《Nature》“垃圾”DNA的新启示

　　

生物通报道，虽然名为“Junk DNA”但实际上，很多科学家已经为这些重复序列DNA正名了，垃圾DNA不仅不再是无用的基因组序列，反而成为具有多种功能的重要序列，比如说，垃圾DNA曾被发现对人类的进化具有重要的作用，Nature的一篇文章又发现垃圾DNA的新功能，文章Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice解析了垃圾DNA与心脏疾病的可能关联。

 

参与研究的有来自美国国立Lawrence Berkeley实验室基因组研究部，美国能源与基因组研究所，美国西南医学中心遗传分子实验室，内科研究实验室的科研工作者。通讯作者是来自Lawrence Berkeley实验室和能源与基因组研究所的Len A. Pennacchio教授。

 

在基因组中存在有一部分不能表达蛋白的非编码序列，有很长的一段时间科学家们没有认为这些非编码的作用，因此，这些重复的DNA片段被冠以垃圾DNA（Junk DNA）的称号。

 

早在2007年，两篇发表在Science上的研究（McPherson, R. et al. Science 316, 1488-1491 (2007). ；Helgadottir, A. et al. Science 316, 1491-1493 (2007).）发现，对人类全基因组扫描发现，上千名参与者染色体9p21上的非编码序列的长度与心脏病的发生有巨大的关联，尤其是，某个单核甘酸的突变与冠心病（coronary artery disease，CAD）的发生有极大的关联。

 

最新的证据支持来自Len A. Pennacchio教授2010年发表在Nature在线版上的研究性文章，Len A. Pennacchio教授研究小组十分好奇，非编码DNA序列是如何与冠心病发生关联的，如果将这些非编码区域的DNA敲除掉会有怎样的变化？

 

Len A. Pennacchio教授研究组以小鼠为模型，敲除这些非编码DNA，结果出现了科学家们意想不到的结局，在离这段DNA序列约100,000个碱基对的位置，两个基因表达量显著地降低了。最终，与空白对照组小鼠相比，大部分试验组的小鼠寿命缩短，有些则早早地患上了癌症。

 

Len A. Pennacchio教授研究组对这些试验鼠进行遗传学分析，结果发现非编码DNA的敲除可增强小鼠患心脏病的几率。在试验中，两个显著降低表达量的基因分别是：Cdkn2a与Cdkn2b，这两个基因主要在心肌和其他组织中担任抑制细胞周期分裂抑制子的角色。当这两个基因周围的非编码DNA被敲除后，引发的两基因表达量降低导致无法抑制心肌细胞过度繁殖，呈现心肌细胞比正常情况下繁殖增速的现象，最终影响动脉血管血液顺畅流动。引发心脏疾病。

 

Len A. Pennacchio教授表示，目前，在小鼠体内适用的机制是否同样存在于人类，他们暂时不清楚。但是，人类有与小鼠类似的情况存在，如，控制细胞分裂周期的基因表达异常时会影响冠状动脉的细胞分裂速度增速，这些过多的细胞会使得冠状动脉狭窄，最终引发心肌梗塞。

 

下一步，Len A. Pennacchio教授等人将研究人类相关垃圾DNA是否也具有类似的功能。

（生物通 张欢）

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Letter

Nature advance online publication 21 February 2010 | doi:10.1038/nature08801; Received 29 August 2009; Accepted 1 January 2010; Published online 21 February 2010

 

Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice

 

Axel Visel1,2, Yiwen Zhu1, Dalit May1, Veena Afzal1, Elaine Gong1, Catia Attanasio1, Matthew J. Blow1,2, Jonathan C. Cohen3, Edward M. Rubin1,2 & Len A. Pennacchio1,2

 

Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA

US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA

Department of Molecular Genetics, Department of Internal Medicine, and Center for Human Nutrition, UT Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA

Correspondence to: Len A. Pennacchio1,2 Correspondence and requests for materials should be addressed to L.A.P. (Email: [e-mail]).

 

【Abstract】

Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide1, 2. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4Δ70kb/Δ70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4Δ70kb/Δ70kb mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4Δ70kb/Δ70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.