NSF2026: EAGER: The evolution and diversity of the human brain

人类特有的认知能力在许多形式上都很明显。例如，没有其他物种可以与人类的言语和语言能力或代际知识积累能力相媲美。但是人类特有的大脑进化和认知的基因基础是什么呢？该项目将把我们已灭绝的近亲(尼安德特人和丹尼索瓦人)的基因组与人类基因组进行对比，以确定可能在人类特有大脑的进化中发挥作用的遗传变异。基因组学方法将被用于将这些基因的古老版本插入到人类衍生细胞中。随后将对携带已灭绝数千年的遗传变异的细胞生物学进行研究，以帮助发现人类大脑发育和认知中最近进化的功能。该项目将提供计算基因组分析和实验性基因组操作方面的研究生培训机会。这一项目的成果极有可能引起公众的普遍关注，因为它们涉及人类独特性的基本方面，该项目可能会创造机会，通过公共媒体渠道广泛传播。此外，该项目可能通过实验描述在大脑早期发育中起作用的基因的功能，从而为临床和生物医学研究提供信息。这项拟议的研究丰富了NSF2026 Idea Machine的获奖条目，这些条目包括《驾驭人类思维多样性》和《体验式认知的理解尺度》。该项目旨在发现和描述最近进化的人类特有的遗传变体在人类衍生的皮质器官中的功能作用。人类特有的变异将通过对人类及其最近的灭绝祖先尼安德特人和丹尼索瓦人的基因组进行创新的计算分析(重建的祖先重组图)来发现。这种方法可以识别存在于所有人类中，但在古老物种中不存在的变异。参与神经发育的基因中存在的变异，已经在这一组中得到了丰富，将优先用于遗传和功能分析。利用对一组人类来源的iPS细胞的基因组编辑，该项目将把已经灭绝的古老变体重新引入各种人类遗传背景。每个编辑的iPS系和未编辑的对照将通过皮质器官诱导阶段进行生长、发育和适当的分子内表型(如基因表达)的分析。与对照的表型偏差可能揭示最近的基因创新在人脑发育中的功能作用。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。

Human-specific cognitive capacity is evident in many forms. For example, no other species rivals humans’ capacity for speech and language or inter-generational accumulation of knowledge. But what are the genetic underpinnings of human-specific brain evolution and cognition? This project will contrast the genomes of our closest extinct relatives (Neanderthals and Denisovans) with human genomes to identify genetic variants that may play a role in the evolution of human-specific brain. Genomic methods will be used to insert the archaic versions of these genes into human-derived cells. The biology of cells that carry genetic variants that have been extinct for thousands of years will then be studied to help discover recently evolved functions in human brain development and cognition. This project will provide graduate training opportunities in computational genome analysis and experimental genome manipulation. The results of this project have high potential for general public interest as they address fundamental aspects of human uniqueness, and the project may generate opportunities for wide dissemination via public media channels. Further, this project may inform clinical and biomedical research by experimentally describing the functions of genes that work in early brain development. The proposed research enriches the NSF2026 Idea Machine winning entries of 'Harnessing the Human Diversity of Mind' and 'Understanding Scaling of Embodied Cognition.' This project aims to discover and describe functional roles for recently evolved human-specific genetic variants in human-derived cortical organoids. Human-specific variants will be discovered using an innovative computational analysis (a reconstructed ancestral recombination graph) of the genomes of humans and their closest, extinct ancestors – Neanderthals and Denisovans. This approach allows identification of variants that are present in all humans, but absent in the archaic species. Variants present in genes involved in neural development, enriched in this set already, will be prioritized for genetic and functional analysis. Using genome editing of a panel of human-derived iPS cells, this project will re-introduce the extinct archaic variants into various human genetic backgrounds. Each edited iPS line and unedited controls will be assayed for growth, development, and appropriate molecular endophenotypes such as gene expression through stages of cortical organoid induction. Phenotypic deviation from controls may reveal the function roles of the recent genetic innovations in human brain development.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.