Author ORCID Identifier
https://orcid.org/0000-0001-9787-4764
Date of Award
Winter 2025
Document Type
Thesis (Ph.D.)
Department or Program
Biochemistry and Cell Biology
First Advisor
Duane A. Compton
Second Advisor
Kristina M. Godek
Abstract
Aberrant mitotic chromosome segregation results in the generation of cells with aneuploidy, an incorrect number of chromosomes. Aneuploidy can compromise the viability of the developing embryo and is the leading cause of pregnancy loss, failed embryo implantation, and congenital birth defects. Yet, widescale analysis of human embryos from in vitro fertilization (IVF) clinics suggests that aneuploidy is common, with upwards of 70% of preimplantation embryos being aneuploid.
Mitotic chromosome missegregation during post-zygotic development results in mosaic embryos made up of both diploid and aneuploid cells. Strikingly, upon transplant for pregnancy, mosaic embryos have been reported to result in healthy birth without genetic abnormalities. A genetically normal offspring from an embryo comprised of aneuploid cells causes a discrepancy in knowledge, as it is well established that aneuploidy is detrimental to embryonic development. Consequently, the cellular processes required for proper development of a mosaic embryo are not fully understood. Human pluripotent stem cells (hPSCs) also exhibit high rates of erroneous chromosome missegregation and aneuploidy during prolonged propagation in vitro, suggesting that these are both inherent features of embryonic and pluripotent stem cells. My thesis work aims to uncover both the causes and consequences of aneuploidy in pluripotent stem cell populations.
In Chapter 2, I contribute to efforts to define hPSC mitotic chromosome fidelity. Our results demonstrate that hPSCs inherently possess a low mitotic fidelity which is directly correlated with a cell’s developmental potential. In Chapter 3, I investigate the immediate consequences of chromosome missegregation and aneuploidy in hPSCs and observe the long-term fate of aneuploid cells in mosaic hPSC populations. I find that hPSCs do not elicit a cell autonomous response to and are inherently tolerant of aneuploidy. Furthermore, my data demonstrates that cell competition eliminates aneuploid hPSCs when neighboring more fit diploid hPSCs.
Importantly, our work finds that a pluripotent state confers a low fidelity of chromosome segregation. Moreover, my research reveals that hPSCs are tolerant of aneuploidy, but genomic integrity is preserved through the elimination of aneuploid cells in mosaic environments by cell competition. My thesis provides new insights into the biology of early embryonic cells and hPSCs.
Original Citation
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Deng, C., Ya, A., Compton, D.A., and Godek, K.M. (2023). A pluripotent developmental state confers a low fidelity of chromosome segregation. Stem Cell Rep 18, 475–488. https://doi.org/10.1016/j.stemcr.2022.12.008.
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Ya, A., Deng, C. & Godek, K. Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells. (2024) doi:10.1101/2024.05.08.593217.
Recommended Citation
Ya, Amanda I., "Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells" (2025). Dartmouth College Ph.D Dissertations. 332.
https://digitalcommons.dartmouth.edu/dissertations/332
