@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}, } @inproceedings{3871, abstract = {Nondeterministic weighted automata are finite automata with numerical weights oil transitions. They define quantitative languages 1, that assign to each word v; a real number L(w). The value of ail infinite word w is computed as the maximal value of all runs over w, and the value of a run as the supremum, limsup liminf, limit average, or discounted sum of the transition weights. We introduce probabilistic weighted antomata, in which the transitions are chosen in a randomized (rather than nondeterministic) fashion. Under almost-sure semantics (resp. positive semantics), the value of a word v) is the largest real v such that the runs over w have value at least v with probability I (resp. positive probability). We study the classical questions of automata theory for probabilistic weighted automata: emptiness and universality, expressiveness, and closure under various operations oil languages. For quantitative languages, emptiness university axe defined as whether the value of some (resp. every) word exceeds a given threshold. We prove some, of these questions to he decidable, and others undecidable. Regarding expressive power, we show that probabilities allow its to define a wide variety of new classes of quantitative languages except for discounted-sum automata, where probabilistic choice is no more expressive than nondeterminism. Finally we live ail almost complete picture of the closure of various classes of probabilistic weighted automata for the following, provide, is operations oil quantitative languages: maximum, sum. and numerical complement.}, author = {Chatterjee, Krishnendu and Doyen, Laurent and Henzinger, Thomas A}, location = {Bologna, Italy}, pages = {244 -- 258}, publisher = {Springer}, title = {{Probabilistic weighted automata}}, doi = {10.1007/978-3-642-04081-8_17}, volume = {5710}, year = {2009}, } @inproceedings{3968, abstract = {We describe an algorithm for segmenting three-dimensional medical imaging data modeled as a continuous function on a 3-manifold. It is related to watershed algorithms developed in image processing but is closer to its mathematical roots, which are Morse theory and homological algebra. It allows for the implicit treatment of an underlying mesh, thus combining the structural integrity of its mathematical foundations with the computational efficiency of image processing.}, author = {Edelsbrunner, Herbert and Harer, John}, location = {Zermatt, Switzerland}, pages = {36 -- 50}, publisher = {Springer}, title = {{The persistent Morse complex segmentation of a 3-manifold}}, doi = {10.1007/978-3-642-10470-1_4}, volume = {5903}, year = {2009}, } @article{4136, abstract = {Populations living in a spatially and temporally changing environment can adapt to the changing optimum and/or migrate toward favorable habitats. Here we extend previous analyses with a static optimum to allow the environment to vary in time as well as in space. The model follows both population dynamics and the trait mean under stabilizing selection, and the outcomes can be understood by comparing the loads due to genetic variance, dispersal, and temporal change. With fixed genetic variance, we obtain two regimes: (1) adaptation that is uniform along the environmental gradient and that responds to the moving optimum as expected for panmictic populations and when the spatial gradient is sufficiently steep, and (2) a population with limited range that adapts more slowly than the environmental optimum changes in both time and space; the population therefore becomes locally extinct and migrates toward suitable habitat. We also use a population‐genetic model with many loci to allow genetic variance to evolve, and we show that the only solution now has uniform adaptation.}, author = {Polechova, Jitka and Barton, Nicholas H and Marion, Glenn}, journal = {American Naturalist}, number = {5}, pages = {E186 -- E204}, publisher = {University of Chicago Press}, title = {{Species' range: Adaptation in space and time}}, doi = {10.1086/605958}, volume = {174}, year = {2009}, } @article{4231, abstract = {The evolution of quantitative characters depends on the frequencies of the alleles involved, yet these frequencies cannot usually be measured. Previous groups have proposed an approximation to the dynamics of quantitative traits, based on an analogy with statistical mechanics. We present a modified version of that approach, which makes the analogy more precise and applies quite generally to describe the evolution of allele frequencies. We calculate explicitly how the macroscopic quantities (i.e., quantities that depend on the quantitative trait) depend on evolutionary