280 research outputs found
From Strings to Graphs: Personalized Repeat-Aware Algorithms for Improved Long Read Structural Variant Detection
No full textSomatic structural variants have the ability to cause disease and drive disease progression. The identification of novel somatic structural variants in cancers is often based on the alignment of sequencing reads to a standard reference genome that while effective can be limited. Recent technological advancements have allowed for the use of personalized reference data, such as fully phased diploid assemblies of individuals, in the detection of novel somatic structural variants. In this thesis I present methods and analysis approaches that aim to show how personalized approaches to structural variant detection can help mitigate and reduce some of the current limitations of reference based detection methodsIn Chapter 2 I present a novel approach to quantifying the rate of retrotransposition in addition
to two pipelines to detect rare somatic retrotransposon insertions from long read sequencing data.
These approaches were designed to address limitations in previous rate estimates and allow for the
detection of rare somatic retrotransposon insertions with as little as one supporting read using a
personalized approach with a phased diploid assembly. I subsequently applied these methods to an
analysis of treated cancer samples to assess the efects of the treatment on retrotransposition rate.
In Chapter 3 I describe a phenomenon I term alignment ambiguity, where long read aligners may
represent a single insertion event diferently across multiple reads spanning the insertion, with insertion
calls for the same event possibly placed hundreds to thousands of bases away from each other.
I present a toolkit called somrit designed to address this alignment ambiguity, through the use of
local realignment guided by a consensus sequence. I subsequently show how somrit can be applied
to the detection of rare retrotransposon insertions, demonstrating how it has increased sensitivity
compared to existing approaches for the detection of rare events, and how local realignment can be
used to reduce false positive translocation calls tied to repeat-induced alignment errors.
Lastly in Chapter 4 I discuss challenges faced by current approaches to detect chromosomal translocations,
noting that current methods may generate many false positive calls tied to misalignments when using a read to linear reference alignments. I present SomvarG, a method that aligns reads to a
personalized sequence graph that contains paths for known variants to detect translocations. I then
show how SomvarG can generate sequence graphs that contain known variation not found in the linear
reference genome and how SomvarG can use these graphs to detect chromosomal translocations
with far fewer false positive calls and in less time.Ph.D
The nonlinear future stability of the FLRW family of solutions to the Euler–Einstein system with a positive cosmological constant
No full textOriginal manuscript January 24, 2012In this article, we study small perturbations of the family of Friedmann–Lemaître–Robertson–Walker cosmological background solutions to the 1 + 3 dimensional Euler–Einstein system with a positive cosmological constant. These background solutions describe an initially uniform quiet fluid of positive energy density evolving in a spacetime undergoing accelerated expansion. Our nonlinear analysis shows that under the equation of state p=c[2 over s]ρ, 0 < c[2 over s] < 1/3 , the background solutions are globally future-stable. In particular, we prove that the perturbed spacetime solutions, which have the topological structure [0,∞) × T[superscript 3], are future-causally geodesically complete. These results are extensions of previous results derived by the author in a collaboration with I. Rodnianski, in which the fluid was assumed to be irrotational. Our novel analysis of a fluid with non-zero vorticity is based on the use of suitably defined energy currents.National Science Foundation (U.S.). All-Institutes Postdoctoral Fellowship (Mathematical Sciences Research Institute (Berkeley, Calif.) Grant DMS-0441170
Measurement of the relative fraction of ttbar events produced via gluon fusion in ppbar collision at s**(1/2) = 1.96 TeV at CDF
No full textIn this thesis we present a measurement of the relative fraction of t{bar t} events produced via gluon-fusion to the total number of t{bar t} events. Using the kinematics of the production and decay of the top and antitop quark pair, we trained a Neural Network to discriminate the gluon-fusion events. The Neural Network was then used as a template to fit for the gluon-fusion fraction in data. Using a total integrated luminosity of 955 pb{sup -1} we find {sigma}(gg{yields}t{bar t})/{sigma}(p{bar p}{yields}t{bar t}) < 0.33 at 68% confidence level and {sigma}(gg{yields}t{bar t})/{sigma}(p{bar p}{yields}t{bar t}) < 0.61 at 95% confidence level
A methodology for the concurrent design of products and their assembly sequence
No full textThis thesis reports on the development of a Two-Tier methodology that provides
support for assembly sequence construction, validation and evaluation in parallel with
the design. This facilitates the production of products that are optimised for
assemblability. The proposed approach diverges significantly from many of the
sequence generation methods developed to date, which assume that assembly
planning starts at the conclusion of the design process. It is believed that the latter
approach misses an important opportunity to concurrently implement design and
sequence improvements that would result in products inherently suited to assembly.
