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

Abstract

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.

Figure 1. Five types of CNVs.

(A) ^classicalCNVs are identified solely by variation among individuals in the copy number of genomic regions. (B) ^{de nov}°CNVs are present in an individual but not in the soma of either of the parents. (C) ^cancerCNAs are copy number alterations that occur specifically in the cancer cells (orange) of an individual and, therefore, are absent from the healthy cells of the same individual (black). In this study we required ^cancerCNAs to be recurrent between individuals. (D) ^somaticCNVs are defined by regions that vary in copy number among the healthy somatic cells of an individual. (E) ^iPSCNVs are defined by regions that vary in copy number within a population of iPS cells and which are not detectable in the fibroblast cells from which the iPS cells were derived.

Figure 2. Partial correlation analyses.

The positive correlation between the positions of UCEs and ^cancerCNAs (first row) and the negative correlation between the positions of UCEs and ^classicalCNVs (second row) remain even after accounting for the correlation between the positions of UCEs and the genomic features listed across the top. P-values correspond to analyses in which the genome was divided into 50 kb windows and then assessed for the number of base pairs encompassed by the various genetic features within each window. Analyses using 10 kb and 100 kb bins also produced significant values across the board.

Figure 3. Timescales through which different types of genomic variation have been present and their relationships to UCEs.