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GTEx数据库应用之尼安德特人基因仍影响现代人

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发表于 2017-3-6 16:11:51 | 显示全部楼层 |阅读模式
我在论坛不止一次推荐过这个数据库,是几千个死囚或者车祸等人捐赠的各种器官的RNA-seq表达数据集。
所以是正常组织的表达 数据库,当然,还有相应的基因型数据咯。

其实重点就是生物学知识,你有什么生物学知识,你才能对数据做什么分析。

最新的一篇文章;
Cell, McCoy et al.: "Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression" http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9
里面提到了如何对GTEx数据库里面的数据进行挖掘。


社评如下:
The last Neanderthal died 40,000 years ago, but much of their genome lives on, in bits and pieces, through modern humans. The impact of Neanderthals' genetic contribution has been uncertain: Do these snippets affect our genome's function, or are they just silent passengers along for the ride? In Cell on February 23, researchers report evidence that Neanderthal DNA sequences still influence how genes are turned on or off in modern humans. Neanderthal genes' effects on gene expression likely contribute to traits such as height and susceptibility to schizophrenia or lupus, the researchers found.

"Even 50,000 years after the last human-Neanderthal mating, we can still see measurable impacts on gene expression," says geneticist and study co-author Joshua Akey of the University of Washington School of Medicine. "And those variations in gene expression contribute to human phenotypic variation and disease susceptibility."

Previous studies have found correlations between Neanderthal genes and traits such as fat metabolism, depression, and lupus risk. However, figuring out the mechanism behind the correlations has proved difficult. DNA can be extracted from fossils and sequenced, but RNA cannot. Without this source of information, scientists can't be sure exactly if Neanderthal genes functioned differently than their modern human counterparts. They can, however, look to gene expression in modern humans who possess Neanderthal ancestry.

In this study, researchers analyzed RNA sequences in a dataset called the Genotype-Tissue Expression (GTEx) Project, looking for people who carried both Neanderthal and modern human versions of any given gene--one version from each parent. For each such gene, the investigators then compared expression of the two alleles head-to-head in 52 different tissues.

"We find that for about 25% of all those sites that we tested, we can detect a difference in expression between the Neanderthal allele and the modern human allele," says the study's first author, UW postdoctoral researcher Rajiv McCoy.

Expression of Neanderthal alleles tended to be especially low in the brain and the testes, suggesting that those tissues may have experienced more rapid evolution since we diverged from Neanderthals approximately 700,000 years ago. "We can infer that maybe the greatest differences in gene regulation exist in the brain and testes between modern humans and Neanderthals," says Akey.

One example uncovered by this study is a Neanderthal allele of a gene called ADAMTSL3 that decreases risk of schizophrenia, while also influencing height. "Previous work by others had already suggested that this allele affects alternative splicing. Our results support this molecular model, while also revealing that the causal mutation was inherited from Neanderthals," says McCoy. Alternative splicing refers to a process in which mRNAs are modified before they leave the cell's nucleus. When the Neanderthal mutation is present, the cell's machinery removes a segment of the mRNA that is expressed in the modern human version. The cell ends up making a modified protein because of a single mutation from a Neanderthal ancestor.

The connection between that modified protein, height, and schizophrenia still requires more investigation, but it's an example of how small differences between modern humans and Neanderthals can contribute to variation in people.

"Hybridization between modern humans and Neanderthals increased genomic complexity," explains Akey. "Hybridization wasn't just something that happened 50,000 years ago that we don't have to worry about anymore. Those little bits and pieces, our Neanderthal relics, are influencing gene expression in pervasive and important ways."

Next steps may include investigating whether Denisovans--another species of hominins that crossbred with modern humans--are contributing to gene expression, as well as applying the side-by-side method of expression analysis more broadly. For this study, McCoy and his colleagues had to develop a new statistical approach to sift through the immense amount of RNA data, but the same technique could be used to compare gene expression differences between modern human alleles.

###

This work is partially supported by the National Institutes of Health.

Cell, McCoy et al.: "Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression" http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9

Cell (@CellCellPress), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit: http://www.cell.com/cell. To receive Cell Press media alerts, contact press@cell.com.

该研究合作者、美国华盛顿大学医学院遗传学家Joshua Akey表示,“在人类最后一次与尼安德特人交配5万年后,我们仍然可以看到基因表达的可测量影响。而这些基因表达产生的变化与人们表型变异和疾病易感性有关。”

在该研究中,研究人员分析了GTEx项目数据库中的RNA序列,寻找携带某种给定基因的尼安德特人版本和现代人版本的参与者,然后比较这些等位基因在52个不同组织中的表达方式。

结果显示,尼安德特人后代基因仍在几十种组织类型中保持活跃状态。“在所有检测位点中,有1/4的尼安德特人等位基因以不同的方式表达。”该研究第一作者、华盛顿大学医学院博士后Rajiv McCoy说。

新研究还揭示,尼安德特人的等位基因在某些情况下可以影响基因ADAMTSL3的存在—— 一种精神分裂症的危险因素,而且,尼安德特人的DNA也可以使一个人更高。此外,该研究组开发出一种新统计方法能够筛选海量RNA数据。

不过,研究人员表示,要弄清古老DNA与身高和精神分裂症之间的关联还需进一步研究。未来,该研究还将调查丹尼索瓦人基因是否对现代基因表达产生影响





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发表于 2017-3-7 17:52:02 | 显示全部楼层
这个文章确实是数据挖掘的好例子啊。GTEx的数据就摆在那里,但是会用的不多啊。这篇文章先用genotype的数据找到尼安德特人的后代,然后再用RNA-seq的数据来比较各种组织、脑区的表达差异。最后落脚到一些感兴趣的性状。ADAMTSL3不仅能降低精神分裂症的风险,还能使人更高,感觉不少人都想变成尼安德特的后代了吧,哈哈哈。三个人数据挖掘发了一篇cell,谁还敢说数据分析不能发好文章啊。最后,楼主的文章链接好像有点bug啊
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