forces, in a way that is independent of the microscopic details. We first show that the stationary distribution of allele frequencies under drift, selection, and mutation maximizes a certain measure of entropy, subject to constraints on the expectation of observable quantities. We then approximate the dynamical changes in these expectations, assuming that the distribution of allele frequencies always maximizes entropy, conditional on the expected values. When applied to directional selection on an additive trait, this gives a very good approximation to the evolution of the trait mean and the genetic variance, when the number of mutations per generation is sufficiently high (4Nμ > 1). We show how the method can be modified for small mutation rates (4Nμ → 0). We outline how this method describes epistatic interactions as, for example, with stabilizing selection.}, author = {Barton, Nicholas H and De Vladar, Harold}, journal = {Genetics}, number = {3}, pages = {997 -- 1011}, publisher = {Genetics Society of America}, title = {{Statistical mechanics and the evolution of polygenic quantitative traits}}, doi = {10.1534/genetics.108.099309}, volume = {181}, year = {2009}, } @article{4242, abstract = {Felsenstein distinguished two ways by which selection can directly strengthen isolation. First, a modifier that strengthens prezygotic isolation can be favored everywhere. This fits with the traditional view of reinforcement as an adaptation to reduce deleterious hybridization by strengthening assortative mating. Second, selection can favor association between different incompatibilities, despite recombination. We generalize this “two allele” model to follow associations among any number of incompatibilities, which may include both assortment and hybrid inviability. Our key argument is that this process, of coupling between incompatibilities, may be quite different from the usual view of reinforcement: strong isolation can evolve through the coupling of any kind of incompatibility, whether prezygotic or postzygotic. Single locus incompatibilities become coupled because associations between them increase the variance in compatibility, which in turn increases mean fitness if there is positive epistasis. Multiple incompatibilities, each maintained by epistasis, can become coupled in the same way. In contrast, a single-locus incompatibility can become coupled with loci that reduce the viability of haploid hybrids because this reduces harmful recombination. We obtain simple approximations for the limits of tight linkage, and strong assortment, and show how assortment alleles can invade through associations with other components of reproductive isolation.}, author = {Barton, Nicholas H and De Cara, Maria}, journal = {Evolution; International Journal of Organic Evolution}, number = {5}, pages = {1171 -- 1190}, publisher = {Wiley}, title = {{The evolution of strong reproductive isolation}}, doi = {10.1111/j.1558-5646.2009.00622.x}, volume = {63}, year = {2009}, } @article{3870, abstract = {Games on graphs with omega-regular objectives provide a model for the control and synthesis of reactive systems. Every omega-regular objective can be decomposed into a safety part and a liveness part. The liveness part ensures that something good happens “eventually.” Two main strengths of the classical, infinite-limit formulation of liveness are robustness (independence from the granularity of transitions) and simplicity (abstraction of complicated time bounds). However, the classical liveness formulation suffers from the drawback that the time until something good happens may be unbounded. A stronger formulation of liveness, so-called finitary liveness, overcomes this drawback, while still retaining robustness and simplicity. Finitary liveness requires that there exists an unknown, fixed bound b such that something good happens within b transitions. While for one-shot liveness (reachability) objectives, classical and finitary liveness coincide, for repeated liveness (Buchi) objectives, the finitary formulation is strictly stronger. In this work we study games with finitary parity and Streett objectives. We prove the determinacy of these games, present algorithms for solving these games, and characterize the memory requirements of winning strategies. We show that finitary parity games can be solved in polynomial time, which is not known for infinitary parity games. For finitary Streett games, we give an EXPTIME algorithm and show that the problem is NP-hard. Our algorithms can be used, for example, for synthesizing controllers that do not let the response time of a system increase without bound.