David C. Torney

Evolution and distribution of (GT)n repetitive sequences in mammalian genomes

The dinucleotide repetitive sequence, (GT)n, is highly interspersed in eukaryotic genomes and may have functional roles in genetic recombination or the modulation of transcriptional activity. We have examined the distribution and conservation of position of GT repetitive sequences in several mammalian genomes. The distribution of GT repetitive sequences in the human genome was determined by the analysis of over 3700 cosmid clones containing human insert DNA. On average, a GT repetitive sequence occurs every 30 kb in DNA from euchromatic regions. GT repetitive sequences are significantly underrepresented in centric heterochromatin. The density of GT repetitive sequences in the human genome could also be estimated by analyzing GenBank genomic sequences that include introns and flanking sequences. The frequency of GT repetitive sequences found in GenBank human DNA sequences was in close agreement with that obtained by experimental methods. GenBank genomic sequences also revealed that (GT)n repetitive sequences (n greater than 6) occur every 18 and 21 kb, on average, in mouse and rat genomes. Comparative analysis of 31 homologous sequences containing (GT)n repetitive sequences from several mammals representing four orders revealed that the positions of these repeats have been conserved between closely related species, such as humans and other primates. To a lesser extent, positions of GT repetitive sequences have been conserved between species in distantly related groups such as primates and rodents. The distribution and conservation of GT repetitive sequences is discussed with respect to possible functional roles of the repetitive sequence.

Distributed sensor networks for detection of mobile radioactive sources

The ability to track illicit radioactive transport through an urban environment has obvious national security applications. This goal may be achieved by means of individual portal monitors, or by a network of distributed sensors. We have examined the distributed sensing problem by modeling a network of scintillation detectors measuring a Cesium-137 source. We examine signal-to-noise behavior that arises in the simple combination of data from networked radiation sensors. We find that, in the ideal case, large increases in signal-to-noise compared to an individual detector can be achieved, even for a moving source. We also discuss statistical techniques for localizing and tracking single and multiple radioactive sources.

Base compositional structure of genomes.

We model the base compositional structure of the human and Escherichia coli genomes. Three particular properties are first quantified: (1) There is a significant tendency for any region of either genome to have a strand-symmetric base composition. (2) The variation in base composition from region to region, within each genome, is very much larger than expected from common homogeneous stochastic models. (3) A given local base composition tends to persist over a scale of at least kilobases (E. coli) or tens of kilobases (human). Multidomain stochastic models from the literature are reviewed and sharpened. In particular, quantitative measurements of the third property lead us to suggest a significant shift in the style of domain models, in which the variation of A+T content with position is modeled by a random walk with frequent small steps rather than with large quantum jumps. As an application, we suggest a way to reduce the amount of computation in the assembly of large sequences from sequences of randomly chosen fragments.

A COMPARATIVE SURVEY OF NON-ADAPTIVE POOLING DESIGNS

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Radioactive source detection by sensor networks

Detection limits of sensor networks for moving radioactive sources are characterized, using Bayesian methods in conjunction with computer simulation. These studies involve point sources moving at constant velocity, emulating vehicular conveyance on a straight road. For networks involving ten nodes, respective Bayesian methods are implementable in real time. We probe the increased computational requirements incurred by larger numbers of nodes and source trajectory parameters. The complexity appears quadratic in the number of nodes and, also, numerous trajectory parameters may be used. We investigate the consequences of different levels of background radiation. Simulations are shown to be useful for ranking candidate node layouts. We study the detection capabilities of individual sensors and the scalability of detection with sensor density; near the detection limit, increasing the number of sensors can accrue subproportional network sensitivity.

Group testing with DNA chips: generating designs and decoding experiments

DNA microarrays are a valuable tool for massively parallel DNA-DNA hybridization experiments. Currently, most applications rely on the existence of sequence-specific oligonucleotide probes. In large families of closely related target sequences, such as different virus subtypes, the high degree of similarity often makes it impossible to find a unique probe for every target. Fortunately, this is unnecessary. We propose a microarray design methodology based on a group testing approach. While probes might bind to multiple targets simultaneously, a properly chosen probe set can still unambiguously distinguish the presence of one target set from the presence of a different target set. Our method is the first one that explicitly takes cross-hybridization and experimental errors into account while accommodating several targets. The approach consists of three steps: (1) Pre-selection of probe candidates, (2) Generation of a suitable group testing design, and (3) Decoding of hybridization results to infer presence or absence of individual targets. Our results show that this approach is very promising, even for challenging data sets and experimental error rates of up to 5%. On a data set of 28S rDNA sequences we were able to identify 660 sequences, a substantial improvement over a prior approach using unique probes which only identified 408 sequences.

