3篇Science文章：大规模人类基因表达差异图谱

2015-05-11 佚名生物通

在美国国立卫生研究院基因型-组织表达（GTEx）项目的资金资助下，研究人员构建出了一个万众期待的新数据资源，它可以帮助确立个体基因组构成之间的差异对于基因活性的影响以及对疾病的贡献。借助于这一新资源，科学家们可以同时探究许多不同人类组织和细胞的潜在基因组学，并有望为研究和了解人类生物学开辟新途径。GTEx的研究人员将他们为期两年研究的初步结果发布在5月7日《科学》(Science)和其他期刊的

在美国国立卫生研究院基因型-组织表达（GTEx）项目的资金资助下，研究人员构建出了一个万众期待的新数据资源，它可以帮助确立个体基因组构成之间的差异对于基因活性的影响以及对疾病的贡献。借助于这一新资源，科学家们可以同时探究许多不同人类组织和细胞的潜在基因组学，并有望为研究和了解人类生物学开辟新途径。

GTEx的研究人员将他们为期两年研究的初步结果发布在5月7日《科学》(Science)和其他期刊的多篇研究论文中。这些研究工作使人们重新认识了在不同的组织中基因组变异是如何控制基因的开启和关闭方式与时间，表达和沉默基因的数量，以及如何使得人们容易罹患癌症、心脏病和糖尿病一类的疾病的。

在一篇主要的Science文章中，研究人员分析了来自175名个体和43个不同组织类型的1,600多个组织样本的基因活性读值。研究人员通过测量RNA来评估了基因的活性。他们致力分析了9种最容易获得的组织类型的样本，包括脂肪、心脏、肺、骨骼肌、皮肤、甲状腺、血液、胫动脉和神经。

每个细胞的基因组蓝图都是相同的，但随着时间的推移开启及关闭的一组基因以及这些基因的表达水平却造成了肾细胞和肝细胞的差异。GTEx研究人员借助于一种叫做表达数量性状基因座(eQTL)分析的方法，测量了变异对基因表达活性的影响。eQTL是指特定基因组位置上的一个变异与特异组织中基因活性水平的关联。GTEx的其中一个目标就是要鉴别出所有基因的eQTLs，并评估它们是否对多个组织造成了影响。

研究人员发现了一组在不同组织类型之间具有普遍活性的变异。事实上，大约一半蛋白质编码基因的eQTLs在所有9种组织中活化。他们在研究的每种组织中鉴别出了大约900-2,200个eQTL基因——与附近基因组变异有关联的基因，所有的组织则有6,486个eQTL基因。

论文的公共通讯作者、哈佛-麻省理工Broad研究所GTEx实验室数据分析与协调中心负责人Kristin Ardlie说：“我们不知道在不同的组织中这种调控有多么特异。分析结果表明，大量变异的效应跨越多个组织，同时有几组变异显示组织特异性效应。”

比较组织特异性eQTLs与遗传疾病关联可能有助于认识与疾病最相关的组织。研究人员还发现一些组织之间共享了大量的eQTL，这可以帮助解释基因组变异是如何影响不同组织的。

甚至在多个组织中活化之时，同一变异有时在不同的组织中也可以产生不同的影响。例如，GTEx研究人员发现有一个变异影响了两个与血液相关的基因的活性，虽然在其他组织中有着更高的总体基因活性，它对胫动脉中血压相关的基因表达造成了更强的影响。他们还指出在活体供者的组织和已故捐赠人的GTEx样本中看到了相同的基因活性谱。

发表于Science杂志上的两项姊妹研究利用GTEx数据，检测了不同组织中基因活性的其他方面。一项研究确定了蛋白质截短变异（protein-truncating variants,PTVs）对于基因活性的影响。PTVs缩短了基因的蛋白质编码序列，影响了它们的功能。一些罕见的PTVs可以导致杜氏肌营养不良一类的疾病。每个人的基因组中携带着大约100个PTVs，大多数PTVs影响很小或没有影响，在一些情况下甚至可以预防疾病。

牛津大学的Manuel Rivas博士和同事们利用 GTEx数据和来自一个大型欧洲项目的信息，研究了600多人的基因读值。研究小组发现一些PTVs是通过降解基因转录物或是破坏剪接过程来影响了蛋白质生成。研究人员利用GTEx数据在两种情况下检测了一些个体和组织类型中的这些效应。研究小组现正在开发更好的方法来预测患者中发现的一些PTVs的影响。

在另一项姊妹研究中，西班牙基因组调控中心生物信息学和基因组项目协调人Roderic Guigo博士和同事们，探讨了在近1,500个 GTEx组织样本中基因读值的模式。研究人员发现，组织之间的基因活性差异要比个体间大得多。

研究人员发现不到2,000个基因随年龄发生改变，包括与帕金森病和阿尔茨海默氏症等一些神经退行性疾病相关的基因。他们还发现有750多个基因在男女之间显示活性差异。一些基因与男女之间患病率显示差异的一些疾病有关联，包括5个与心脏病相关的基因。

原始出处：

GTEx Consortium.The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans.Science. 2015 May 8;348(6235):648-60. doi: 10.1126/science.1262110. Epub 2015 May 7.

Melé M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, Young TR, Goldmann JM, Pervouchine DD, Sullivan TJ, Johnson R, Segrè AV, Djebali S, Niarchou A, Consortium TG, Wright FA, Lappalainen T, Calvo M, Getz G, Dermitzakis ET, Ardlie KG, Guigó R.The human transcriptome across tissues and individuals. Science. 2015 May 8;348(6235):660-665.

Effect of predicted protein-truncating genetic variants on the human transcriptome. 2015 May 8;348(6235):666-9. doi: 10.1126/science.1261877.

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2015-06-27 仁心济世

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2015-12-25 ylz8403

#大规模#

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2015-05-13 huaxipanxing

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2015-05-13 bioon1

#基因表达#

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2015-05-13 jichang

#SCIE#

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