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Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells


Ultraconserved elements (UCEs) display a level of sequence conservation that has defied explanation. They are also dosage sensitive, being depleted from copy number variants (CNVs) in healthy cells. Here we address the process underlying this dosage sensitivity in order to gain insights into the way that UCE dosage affects cells. Our studies demonstrate that, in contrast to CNVs inherited by healthy individuals, cancer-specific CNVs are, as a rule, not depleted for UCEs and may even be enriched. Furthermore, by discovering that CNVs arising anew in the healthy, as opposed to diseased, body are depleted of UCEs, we obtain evidence that healthy cells may be responsive to changes in UCE dosage in a way that is disrupted in cancer cells. After examining CNVs over time in cell culture, we postulate that selection against UCE-disrupting CNVs in healthy cells acts rapidly, raising the surprising possibility of exploring in cell culture how UCE dosage sensitivity may explain ultraconservation. Our observations suggest that an understanding of the different responses of healthy and cancer cells to changes in UCE dosage could be harnessed to address genomic instabilities in cancer.


Vyšlo v časopise: Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004646
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004646

Souhrn

Ultraconserved elements (UCEs) display a level of sequence conservation that has defied explanation. They are also dosage sensitive, being depleted from copy number variants (CNVs) in healthy cells. Here we address the process underlying this dosage sensitivity in order to gain insights into the way that UCE dosage affects cells. Our studies demonstrate that, in contrast to CNVs inherited by healthy individuals, cancer-specific CNVs are, as a rule, not depleted for UCEs and may even be enriched. Furthermore, by discovering that CNVs arising anew in the healthy, as opposed to diseased, body are depleted of UCEs, we obtain evidence that healthy cells may be responsive to changes in UCE dosage in a way that is disrupted in cancer cells. After examining CNVs over time in cell culture, we postulate that selection against UCE-disrupting CNVs in healthy cells acts rapidly, raising the surprising possibility of exploring in cell culture how UCE dosage sensitivity may explain ultraconservation. Our observations suggest that an understanding of the different responses of healthy and cancer cells to changes in UCE dosage could be harnessed to address genomic instabilities in cancer.


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Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 10
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