Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells

Ultraconserved elements (UCEs) are strongly depleted from segmental duplications and copy number variations (CNVs) in the human genome, suggesting that deletion or duplication of a UCE can be deleterious to the mammalian cell. Here we address the process by which CNVs become depleted of UCEs. We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs. In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched. This observation raises the possibility that CNVs that arise somatically and are relatively newly formed are less likely to have established a CNV profile that is depleted for UCEs. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. In support of this latter explanation, somatic CNVs that are not associated with disease are depleted for UCEs. Finally, we show that it is possible to observe the CNVs of induced pluripotent stem (iPS) cells become depleted of UCEs over time, suggesting that depletion may be established through selection against UCE-disrupting CNVs without the requirement for meiotic divisions.
Author Summary 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.