Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.
Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.
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DOI：
10.1371/journal.pgen.1004646
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Wu CT
中科院分区：
文献类型：
--
作者：
McCole RB;Fonseka CY;Koren A;Wu CT
超保守元件（UCE）从人类基因组中的片段重复和拷贝数变异（CNV）中被强烈耗尽，表明UCE的缺失或重复可能对哺乳动物细胞有害。在这里，我们解决的过程中，CNVs成为耗尽的UCE。我们开始表明，耗尽的UCE的特点是最近的大规模人类CNV数据集，然后发现，即使是新形成的从头CNV，通过减数分裂最多一次，显着耗尽的UCE。与此形成鲜明对比的是，通常情况下，癌细胞中特异性产生的CNV不会因UCE而耗尽，甚至可以显著富集。这一观察结果提出了这样一种可能性，即体细胞产生的并且相对新形成的CNV不太可能已经建立了UCE耗尽的CNV谱。或者，缺乏来自癌症CNV的UCE消耗可能反映了疾病状态。为了支持后一种解释，与疾病无关的体细胞CNV对于UCE是耗尽的。最后，我们表明，它是可能的，以观察诱导多能干细胞（iPS）的CNVs成为耗尽UCE随着时间的推移，这表明，耗尽可能是建立通过选择对UCE破坏CNVs，而无需减数分裂分裂。超保守元件（UCE）显示出一种无法解释的序列保守性。它们也是剂量敏感的，从健康细胞中的拷贝数变体（CNV）中耗尽。在这里，我们解决了这个剂量敏感性的过程，以深入了解UCE剂量影响细胞的方式。我们的研究表明，与健康个体遗传的CNV相反，癌症特异性CNV通常不会耗尽UCE，甚至可能会富集。此外，通过发现在健康而不是患病的身体中重新产生的CNV耗尽了UCE，我们获得了健康细胞可能以在癌细胞中被破坏的方式对UCE剂量变化作出反应的证据。在细胞培养中随着时间的推移检查CNVs后，我们假设健康细胞中对UCE破坏CNVs的选择作用迅速，这提高了在细胞培养中探索UCE剂量敏感性如何解释超敏反应的惊人可能性。我们的观察表明，了解健康细胞和癌细胞对UCE剂量变化的不同反应可以用来解决癌症中的基因组不稳定性。
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. 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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影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
64.8
作者：
通讯作者：
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影响因子：
5.2
作者：
Dekel-Naftali, Michal;Aviram-Goldring, Ayala;Rienstein, Shlomit
通讯作者：
Rienstein, Shlomit
影响因子：
9.8
作者：
Ahituv N;Zhu Y;Visel A;Holt A;Afzal V;Pennacchio LA;Rubin EM
通讯作者：
Rubin EM
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel