| Summary: | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Physics, 2010. === This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. === Cataloged from student-submitted PDF version of thesis. === Includes bibliographical references (p. 77-84). === Exploring the forces that drive evolution at the gene network level and investigating underlying principles behind this process are fundamental questions in the context of understanding how evolution shapes transcriptional circuits. In this thesis I present two different explorations along these lines with special emphasis on the contribution of gene dosage variations to the alteration of phenotypes. On one hand I describe the design of an experimental system for observing evolution in vivo in the yeast Saccharomyces cerevisiae, the construction of a simple two-component genetic system and how I used the setup to explore its adaptative capabilities. An external inducer allowed me to tune the basal state of the system and by doing this I was able to tune the relative contribution of gene duplications and point mutations to the evolution of the system against an imposed fitness defect. This illustrates how the number of evolutionary solutions available against an imposed fitness constraint depends on the operating point of the underlying circuit. Increasing in complexity I then describe an analysis of the effect of gene dosage variations in the context of the galactose uptake network in the same organism. This network is composed of four regulatory elements and it contains several feed- back loops built into it, which makes its analysis nontrivial. The effect of dosage variations was explored experimentally by systematically deleting one of two copies of each regulatory gene in a diploid background. Surprisingly the system turned out to be invariant to proportional changes in all its regulatory elements, a property that we call network-dosage invariance. I developed a modeling framework for rationalizing these observations and found that the presence of both an activator and inhibitor interacting with a 1-to-1 stochiometry as well as certain topological constraints are requirements for such a behavior. This provides insight into what kind of regulatory circuits are robust to global effects like genomic duplications events, ploidy changes or global variations in the concentration of transcription factors. This work could be extended to the study of more complicated circuits, allowing the systematic exploration of evolutionary properties of small scale genetic systems. === by Bernardo Fabián Pando. === Ph.D.
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