灵长类特异长链非编码RNA对灵长类大脑发育的影响

Long non-coding RNAs are involved in controlling X-inactivation, imprinting and dynamic expression of genes by mainly regulating epigenetic modification. In our investigation of evolution of ANRIL and HOTAIR, We found that many lncRNAs might be highly clade-specific. In one research reported, it is estimated that 30% of human lncRNAs might be primate-specific. Since one lncRNA can contain several functional domains, this makes lncRNAs an adaptive genetic Substrate
. For example, one functional domain can explore new functional properties. This leads us to consider the effect of primate-specific lncRNAs on evolution of clade-specific biological process. .As we all know, primate evolution is characterized by brain size, and the most dramatically expanded human brain region is the cortex, which serves as the seat of our higher cognitive functions. Primate brain evolution is highly related to adaptive evolution of regulatory elements, such as promoters. As the main regulatory elements in genomes, lncRNAs have been demonstrated to play an important role in central nervous system development and function. Abnormal expression of these lncRNAs is also associated with central nervous system disorders. The most interesting fouding is that thousands of lncRNAs have appeared during nervous system evolution. Therefore, we guess that primate-specific lncRNAs should have an important effect on primate brain evolution. .In our previous work, we has developed LongTarget for predicting lncRNA’s targets. This makes it possible for us to decipher lncRNA functions in a large number. LongTarget shows high sensitivity and specificity. It also has received a lot of positive feedback from domestic and foreign counterparts. We also obtained about homologues of 14000 human lncRNAs in 16 mammals, which include eutherias, marsupials, and monotremes. .In this proposed research, we aim to detect primate-specific lncRNAs and investigate the role of these lncRNAs in central nervous system development and function by using LongTarget to predict their targets and combining annotation of GO or KEGG databases. We also plan to reveal the effect of these central nervous system related primate-specific lncRNAs on primate brain evolution by analyzing their evolution in primates, human population and non-human primates population and combining brain function difference. In parallel, we will check whether these lncRNAs is differentially expressed in Glioblastoma Multiforme, the most common and deadliest primary brain tumor in adults..We believe that successful completion of the propose study will provide biological mechnisms underlying the difference of nervous system diseases among different mammals and make contribution to promoting or improving treatment of these diseases.

长链非编码RNA(lncRNA)在中枢神经系统中起着重要作用，但灵长类特异lncRNA对灵长类大脑进化的影响目前尚不明确。.既往我们探讨了人类lncRNA在16个物种的同源物，并开发了用于预测lncRNA功能的软件LongTarget。本项目拟在前期的工作基础上筛选灵长类特异lncRNA，鉴定其在中枢神经系统发育与可塑中起到的作用，并揭示中枢神经系统相关的灵长类特异lncRNA对灵长类大脑进化的影响，同时结合测序数据，验证灵长类特异lncRNA在中枢神经系统中的功能，以期揭示灵长类特异lncRNA对灵长类大脑进化的影响。.该研究有望为中枢神经系统疾病发生与发展的物种间差异提供分子机制，从而为中枢神经系统疾病治疗方案的提出或改进提供可靠的研究方向。

lncRNA可通过表观修饰来调控基因表达，作为基因表达调控网络中的重要一员，lncRNA呈现出高度的种系特异性。但这些灵长类/人类特异的lncRNA受到了怎样的适应性进化，以及如何影响着大脑功能等各种生理病理过程还尚不清楚。我们鉴定了13562个人类lncRNA在16个哺乳动物中的同源基因，发现了4355个灵长类特异lncRNA，其中66个为人类特异lncRNA。对这66个人类特异lncRNA进行了全基因组范围内的目标基因预测和功能注释，我们发现这些目标基因主要富集于大脑发育、代谢、免疫和生殖。同时，我们对这些lncRNA进行了适应性进化分析，发现lncRNA RP11-848P1.4和RP11-598D14.1呈现较强的选择信号。进一步地，为了深入揭示lncRNA表观修饰来调控基因表达的临床意义，我们采用了联合肿瘤测序数据和计算预测的整合方法，发现lncRNA倾向于表观调控多个目标基因的表达，且与肿瘤的发生发展息息相关。本研究全面且系统地揭示了lncRNA的种系特异性，获得了受到了适应性进化的人类特异lncRNA，同时提供了一种联合测序数据和计算预测来分析lncRNA的流程，可用于揭示lncRNA和目标基因的共表达网络。