Long Non-Coding RNAs in Primate Brain Evolution

长的非编码RNA(LncRNAs)被认为是神经系统中的关键角色。数以万计的lncRNA在大脑中表达，对重要的大脑功能有贡献，并与神经退行性疾病和精神疾病有关。尽管有相当大的努力，但在lncRNAs的结构特别是功能注释方面仍然存在很大差距，限制了我们对它们在神经系统中作用的了解。大脑的许多特征都是人类特有的。因此，像lncRNA那样快速进化的基因是对这些创新的进化负有主要责任的最佳候选。由于生物功能必须从进化的角度来研究，我们在这里的目标是建立一个完整的人类lncRNAs目录，包括通过整理和连贯地重新分析已有的大量可用数据来注释它们的序列、结构、表达和进化变化。在第一个资助阶段，我们编制了一个进化年轻的、主要与大脑相关的lncRNAs目录，开发了一个通用的、有效的算法来从不同的RNA-Seq数据中重建转录结构，并设计了对lncRNAs进行正选择的统计检验。在此基础上，我们现在想重点研究lncRNAs的功能进化。我们建议研究包括古人类在内的哺乳动物中lncRNA的进化变化，开发基于其结构和初级序列来区分其功能的方法，预测和比较灵长类动物中的lncRNA靶基因，并将进化变化与复杂的脑功能和疾病联系起来。我们的进一步目标是以用户友好的方式向科学界提供我们的lncRNA目录及其详细注释和功能信息。

Long non-coding RNAs (lncRNAs) have been identified as key players in the nervous system. Tens of thousands of lncRNAs are expressed in the brain, contribute to important brain functions and show associations with neurodegenerative and psychiatric diseases. Despite considerable efforts, there is still a large gap in the structural and in particular functional annotation of lncRNAs limiting our understanding of their role in the nervous system. Many characteristics of the brain are human specific. Genes that evolve quickly, as lncRNAs do, are therefore the best candidates to be primarily responsible for the evolution of these innovations. Since biological function has to be studied in the light of evolution, we aim here at establishing a full catalog of human lncRNAs, including an annotation of their sequence, structure, expression, and evolutionary changes by collating and coherently re-analyzing the wealth of already available high throughout data. In the first funding phase we have compiled a catalog of evolutionarily young, mostly brain-related lncRNAs, developed a generic, efficient algorithm for the reconstruction of transcript structures from diverse RNA-Seq data, and devised a statistical test for positive selection on lncRNAs. On this basis, we now want to focus on the functional evolution of lncRNAs. We propose to investigate evolutionary changes in lncRNAs across mammals including archaic humans, develop methods for distinguishing lncRNAs that function primarily based on their structure vs. on their primary sequence, predict and compare lncRNA target genes in primates, and relate evolutionary changes to complex brainfunctions and disorders. It is further our goal to provide our lncRNA catalog with its detailed annotations and functional information to the scientific community in a user-friendly manner.