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Access Type

WSU Access

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Henry Heng

Abstract

Multi-level heterogeneity is a characteristic feature of cancer cell populations. However, how a cell population regulates and maintains its cell population heterogeneity is not well understood. Based on conventional theories of genetic inheritance, cell division is precise, where a daughter cell inherits an identical karyotype from its mother cell. Therefore, errors that are generated during cell division occur at low frequencies that take prolonged time periods to accumulate. However, the overwhelming heterogeneity found in unstable cancers is largely inconsistent with current models of genetic inheritance. In order to determine the mechanism of how heterogeneity is regulated, the pattern of inherited traits, including karyotype and growth rate, are compared in cell lines with different degrees of genome instability. Single cell and population-based assays were conducted and illustrate the following: 1) single unstable cells cannot pass a specific karyotype or growth rate and instead pass a heterogeneous array of karyotypes and growth rates; 2) genome heterogeneity is linked to other heterogeneous features of the system, like growth heterogeneity; 3) cells that are outliers dominate cell population dynamics when the cell population is unstable; and 4) the statistical average does not give an accurate portrayal of unstable cell populations. Altogether, this suggests that genome instability leads to genome replacement-mediated macro-cellular evolution that precludes the clonal expansion of a few abnormal cells; and 2) a given degree of heterogeneity can be inherited from a single cell. Because a given degree of heterogeneity is inherited, and the specific variants change between cell passages, this inheritance is termed fuzzy inheritance. According to fuzzy inheritance, rather than passing specific changes, the potential to generate genomic variation is passed. Fuzzy inheritance provides a cell population with the necessary evolvability and explains how heterogeneity is regulated and maintained in normal tissue and in cancer cells.

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