12,533 research outputs found
A Hierarchical Approach to Protein Molecular Evolution
Biological diversity has evolved despite the essentially infinite complexity
of protein sequence space. We present a hierarchical approach to the efficient
searching of this space and quantify the evolutionary potential of our approach
with Monte Carlo simulations. These simulations demonstrate that non-homologous
juxtaposition of encoded structure is the rate-limiting step in the production
of new tertiary protein folds. Non-homologous ``swapping'' of low energy
secondary structures increased the binding constant of a simulated protein by
relative to base substitution alone. Applications of our approach
include the generation of new protein folds and modeling the molecular
evolution of disease.Comment: 15 pages. 2 figures. LaTeX styl
DNA as a universal substrate for chemical kinetics
Molecular programming aims to systematically engineer molecular and chemical systems of autonomous function and ever-increasing complexity. A key goal is to develop embedded control circuitry within a chemical system to direct molecular events. Here we show that systems of DNA molecules can be constructed that closely approximate the dynamic behavior of arbitrary systems of coupled chemical reactions. By using strand displacement reactions as a primitive, we construct reaction cascades with effectively unimolecular and bimolecular kinetics. Our construction allows individual reactions to be coupled in arbitrary ways such that reactants can participate in multiple reactions simultaneously, reproducing the desired dynamical properties. Thus arbitrary systems of chemical equations can be compiled into real chemical systems. We illustrate our method on the Lotka–Volterra oscillator, a limit-cycle oscillator, a chaotic system, and systems implementing feedback digital logic and algorithmic behavior
A Knowledge Gradient Policy for Sequencing Experiments to Identify the Structure of RNA Molecules Using a Sparse Additive Belief Model
We present a sparse knowledge gradient (SpKG) algorithm for adaptively
selecting the targeted regions within a large RNA molecule to identify which
regions are most amenable to interactions with other molecules. Experimentally,
such regions can be inferred from fluorescence measurements obtained by binding
a complementary probe with fluorescence markers to the targeted regions. We use
a biophysical model which shows that the fluorescence ratio under the log scale
has a sparse linear relationship with the coefficients describing the
accessibility of each nucleotide, since not all sites are accessible (due to
the folding of the molecule). The SpKG algorithm uniquely combines the Bayesian
ranking and selection problem with the frequentist regularized
regression approach Lasso. We use this algorithm to identify the sparsity
pattern of the linear model as well as sequentially decide the best regions to
test before experimental budget is exhausted. Besides, we also develop two
other new algorithms: batch SpKG algorithm, which generates more suggestions
sequentially to run parallel experiments; and batch SpKG with a procedure which
we call length mutagenesis. It dynamically adds in new alternatives, in the
form of types of probes, are created by inserting, deleting or mutating
nucleotides within existing probes. In simulation, we demonstrate these
algorithms on the Group I intron (a mid-size RNA molecule), showing that they
efficiently learn the correct sparsity pattern, identify the most accessible
region, and outperform several other policies
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Inference of single-cell phylogenies from lineage tracing data using Cassiopeia.
The pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale lineage tracing. However, the rapid growth in complexity of data from these assays has outpaced our ability to accurately infer phylogenetic relationships. First, we introduce Cassiopeia-a suite of scalable maximum parsimony approaches for tree reconstruction. Second, we provide a simulation framework for evaluating algorithms and exploring lineage tracer design principles. Finally, we generate the most complex experimental lineage tracing dataset to date, 34,557 human cells continuously traced over 15 generations, and use it for benchmarking phylogenetic inference approaches. We show that Cassiopeia outperforms traditional methods by several metrics and under a wide variety of parameter regimes, and provide insight into the principles for the design of improved Cas9-enabled recorders. Together, these should broadly enable large-scale mammalian lineage tracing efforts. Cassiopeia and its benchmarking resources are publicly available at www.github.com/YosefLab/Cassiopeia
Error-speed correlations in biopolymer synthesis
Synthesis of biopolymers such as DNA, RNA, and proteins are biophysical
processes aided by enzymes. Performance of these enzymes is usually
characterized in terms of their average error rate and speed. However, because
of thermal fluctuations in these single-molecule processes, both error and
speed are inherently stochastic quantities. In this paper, we study
fluctuations of error and speed in biopolymer synthesis and show that they are
in general correlated. This means that, under equal conditions, polymers that
are synthesized faster due to a fluctuation tend to have either better or worse
errors than the average. The error-correction mechanism implemented by the
enzyme determines which of the two cases holds. For example, discrimination in
the forward reaction rates tends to grant smaller errors to polymers with
faster synthesis. The opposite occurs for discrimination in monomer rejection
rates. Our results provide an experimentally feasible way to identify
error-correction mechanisms by measuring the error-speed correlations.Comment: PDF file consist of the main text (pages 1 to 5) and the
supplementary material (pages 6 to 12). Overall, 7 figures split between main
text and S
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Cancer cell lines show high heritability for motility but not generation time
Tumour evolution depends on heritable differences between cells in traits affecting cell survival or replication. It is well established that cancer cells are genetically and phenotypically heterogeneous; however, the extent to which this phenotypic variation is heritable is far less well explored. Here, we estimate the broad-sense heritability (H2) of two cell traits related to cancer hallmarks––cell motility and generation time––within populations of four cancer cell lines in vitro and find that motility is strongly heritable. This heritability is stable across multiple cell generations, with heritability values at the high end of those measured for a range of traits in natural populations of animals or plants. These findings confirm a central assumption of cancer evolution, provide a first quantification of the evolvability of key traits in cancer cells and indicate that there is ample raw material for experimental evolution in cancer cell lines. Generation time, a trait directly affecting cell fitness, shows substantially lower values of heritability than cell speed, consistent with its having been under directional selection removing heritable variation
Effects of Noise on Ecological Invasion Processes: Bacteriophage-mediated Competition in Bacteria
Pathogen-mediated competition, through which an invasive species carrying and
transmitting a pathogen can be a superior competitor to a more vulnerable
resident species, is one of the principle driving forces influencing
biodiversity in nature. Using an experimental system of bacteriophage-mediated
competition in bacterial populations and a deterministic model, we have shown
in [Joo et al 2005] that the competitive advantage conferred by the phage
depends only on the relative phage pathology and is independent of the initial
phage concentration and other phage and host parameters such as the
infection-causing contact rate, the spontaneous and infection-induced lysis
rates, and the phage burst size. Here we investigate the effects of stochastic
fluctuations on bacterial invasion facilitated by bacteriophage, and examine
the validity of the deterministic approach. We use both numerical and
analytical methods of stochastic processes to identify the source of noise and
assess its magnitude. We show that the conclusions obtained from the
deterministic model are robust against stochastic fluctuations, yet deviations
become prominently large when the phage are more pathological to the invading
bacterial strain.Comment: 39 pages, 7 figure
How crystals that sense and respond to their environments could evolve
An enduring mystery in biology is how a physical entity simple enough to have arisen spontaneously could have evolved into the complex life seen on Earth today. Cairns-Smith has proposed that life might have originated in clays which stored genomes consisting of an arrangement of crystal monomers that was replicated during growth. While a clay genome is simple enough to have conceivably arisen spontaneously, it is not obvious how it might have produced more complex forms as a result of evolution. Here, we examine this possibility in the tile assembly model, a generalized model of crystal growth that has been used to study the self-assembly of DNA tiles. We describe hypothetical crystals for which evolution of complex crystal sequences is driven by the scarceness of resources required for growth. We show how, under certain circumstances, crystal growth that performs computation can predict which resources are abundant. In such cases, crystals executing programs that make these predictions most accurately will grow fastest. Since crystals can perform universal computation, the complexity of computation that can be used to optimize growth is unbounded. To the extent that lessons derived from the tile assembly model might be applicable to mineral crystals, our results suggest that resource scarcity could conceivably have provided the evolutionary pressures necessary to produce complex clay genomes that sense and respond to changes in their environment
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