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Horn, Florian}, journal = {ACM Transactions on Computational Logic}, number = {1}, publisher = {ACM}, title = {{Finitary winning in omega-regular games}}, doi = {10.1145/1614431.1614432}, volume = {11}, year = {2009}, } @article{517, author = {Barton, Nicholas H}, journal = {Genetics Research}, number = {5-6}, pages = {475 -- 477}, publisher = {Cambridge University Press}, title = {{Identity and coalescence in structured populations: A commentary on 'Inbreeding coefficients and coalescence times' by Montgomery Slatkin}}, doi = {10.1017/S0016672308009683}, volume = {89}, year = {2008}, } @article{9457, abstract = {Eukaryotic chromatin is separated into functional domains differentiated by posttranslational histone modifications, histone variants, and DNA methylation1–6. Methylation is associated with repression of transcriptional initiation in plants and animals, and is frequently found in transposable elements. Proper methylation patterns are critical for eukaryotic development4,5, and aberrant methylation-induced silencing of tumor suppressor genes is a common feature of human cancer7. In contrast to methylation, the histone variant H2A.Z is preferentially deposited by the Swr1 ATPase complex near 5′ ends of genes where it promotes transcriptional competence8–20. How DNA methylation and H2A.Z influence transcription remains largely unknown. Here we show that in the plant Arabidopsis thaliana, regions of DNA methylation are quantitatively deficient in H2A.Z. Exclusion of H2A.Z is seen at sites of DNA methylation in the bodies of actively transcribed genes and in methylated transposons. Mutation of the MET1 DNA methyltransferase, which causes both losses and gains of DNA methylation4,5, engenders opposite changes in H2A.Z deposition, while mutation of the PIE1 subunit of the Swr1 complex that deposits H2A.Z17 leads to genome-wide hypermethylation. Our findings indicate that DNA methylation can influence chromatin structure and effect gene silencing by excluding H2A.Z, and that H2A.Z protects genes from DNA methylation.}, author = {Zilberman, Daniel and Coleman-Derr, Devin and Ballinger, Tracy and Henikoff, Steven}, issn = {1476-4687}, journal = {Nature}, keywords = {Multidisciplinary}, number = {7218}, pages = {125--129}, publisher = {Springer Nature}, title = {{Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks}}, doi = {10.1038/nature07324}, volume = {456}, year = {2008}, } @article{9537, abstract = {DNA methylation is an ancient process found in all domains of life. Although the enzymes that mediate methylation have remained highly conserved, DNA methylation has been adapted for a variety of uses throughout evolution, including defense against transposable elements and control of gene expression. Defects in DNA methylation are linked to human diseases, including cancer. Methylation has been lost several times in the course of animal and fungal evolution, thus limiting the opportunity for study in common model organisms. In the past decade, plants have emerged as a premier model system for genetic dissection of DNA methylation. A recent combination of plant genetics with powerful genomic approaches has led to a number of exciting discoveries and promises many more.}, author = {Zilberman, Daniel}, issn = {1369-5266}, journal = {Current Opinion in Plant Biology}, number = {5}, pages = {554--559}, publisher = {Elsevier }, title = {{The evolving functions of DNA methylation}}, doi = {10.1016/j.pbi.2008.07.004}, volume = {11}, year = {2008}, } @article{12201, abstract = {The development of plant lateral organs is interesting because, although many of the same genes seem to be involved in the early growth of primordia, completely different gene combinations are required for the complete development of organs such as leaves and stamens. Thus, the genes common to the development of most organs, which generally form and polarize the primordial ‘envelope’, must at some stage interact with those that ‘install’ the functional content of the organ – in the case of the stamen, the four microsporangia. Although distinct genetic pathways of organ initiation, polarity establishment and setting up the reproductive cell line can readily be recognized, they do not occur sequentially. Rather, they are activated early and run in parallel. There is evidence for continuing crosstalk between these pathways.}, author = {Feng, Xiaoqi and Dickinson, Hugh G.