The industrial assembly planning process was found to be completely different from
the automatic sequence generation approach. The Two-Tier methodology has its
foundations in this manual process, which uses a breadth-first, depth-second search. A
constraint-based method is used to interactively validate the sequence. In direct
contrast to traditional sequence generators, the hard and soft constraints are invoked
throughout the process. A novel approach to sequence evaluation allows the user to
quantitatively determine the suitability of the sequence at any time during the
construction process.
However, designers are rarely assembly experts and it is unreasonable to expect
practical sequences to be generated without assistance. Thus, a set of generic
assembly planning rules was identified from industrial surveys by the author. These
were collaboratively implemented into an Expert Assembler, which currently consists
of two mini advisors. Support is available to identify the most suitable base
component and the most appropriate component to add next.
The Two-Tier methodology has been implemented into a computer-based system
called SPADE (Sequence Planning And Design Environment). A four-layer model
holds the product data that underpins this implementation. The methodology and
SPADE have been successfully tested using representative case studies and the results
are reported as part of this thesis
On the questions of local and global well-posedness for the hyperbolic PDEs occurring in some relativistic theories of gravity and electromagnetism
No full textThe two hyperbolic systems of PDEs we consider in this work are the source-free Maxwell-Born-Infeld (MBI) field equations and the Euler-Nordstr??m system for gravitationally self-interacting fluids. The former system plays a central role in Kiessling's recently proposed self-consistent model of classical
electrodynamics with point charges, a model that does not suffer from the infinities found in the classical Maxwell-Maxwell model with point charges. The latter system is a scalar gravity caricature of the incredibly more complex Euler-Einstein system. The primary original contributions of the thesis can be summarized as follows:
1) We give a sharp non-local criterion for the formation of singularities in plane-symmetric solutions to the source-free MBI field equations. We also use a domain of dependence argument to show that 3-d initial data agreeing with certain plane-symmetric data on a large enough ball lead to solutions that form singularities in finite time. This work is an extension of a theorem of Brenier, who studied singularity formation in periodic plane-symmetric solutions.
2) We prove well-posedness for the Euler-Nordstr??m system with a cosmological constant k (EN_k) for initial data that are an H^N perturbation (not necessarily small) of a uniform, quiet fluid, for N [greater than]= 3. The method of proof relies on the framework of energy currents that has been recently developed by Christodoulou. We turn to this method out of necessity: two common frameworks for showing well-posedness in H^N, namely symmetric hyperbolicity and strict hyperbolicity, do not apply to the EN_k system, while Christodoulou's techniques apply to all hyperbolic systems derivable from a Lagrangian, of which the EN_k system is an example.
