The Evolution of DNA methylation patterns in neurons of the frontal cortex of humans and non-human primates

人类和非人类灵长类动物额叶皮层神经元 DNA 甲基化模式的进化

• 批准号: 280627290
• 负责人: Professor Dr. Thomas Haaf, since 7/2016
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280627290?language=en
• 关键词: Evolution; DNA; methylation; patterns; neurons

In the evolutionary history of primates one of the most distinctive features among all traits attributed exclusively to the genus homo is brain size. Similar to enzephalization, communication abilities seem to evolve peaking in language which is uniquely assigned to humans and a key component of cognitive abilities. Language is suggested to be both a driving force as well as an outcome of brain acceleration. In order to understand the mechanisms behind brain evolution it is thus essential to understand the evolutionary roots as well as the biological and molecular basis of human specific communication abilities, in particular language, an issue best to be addressed through human-primate comparisons. Apart from the ongoing debates among linguists considering the faculty of language of human language, there seems to be a certain agreement that one key feature is the ability to assess mental states of other individuals. But particularly this essential competence is severely interfered with autism spectrum disorders (ASD). Inference from a genetic cause of a disease to the function of a gene is a common research approach, thus it is not surprising to note that prominent genes in ASD are as well considered as communication or language genes like for example CNTNAP2. Given the high similarity between the chimpanzee and human DNA sequences, comparisons of gene expression in these two species in the last decade indicated that gene regulation might have had a bigger impact on primate evolution than DNA sequence. Up to now only a minority of studies focussed on mechanisms underlying primate specific DNA methylation patterns. However, the most of these studies used bulk tissue for research on human and non-human primate brains instead of single cell types like neurons or glia cells. We suggest that during human brain evolution neuronal DNA methylation patterns developed differently between humans and primates.In order to adress this issue we want to apply laser captured microdissection (LCM) for the separation of neurons and other cell types from bulk brain tissue. Together with downstream technologies like Next Generation Sequencing (NGS)-based RNAseq and Reduced Representative Bisulfite Sequencing (RRBS), and Pyrosequencing, the outlined strategies will enable us to assess species specific methylation patterns as well as their impact on genomewide gene regulation and of selected candidate genes. This research project will provide insights into the molecular evolution of human communication/language as well as brain evolution and potentially can open up avenues for therapeutic interventions of ASD and associated language disorders.

在灵长类动物的进化史上，人类特有的所有特征中最显著的特征之一就是大脑的大小。与顺序化类似，交流能力似乎在语言中达到顶峰，这是人类独有的，也是认知能力的关键组成部分。语言被认为既是大脑加速的动力，也是大脑加速的结果。因此，为了了解大脑进化背后的机制，必须了解人类特定交流能力，特别是语言的进化根源以及生物学和分子基础，这一问题最好通过人与灵长类动物的比较来解决。除了语言学家对人类语言能力的持续争论外，似乎有一种共识，即一个关键特征是评估其他人的心理状态的能力。但尤其是，这种基本能力严重干扰了自闭症谱系障碍(ASD)。从疾病的遗传原因到基因功能的推断是一种常见的研究方法，因此，注意到ASD中的突出基因与沟通或语言基因如CNTNAP2一样被考虑也就不足为奇了。鉴于黑猩猩和人类DNA序列的高度相似性，过去十年对这两个物种基因表达的比较表明，基因调控对灵长类进化的影响可能比DNA序列更大。到目前为止，只有少数研究集中在灵长类特有的DNA甲基化模式的潜在机制上。然而，这些研究大多使用大量组织来研究人类和非人类灵长类动物的大脑，而不是像神经元或神经胶质细胞这样的单一细胞类型。我们认为，在人类大脑进化过程中，神经元DNA甲基化模式在人类和灵长类动物之间发展不同。为了解决这个问题，我们希望应用激光捕获显微解剖(LCM)从大块脑组织中分离神经元和其他类型的细胞。结合下游技术，如基于下一代测序(NGS)的RNAseq和简化代表性亚硫酸盐测序(RRBS)，以及焦磷酸测序，概述的策略将使我们能够评估物种特有的甲基化模式及其对全基因组基因调控和选定候选基因的影响。这一研究项目将为人类交流/语言的分子进化以及大脑进化提供见解，并可能为自闭症和相关语言障碍的治疗干预开辟道路。