}, issn = {0168-9525}, journal = {Trends in Genetics}, keywords = {Genetics}, number = {10}, pages = {503--510}, publisher = {Elsevier BV}, title = {{Packaging the male germline in plants}}, doi = {10.1016/j.tig.2007.08.005}, volume = {23}, year = {2007}, } @article{9487, abstract = {Cytosine DNA methylation is considered to be a stable epigenetic mark, but active demethylation has been observed in both plants and animals. In Arabidopsis thaliana, DNA glycosylases of the DEMETER (DME) family remove methylcytosines from DNA. Demethylation by DME is necessary for genomic imprinting, and demethylation by a related protein, REPRESSOR OF SILENCING1, prevents gene silencing in a transgenic background. However, the extent and function of demethylation by DEMETER-LIKE (DML) proteins in WT plants is not known. Using genome-tiling microarrays, we mapped DNA methylation in mutant and WT plants and identified 179 loci actively demethylated by DML enzymes. Mutations in DML genes lead to locus-specific DNA hypermethylation. Reintroducing WT DML genes restores most loci to the normal pattern of methylation, although at some loci, hypermethylated epialleles persist. Of loci demethylated by DML enzymes, >80% are near or overlap genes. Genic demethylation by DML enzymes primarily occurs at the 5′ and 3′ ends, a pattern opposite to the overall distribution of WT DNA methylation. Our results show that demethylation by DML DNA glycosylases edits the patterns of DNA methylation within the Arabidopsis genome to protect genes from potentially deleterious methylation.}, author = {Penterman, Jon and Zilberman, Daniel and Huh, Jin Hoe and Ballinger, Tracy and Henikoff, Steven and Fischer, Robert L.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {16}, pages = {6752--6757}, publisher = {National Academy of Sciences}, title = {{DNA demethylation in the Arabidopsis genome}}, doi = {10.1073/pnas.0701861104}, volume = {104}, year = {2007}, } @misc{9504, author = {Zilberman, Daniel}, booktitle = {Nature Genetics}, issn = {1546-1718}, number = {4}, pages = {442--443}, publisher = {Nature Publishing Group}, title = {{The human promoter methylome}}, doi = {10.1038/ng0407-442}, volume = {39}, year = {2007}, } @article{9524, abstract = {Cytosine methylation is the most common covalent modification of DNA in eukaryotes. DNA methylation has an important role in many aspects of biology, including development and disease. Methylation can be detected using bisulfite conversion, methylation-sensitive restriction enzymes, methyl-binding proteins and anti-methylcytosine antibodies. Combining these techniques with DNA microarrays and high-throughput sequencing has made the mapping of DNA methylation feasible on a genome-wide scale. Here we discuss recent developments and future directions for identifying and mapping methylation, in an effort to help colleagues to identify the approaches that best serve their research interests.}, author = {Zilberman, Daniel and Henikoff, Steven}, issn = {1477-9129}, journal = {Development}, number = {22}, pages = {3959--3965}, publisher = {The Company of Biologists}, title = {{Genome-wide analysis of DNA methylation patterns}}, doi = {10.1242/dev.001131}, volume = {134}, year = {2007}, } @article{9505, abstract = {Cytosine methylation, a common form of DNA modification that antagonizes transcription, is found at transposons and repeats in vertebrates, plants and fungi. Here we have mapped DNA methylation in the entire Arabidopsis thaliana genome at high resolution. DNA methylation covers transposons and is present within a large fraction of A. thaliana genes. Methylation within genes is conspicuously biased away from gene ends, suggesting a dependence on RNA polymerase transit. Genic methylation is strongly influenced by transcription: moderately transcribed genes are most likely to be methylated, whereas genes at either extreme are least likely. In turn, transcription is influenced by methylation: short methylated genes are poorly expressed, and loss of methylation in the body of a gene leads to enhanced transcription. Our results indicate that genic transcription and DNA methylation are closely interwoven processes.}, author = {Zilberman, Daniel and Gehring, Mary and Tran, Robert K. and Ballinger, Tracy and Henikoff, Steven}, issn = {1546-1718}, journal = {Nature Genetics}, number = {1}, pages = {61--69}, publisher = {Nature Publishing Group}, title = {{Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription}}, doi = {10.1038/ng1929}, volume = {39}, year = {2006}, } @article{9491, abstract = {Cytosine DNA methylation in vertebrates is widespread, but methylation in plants is found almost exclusively at transposable elements and repetitive DNA [1]. Within regions of methylation, methylcytosines are typically found in CG, CNG, and asymmetric contexts. CG sites are maintained by a plant homolog of mammalian Dnmt1 acting on hemi-methylated DNA after replication. Methylation of CNG and asymmetric sites appears to be maintained at each cell cycle by other mechanisms. We report a new type of DNA methylation