Computational comparative genomics : genes, regulation, evolution

Understanding the biological signals encoded in a genome is a key challenge of computational biology. These signals are encoded in the four-nucleotide alphabet of DNA and are responsible for all molecular processes in the cell. In particular, the genome contains the blueprint of all protein-coding genes and the regulatory motifs used to coordinate the expression of these genes. Comparative genome analysis of related species provides a general approach for identifying these functional elements, by virtue of their stronger conservation across evolutionary time. In this thesis we address key issues in the comparative analysis of multiple species. We present novel computational methods in four areas (1) the automatic comparative annotation of multiple species and the determination of orthologous genes and intergenic regions (2) the validation of computationally predicted protein-coding genes (3) the systematic de-novo identification of regulatory motifs (4) the determination of combinatorial interactions between regulatory motifs. We applied these methods to the comparative analysis of four yeast genomes, including the best-studied eukaryote, Saccharomyces cerevisiae or baker's yeast. Our results show that nearly a tenth of currently annotated yeast genes are not real, and have refined the structure of hundreds of genes. Additionally, we have automatically discovered a dictionary of regulatory motifs without any previous biological knowledge. These include most previously known regulatory motifs, and a number of novel motifs. We have automatically assigned candidate functions to the majority of motifs discovered, and defined biologically meaningful combinatorial interactions between them. Finally, we defined the regions and mechanisms of rapid evolution, with important biological implications.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Kamvysselis, Manolis, 1977-

Advisor dc:contributor.advisor

• Eric S. Lander and Bonnie A. Berger.

• Electrical Engineering and Computer Science.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/7999

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/7999