Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of ...matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2006.
Includes bibliographical references (p. 59-60).
The design of hypersonic airbreathing aircraft ...pushes the envelope of current state-ofthe-art aerospace propulsion and materials technology. Therefore, these aircraft are highly integrated to produce adequate thrust, reduce drag, and limit surface heating. Consequently, every aircraft component (e.g., wings, fuselage, propulsion system) is sensitive to changes in every other component. Including Radar Cross Section (RCS) considerations further complicates matters. During preliminary design, this requires the rapid analysis of different aircraft configurations to investigate component interactions and determine performance trends. This thesis presents a framework and accompanying software for performing such an analysis. The intent is to optimize a hypersonic airbreathing aircraft design in terms of aerodynamic performance and RCS. Computational Fluid Dynamics (CFD) and Computational Electromagnetics (CEM) are the two main framework software components. CFD simulates airflow around the aircraft to analyze its aerodynamic performance. Alternately, CEM simulates the electromagnetic signature of the aircraft to predict its RCS. The framework begins with the generation of a three-dimensional computer aided design aircraft model. Next, a grid generator discretizes this model. The flow simulation is performed on this grid and the aircraft's aerodynamic characteristics are determined. Flow visualization aids this determination. Then, aircraft geometry refinements are made to improve aerodynamic performance. Afterward, CEM is performed on aerodynamically favorable designs at various aspect angles and frequencies. RCS values are determined and used to rank the different configurations. Also, inverse synthetic aperture radar images are generated to locate major scattering centers and aid the design refinement. The design loop continues in this fashion until an acceptable aircraft design is achieved. The NASA X-43A test vehicle was used to validate this preliminary design framework.
by Daniel L. DiCara.
S.M.
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