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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059964-15
Application #
8657052
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gindhart, Joseph G
Project Start
1999-08-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stowers Institute for Medical Research
Department
Type
DUNS #
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Zhu, Jin; Heinecke, Dominic; Mulla, Wahid A et al. (2015) Single-Cell Based Quantitative Assay of Chromosome Transmission Fidelity. G3 (Bethesda) 5:1043-56
Chen, Guangbo; Mulla, Wahid A; Kucharavy, Andrei et al. (2015) Targeting the adaptability of heterogeneous aneuploids. Cell 160:771-84
Potapova, Tamara A; Unruh, Jay R; Box, Andrew C et al. (2015) Karyotyping human and mouse cells using probes from single-sorted chromosomes and open source software. Biotechniques 59:335-6, 338, 340-2 passim
Mulla, Wahid; Zhu, Jin; Li, Rong (2014) Yeast: a simple model system to study complex phenomena of aneuploidy. FEMS Microbiol Rev 38:201-12
Mendes Pinto, Inês; Rubinstein, Boris; Li, Rong (2013) Force to divide: structural and mechanical requirements for actomyosin ring contraction. Biophys J 105:547-54
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; Kucharavy, Andrei et al. (2012) Actin depolymerization drives actomyosin ring contraction during budding yeast cytokinesis. Dev Cell 22:1247-60
Kaplan, Kenneth B; Li, Rong (2012) A prescription for 'stress'--the role of Hsp90 in genome stability and cellular adaptation. Trends Cell Biol 22:576-83
Zhu, Jin; Pavelka, Norman; Bradford, William D et al. (2012) Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet 8:e1002719
Chen, Guangbo; Rubinstein, Boris; Li, Rong (2012) Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap. Bioessays 34:893-900

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