title: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: McCole
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Biological and Biomedical Sciences PhD program, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Chamith Y
authors.initials: CY
authors.lastname: Fonseka
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: C-Ting
authors.initials: CT
authors.lastname: Wu
mesh_terms: D000818:Animals; D016386:Chromosome Walking; D017124:Conserved Sequence / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D019143:Evolution, Molecular; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008322:Mammals; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000166:cytology; D017384:Sequence Deletion