Discovering Conserved cis-Regulatory Elements That Regulate Expression in Caenorhabditis elegans

The aim of this dissertation is two-fold:: 1) To catalog all <italic>cis</italic>-regulatory elements within the intergenic and intronic regions surrounding every gene in <italic>C.elegans</italic>: i.e. the regulome) and: 2) to determine which cis-regulatory elements are associated with expression under specific conditions. We initially use PhyloNet to predict conserved motifs with instances in about half of the protein-coding genes. This initial first step was valuable as it recovered some known elements and cis-regulatory modules. Yet the results had a lot of redundant motifs and sites, and the approach was not efficiently scalable to the entire regulome of <italic>C. elegans</italic> or other higher-order eukaryotes. Magma: Multiple Aligner of Genomic Multiple Alignments) overcomes these shortcomings by using efficient clustering and memory management algorithms. Additionally, it implements a fast greedy set-cover solution to significantly reduce redundant motifs. These differences make Magma ~70 times faster than PhyloNet and Magma-based predictions occur near ~99% of all <italic>C. elegans</italic> protein-coding genes. Furthermore, we show tractable scaling for higher-order eukaryotes with larger regulomes. Finally, we demonstrate that a Magma-predicted motif, which represents the binding specificity for HLH-30, plays a critical role in the host-defense to pathogenic infections. This novel finding shows that <italic>hlh-30(-)<italic> animals are more susceptible to <italic>S. aureus</italic> and <italic>P. aeruginosa</italic> than their wild type counterparts.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Computational and Systems Biology

Year dc:date.available

2011

Author dc:creator

• Ihuegbu, Nnamdi

Contributors dc:contributor

• Gary Stormo

• Biology
• Computer science
• Genetics

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7M906NX

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1590