Positive Selection on Gene Regulation and the Evolution of the Human Brain

尽管人类和黑猩猩拥有大约98%的相同基因，但它们的大脑却截然不同。科学家们假设，基因组中开启和关闭基因表达的区域对于理解这种差异至关重要。该项目使用进化和实验方法来研究自然选择如何塑造人类大脑中的基因表达。研究人员将分析基因组中显示人类特有适应证据的区域，以更好地理解人类和非人类灵长类动物之间神经分化的出现、性质和重要性。该项目将使用下一代测序平台进行动手培训，提供以学生为主导的教育体验。学生们将获得的关键大数据技能集可以转化为研究生培训和生物技术职业生涯。此外，将通过与尤里卡的合作伙伴关系向当地小学生提供服务！女性STEM留存计划，每年夏天在马萨诸塞州阿默斯特大学运行。这个项目将发现整个基因组的适应和神经细胞变化之间的功能联系。这个项目将利用一个可能的增强子的精选生物信息学目录，测试基因组适应与人类进化过程中发生的神经表型变化之间存在功能联系的假设。为了了解特定于人类调节区的突变的功能后果，将测量与特定基因调节序列相关的基因表达的变化。这将在神经前体细胞和成熟神经元中完成，在人类和黑猩猩细胞系中都是如此。为了从功能上测试这些区域，尖端的高通量增强子分析将被用来测量这10,000个隐含的调控区域如何驱动神经前体细胞和成熟神经元的差异基因表达的显著差异。这两种类型的细胞都将来自诱导多能干细胞(IPSC)系，这些系具有向许多不同类型细胞分化的能力。结果将揭示在严格控制的实验环境中适应和特定于人类的变化之间的功能联系的信息。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Although humans and chimpanzees share approximately 98% of the same genes, they have very different brains. Scientists hypothesize that regions of the genome that turn gene expression on and off are critically important for understanding this difference. This project uses evolutionary and experimental methods to examine how natural selection has shaped gene expression in the human brain. The investigators will analyze regions of the genome showing evidence for adaptations unique to the human lineage, to better understand the advent, nature, and importance of neural differentiation between humans and non-human primates. The project will provide student-led educational experiences using a next-generation sequencing platform for hands-on training. The critical big-data skill set that students will gain is translatable both to graduate training and careers in biotech. Additionally, outreach to local elementary school students will be provided through a partnership with the Eureka! Program for STEM retention of women, which runs every summer at UMass Amherst. This project will find functional links between adaptation across the genome and changes in neural cells. Using a curated bioinformatics catalog of putative enhancers, this project will test the hypothesis that there are functional links between adaptation in the genome and changes in neural phenotypes that occurred during human evolution. In order to understand the functional consequences of mutations particular to human regulatory regions, changes in gene expression associated with particular gene regulatory sequences will be measured. This will be done in neural progenitor cells and in mature neurons, in both human and chimpanzee cell lines. To functionally test these regions, cutting-edge high-throughput enhancer assays will be used to measure significant differences in how these ~10,000 implicated regulatory regions are driving differential gene expression in neural progenitor cells and mature neurons. Both of these cell types will be derived from induced pluripotent stem cell (iPSC) lines, which have the capacity to be driven to many different cell types. The results will reveal information about the functional links between adaptation and human-specific changes in a tightly controlled experimental environment.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.