Aneuploidy, the state of having uneven and abnormal chromosome copy numbers, is a frequently observed genome variation in eukaryotes and is a hallmark of cancer thought to play important roles in cancer evolution and development of drug resistance. The goal of this project is to use a creative combination of cell biology, genetics and genomic analyses in the model organism, the budding yeast Saccharomyces cerevisiae, to gain fundamental insights into how aneuploidy affects genome stability, cellular physiology and stress adaptation. We have recently developed several new methods to generate isogenic aneuploid yeast strains with random chromosome stoichiometry and to follow karyotype dynamics in aneuploid populations. These methods have allowed us to make important observations on the relationship between aneuploidy and cellular stress, and the profound impact of chromosome copy number variation on gene expression and fitness. The proposed study builds upon these findings with four specific aims.
The first aim attempts to further understand the consequence of aneuploidy on gene expression by investigating its potential effects on epigenetic regulatory mechanisms.
The second aim focuses on the question of why aneuploidy has a tendency to promote further chromosome instability leading to karyotypically mosaic populations adaptive to a wide range perturbation.
The third aim i nvestigates the possible existence of a common stress state associated with aneuploidy. The last aim explores a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections.

Public Health Relevance

The proposed project is relevant to public health because aneuploidy, the state of having abnormal chromosome numbers, is a hallmark of cancer, is the cause of several congenital defects, and is linked to Alzheimer's disease and autism. However, the cause and consequence of aneuploidy remain poorly understood. The work proposed aims to gain fundamental insights into the impact of aneuploidy on gene expression and cellular physiology, and the relationship between aneuploidy and cellular stress. We also plan to explore a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-R (02))
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Gindhart, Joseph G
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Stowers Institute for Medical Research
Kansas City
United States
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Mulla, Wahid; Zhu, Jin; Li, Rong (2014) Yeast: a simple model system to study complex phenomena of aneuploidy. FEMS Microbiol Rev 38:201-12
Potapova, Tamara A; Zhu, Jin; Li, Rong (2013) Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev 32:377-89
Mendes Pinto, Ines; Rubinstein, Boris; Li, Rong (2013) Force to divide: structural and mechanical requirements for actomyosin ring contraction. Biophys J 105:547-54
Chen, Guangbo; Bradford, William D; Seidel, Chris W et al. (2012) Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482:246-50
Pavelka, Norman; Rancati, Giulia; Li, Rong (2010) Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer. Curr Opin Cell Biol 22:809-15
Pavelka, Norman; Rancati, Giulia; Zhu, Jin et al. (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468:321-5
Bosl, William J; Li, Rong (2010) The role of noise and positive feedback in the onset of autosomal dominant diseases. BMC Syst Biol 4:93
Kriete, Andres; Bosl, William J; Booker, Glenn (2010) Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses. PLoS Comput Biol 6:e1000820
Rancati, Giulia; Pavelka, Norman; Fleharty, Brian et al. (2008) Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135:879-93
Bosl, William J (2007) Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery. BMC Syst Biol 1:13

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