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Title: Amplification of chromosomal region 20q11.21 provides a selective advantage in human ES cells : effects on growth, differentiation and further genomic instability
Author: Hirst, Adam J. T.
ISNI:       0000 0004 5356 5507
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Human embryonic stem (ES) cells are derived from the inner cell mass of blastocyst stage embryos. Once explanted and culture in vitro, human ES cells retain their pluripotent potential (i.e capacity to differentiate into all somatic cells) and acquire the ability to self-renew indefinitely. These two properties of human ES cells make them an invaluable resource for developmental biology, cell replacement therapies, drug development and toxicology screening. However, it has been widely reported that human ES cells frequently acquire karyotypic changes throughout culture in vitro, termed 'culture-adaptation'. These changes occur sporadically in cultures but appear to be more common in high passage cell lines. The changes also appear to be non-random, frequently involving the gain of chromosomes 1, 12, 17 and 20 suggesting that these chromosomes harbour genes that provide the cells with a selective advantage. These karyotypic abnormalities are also commonly found in human embryonal carcinoma cells and primary human tumours, a concern for the potential use of human ES cells in therapeutic applications. A recent large-scale study by the International Stem Cell Initiative identified a small copy number variant (CNV) on chromosomal region 20q11.21, which was amplified in >20% of 125 karyotypically normal human ES cell lines. Here we show that the high prevalence of 20q11.21 amplification in human ES cells can be attributed to a strong selective advantage provided by BCL-XL. Cell lines containing the CNV show increased protection against apoptosis resulting in increased population growth rates allowing variant cells to rapidly out-compete normal diploid cells. Cell lines containing the 20q11.21 amplification also show altered differentiation patterns and increased survival of polyploidy. We also describe a method for the rapid detection of the 20q11.21 amplification in human ES cell cultures which is sensitive, cost-effective and applicable for stem cell laboratories worldwide.
Supervisor: Andrews, Peter W. ; Knowles, Barbara B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available