Families of Finite Sets in which No Intersection of ℓ Sets Is Covered by the Union of s Others

Abstract In 1964, Kautz and Singleton ( IEEE Trans. Inform. Theory 10 (1964), 363–377) introduced the superimposed code concept. A binary superimposed code of strength s is identified by the incidence matrix of a family of finite sets in which no set is covered by the union of s others ( J. Combin. Theory Ser. A 33 (1982), 158–166 and Israel J. Math. 51 (1985), 75–89). In the present paper, we consider a generalization called a binary superimposed ( s,l )-code which is identified by the incidence matrix of a family defined in the title. We discuss the constructions based on MDS-codes (The Theory of Error-correcting Codes, North-Holland, Amsterdam, The Netherlands, 1983) and derive upper and lower bounds on the rate of these codes.

Competition between solution and cell surface receptors for ligand. Dissociation of hapten bound to surface antibody in the presence of solution antibody

We present a joint theoretical and experimental study on the effects of competition for ligand between receptors in solution and receptors on cell surfaces. We focus on the following experiment. After ligand and cell surface receptors equilibrate, solution receptors are introduced, and the dissociation of surface bound ligand is monitored. We derive theoretical expressions for the dissociation rate and compare with experiment. In a standard dissociation experiment (no solution receptors present) dissociation may be slowed by rebinding, i.e., at high receptor densities a ligand that dissociates from one receptor may rebind to other receptors before separating from the cell. Our theory predicts that rebinding will be prevented when S much greater than N2Kon/(16 pi 2D a4), where S is the free receptor site concentration in solution, N the number of free surface receptor sites per cell, Kon the forward rate constant for ligand-receptor binding in solution, D the diffusion coefficient of the ligand, and a the cell radius. The predicted concentration of solution receptors needed to prevent rebinding is proportional to the square of the cell surface receptor density. The experimental system used in these studies consists of a monovalent ligand, 2,4-dinitrophenyl (DNP)-aminocaproyl-L-tyrosine (DCT), that reversibly binds to a monoclonal anti-DNP immunoglobulin E (IgE). This IgE is both a solution receptor and, when anchored to its high affinity Fc epsilon receptor on rat basophilic leukemia (RBL) cells, a surface receptor. For RBL cells with 6 x 10(5) binding sites per cell, our theory predicts that to prevent DCT rebinding to cell surface IgE during dissociation requires S much greater than 2,400 nM. We show that for S = 200-1,700 nM, the dissociation rate of DCT from surface IgE is substantially slower than from solution IgE where no rebinding occurs. Other predictions are also tested and shown to be consistent with experiment.

Optimal Pooling Designs with Error Detection

Consider a collection of objects, some of which may be “bad,” and a test which determines whether or not a given subcollection contains no bad objects. The nonadaptive pooling (or group testing) problem involves identifying the bad objects using the least number of tests applied in parallel. The “hypergeometric” case occurs when an upper bound on the number of bad objects is knowna priori. Here, practical considerations lead us to impose the additional requirement ofa posterioriconfirmation that the bound is satisfied. A generalization of the problem in which occasional errors in the test outcomes can occur is also considered. Optimal solutions to the general problem are shown to be equivalent to maximum-size collections of subsets of a finite set satisfying a union condition which generalizes that considered by Erdo?s and co-workers. Lower bounds on the number of tests required are derived when the number of bad objects is believed to be either 1 or 2. Steiner systems are shown to be optimal solutions in some cases.

Evaluation of a cosmid contig physical map of human chromosome 16

A cosmid contig physical map of human chromosome 16 has been developed by repetitive sequence finger-printing of approximately 4000 cosmid clones obtained from a chromosome 16-specific cosmid library. The arrangement of clones in contigs is determined by (1) estimating cosmid length and determining the likelihoods for all possible pairwise clone overlaps, using the fingerprint data, and (2) using an optimization technique to fit contig maps to these estimates. Two important questions concerning this contig map are how much of chromosome 16 is covered and how accurate are the assembled contigs. Both questions can be addressed by hybridization of single-copy sequence probes to gridded arrays of the cosmids. All of the fingerprinted clones have been arrayed on nylon membranes so that any region of interest can be identified by hybridization. The hybridization experiments indicate that approximately 84% of the euchromatic arms of chromosome 16 are covered by contigs and singleton cosmids. Both grid hybridization (26 contigs) and pulsed-field gel electrophoresis experiments (11 contigs) confirmed the assembled contigs, indicating that false positive overlaps occur infrequently in the present map. Furthermore, regional localization of 93 contigs and singleton cosmids to a somatic cell hybrid mapping panel indicates that there is no bias in the coverage of the euchromatic arms.