation error. By means of several examples, we show that our approach is particularly well-suited for biochemical reaction networks.}, author = {Didier, Frédéric and Henzinger, Thomas A and Mateescu, Maria and Wolf, Verena}, location = {Trento, Italy}, number = {6}, pages = {118 -- 127}, publisher = {IEEE}, title = {{Fast adaptive uniformization of the chemical master equation}}, doi = {10.1109/HiBi.2009.23}, volume = {4}, year = {2009}, } @inproceedings{3844, abstract = {The Hierarchical Timing Language (HTL) is a real-time coordination language for distributed control systems. HTL programs must be checked for well-formedness, race freedom, transmission safety (schedulability of inter-host communication), and time safety (schedulability of host computation). We present a modular abstract syntax and semantics for HTL, modular checks of well-formedness, race freedom, and transmission safety, and modular code distribution. Our contributions here complement previous results on HTL time safety and modular code generation. Modularity in HTL can be utilized in easy program composition as well as fast program analysis and code generation, but also in so-called runtime patching, where program components may be modified at runtime.}, author = {Henzinger, Thomas A and Kirsch, Christoph and Marques, Eduardo and Sokolova, Ana}, location = {Washington, DC, United States}, pages = {171 -- 180}, publisher = {IEEE}, title = {{Distributed, modular HTL}}, doi = {10.1109/RTSS.2009.9}, year = {2009}, }