3) We insert the speed of light c as a parameter into the EN_k system (and designate the family of systems EN_k^c) in order to study the non-relativistic limit c to infinity. Taking the formal limit in the equations gives the Euler-Poisson system with a cosmological constant (EP_k). Using energy currents, we prove that for fixed initial data, as c goes to infinity, the solutions to the EN_k^c system converge uniformly on a spacetime slab [0,T] x R^3 to the solution of the EP_k system.Ph.D.Includes bibliographical references (p. 140-143)
Isaac T. Goodnow Ledger, Vol. 1 (1857-1864)
No full textVol. 1, 1857-1864: This volume was donated by Isaac Goodnow’s neice, Harriet A. Parkerson. It includes names and donation information related to Goodnow’s fundraising efforts for Bluemont Central College, as well as various financial information about the College. He was part of the New England Emigrant Aid Society and often traveled to Massachusetts and elsewhere in the northeast United States to encourage donations. Donors of note include Jared Sparks, president of Harvard University from 1849-1853, and author Henry Wadsworth Longfellow
Efficient de novo assembly of large genomes using compressed data structures
No full textDe novo genome sequence assembly is important both to generate new sequence assemblies for previously uncharacterized genomes and to identify the genome sequence of individuals in a reference-unbiased way. We present memory efficient data structures and algorithms for assembly using the FM-index derived from the compressed Burrows-Wheeler transform, and a new assembler based on these called SGA (String Graph Assembler). We describe algorithms to error-correct, assemble, and scaffold large sets of sequence data. SGA uses the overlap-based string graph model of assembly, unlike most de novo assemblers that rely on de Bruijn graphs, and is simply parallelizable. We demonstrate the error correction and assembly performance of SGA on 1.2 billion sequence reads from a human genome, which we are able to assemble using 54 GB of memory. The resulting contigs are highly accurate and contiguous, while covering 95% of the reference genome (excluding contigs <200 bp in length). Because of the low memory requirements and parallelization without requiring inter-process communication, SGA provides the first practical assembler to our knowledge for a mammalian-sized genome on a low-end computing cluster.</jats:p
Efficient construction of an assembly string graph using the FM-index
No full textAbstract
Motivation: Sequence assembly is a difficult problem whose importance has grown again recently as the cost of sequencing has dramatically dropped. Most new sequence assembly software has started by building a de Bruijn graph, avoiding the overlap-based methods used previously because of the computational cost and complexity of these with very large numbers of short reads. Here, we show how to use suffix array-based methods that have formed the basis of recent very fast sequence mapping algorithms to find overlaps and generate assembly string graphs asymptotically faster than previously described algorithms.
Results: Standard overlap assembly methods have time complexity O(N2), where N is the sum of the lengths of the reads. We use the Ferragina–Manzini index (FM-index) derived from the Burrows–Wheeler transform to find overlaps of length at least τ among a set of reads. As well as an approach that finds all overlaps then implements transitive reduction to produce a string graph, we show how to output directly only the irreducible overlaps, significantly shrinking memory requirements and reducing compute time to O(N), independent of depth. Overlap-based assembly methods naturally handle mixed length read sets, including capillary reads or long reads promised by the third generation sequencing technologies. The algorithms we present here pave the way for overlap-based assembly approaches to be developed that scale to whole vertebrate genome de novo assembly.
Contact: [email protected]</jats:p
A complete bacterial genome assembled de novo using only nanopore sequencing data
No full textWe have assembled de novo the Escherichia coli K-12 MG1655 chromosome in a single 4.6-Mb contig using only nanopore data. Our method has three stages: (i) overlaps are detected between reads and then corrected by a multiple-alignment process; (ii) corrected reads are assembled using the Celera Assembler; and (iii) the assembly is polished using a probabilistic model of the signal-level data. The assembly reconstructs gene order and has 99.5% nucleotide identity.</p
The effects of meditation on self-regulatory functioning
No full textSelf-regulation may be influenced by multiple factors (Robinson, Schmeichel, & Inzlicht, 2010), some of which may be enhanced via active cognitive training (ACT; Brown, Ryan & Creswell, 2007). My thesis project investigates the underling conceptual components responsible for enhanced self-regulatory functioning, the differential time effects of ACT on self-regulatory functioning, and whether ACT via meditation may improve decision making, directed attention, and persistence among long-term meditation practitioners (n = 60). No reliable differences were found between long-term meditators that rested or meditated then engaged in the self-regulatory tasks. The author discusses the potential reasons for null effects and future directions in research.California State University, Northridge. Department of Psychology.Includes bibliographical references (leaves 34-42
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