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Abstract:
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The yeast knockout collections provide opportunities to perform massively parallel
phenotyping of deletion mutants for almost every yeast open reading frame. I used the
knockout collection to screen for synthetic lethal partners, defined as alleles that cause
lethality when combined but are nonlethal alone, with CTF4 and CTF18 and present the
results in Chapter 2. I developed procedures for interpreting microarrays designed to
compare changes in oligonucleotide TAGs specific to each knockout strain and present
those methods in Chapters 3 and 4. These TAG microarrays allow thousands of
experiments to screen for synthetic lethality among pairs of null alleles to be
accomplished relatively quickly. In Chapter 4, I present 1410 novel predicted synthetic
lethal interactions based on 707 currently completed screens. Interpretation of synthetic
lethality is presented with a computational approach in Chapter 5, termed the congruence
score. High congruence scores associate genes into common pathways, and I use the
method to predict that YLL049W is a component of the dynein-dynactin nuclear
orientation pathway. In Chapter 6, I propose a generalization of the congruence score to
any phenotype, such as growth rate in the presence of various compounds, or even nonquantitative
phenotypes such as cell morphology. This procedure connects genes based
on similarity of multiple phenotypes using an application of information theory to
produce a shared information score. Using gene ontology similarity, I show that high
scores are associated with similarly annotated genes. |