in Arabidopsis, dense CG methylation clusters found at scattered sites throughout the genome. These clusters lack non-CG methylation and are preferentially found in genes, although they are relatively deficient toward the 5′ end. CG methylation clusters are present in lines derived from different accessions and in mutants that eliminate de novo methylation, indicating that CG methylation clusters are stably maintained at specific sites. Because 5-methylcytosine is mutagenic, the appearance of CG methylation clusters over evolutionary time predicts a genome-wide deficiency of CG dinucleotides and an excess of C(A/T)G trinucleotides within transcribed regions. This is exactly what we find, implying that CG methylation clusters have contributed profoundly to plant gene evolution. We suggest that CG methylation clusters silence cryptic promoters that arise sporadically within transcription units.}, author = {Tran, Robert K. and Henikoff, Jorja G. and Zilberman, Daniel and Ditt, Renata F. and Jacobsen, Steven E. and Henikoff, Steven}, issn = {1879-0445}, journal = {Current Biology}, number = {2}, pages = {154--159}, publisher = {Elsevier}, title = {{DNA methylation profiling identifies CG methylation clusters in Arabidopsis genes}}, doi = {10.1016/j.cub.2005.01.008}, volume = {15}, year = {2005}, } @article{9514, abstract = {Background: DNA methylation occurs at preferred sites in eukaryotes. In Arabidopsis, DNA cytosine methylation is maintained by three subfamilies of methyltransferases with distinct substrate specificities and different modes of action. Targeting of cytosine methylation at selected loci has been found to sometimes involve histone H3 methylation and small interfering (si)RNAs. However, the relationship between different cytosine methylation pathways and their preferred targets is not known. Results: We used a microarray-based profiling method to explore the involvement of Arabidopsis CMT3 and DRM DNA methyltransferases, a histone H3 lysine-9 methyltransferase (KYP) and an Argonaute-related siRNA silencing component (AGO4) in methylating target loci. We found that KYP targets are also CMT3 targets, suggesting that histone methylation maintains CNG methylation genome-wide. CMT3 and KYP targets show similar proximal distributions that correspond to the overall distribution of transposable elements of all types, whereas DRM targets are distributed more distally along the chromosome. We find an inverse relationship between element size and loss of methylation in ago4 and drm mutants. Conclusion: We conclude that the targets of both DNA methylation and histone H3K9 methylation pathways are transposable elements genome-wide, irrespective of element type and position. Our findings also suggest that RNA-directed DNA methylation is required to silence isolated elements that may be too small to be maintained in a silent state by a chromatin-based mechanism alone. Thus, parallel pathways would be needed to maintain silencing of transposable elements.}, author = {Tran, Robert K. and Zilberman, Daniel and de Bustos, Cecilia and Ditt, Renata F. and Henikoff, Jorja G. and Lindroth, Anders M. and Delrow, Jeffrey and Boyle, Tom and Kwong, Samson and Bryson, Terri D. and Jacobsen, Steven E. and Henikoff, Steven}, issn = {1465-6906}, journal = {Genome Biology}, number = {11}, publisher = {Springer Nature}, title = {{Chromatin and siRNA pathways cooperate to maintain DNA methylation of small transposable elements in Arabidopsis}}, doi = {10.1186/gb-2005-6-11-r90}, volume = {6}, year = {2005}, } @article{9529, abstract = {Eukaryotic organisms have the remarkable ability to inherit states of gene activity without altering the underlying DNA sequence. This epigenetic inheritance can persist over thousands of years, providing an alternative to genetic mutations as a substrate for natural selection. Epigenetic inheritance might be propagated by differences in DNA methylation, post-translational histone modifications, and deposition of histone variants. Mounting evidence also indicates that small interfering RNA (siRNA)-mediated mechanisms play central roles in setting up and maintaining states of gene activity. Much of the epigenetic machinery of many organisms, including Arabidopsis, appears to be directed at silencing viruses and transposable elements, with epigenetic regulation of endogenous genes being mostly derived from such processes.}, author = {Zilberman, Daniel and Henikoff, Steven}, issn = {0959-437X}, journal = {Current Opinion in Genetics and Development}, number = {5}, pages = {557--562}, publisher = {Elsevier}, title = {{Epigenetic inheritance in Arabidopsis: Selective silence}}, doi = {10.1016/j.gde.2005.07.002}, volume = {15}, year = {2005}, }