Investigating Regulatory Functions of Archaic Hominin Genetic Variants in Modern Human Genomes

当今天生活的人的祖先在10万到5万年前离开他们的祖先家园时，他们与现在已经灭绝的遥远的人类亲戚，如尼安德特人，进行了杂交。由此产生的遗传物质交换意味着，现代人类基因库中包含了少量尼安德特人的遗传变异。在这个项目中，研究人员将研究现存人类中存在的尼安德特人遗传变异如何影响附近基因在各种不同人类细胞类型（如皮肤细胞、免疫细胞、肝细胞、骨骼细胞）中的活性程度。通过对功能变异的识别和向公众传播这些数据，研究人员将促进研究和公众对进化史和遗传变异对人类生物学的影响的理解。这些发现将有助于描述尼安德特人DNA序列对人类细胞功能的功能和医学影响。调查人员还将与博物馆合作，开发能够突出这一研究领域的实际重要性的展览。此外，该项目将通过学生培训和指导活动，促进女性和代表性不足的学者更广泛地参与STEM研究。鉴于最近在高通量功能测试方面的进展，研究人员将进行实验，研究成千上万的尼安德特人遗传变异及其人类对应基因，以研究它们在各种人类细胞类型中调节基因表达的能力。研究人员将通过对特定细胞类型的遗传碱基对进行额外的功能实验来跟踪该方法的关键发现，以检查尼安德特人遗传变异对基因表达和细胞生物学的功能影响。此外，通过直接比较先前的相关发现与实验室实验背景下获得的结果，本研究将加深对这些常用遗传数据集的理解。本项目由美国国家科学基金会生物人类学与人类网络和数据科学联合基金资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

When the ancestors of people living today dispersed from their ancestral homeland between one hundred thousand and fifty thousand years ago, they interbred with now-extinct distant human relatives, such as Neanderthals. The resulting exchange of genetic material means that the modern human gene pool includes a small amount of Neanderthal genetic variation. In this project, researchers will examine how Neanderthal genetic variants that are present in living humans affect the degree to which a nearby gene is active, in a variety of different human cell types (e.g., skin cells, immune cells, liver cells, skeletal cells). Through the identification of functional variants and by the dissemination of such data to the public, the researchers will advance research and public understanding of the effects of evolutionary history and genetic variation on living human biology. The findings will help to characterize the functional and medical impacts of Neanderthal DNA sequences on human cell function. The investigators will also work with museums to develop exhibits that will highlight the practical importance of this field of research. Furthermore, this project will promote broader participation of women and underrepresented scholars in STEM research through student training and mentoring activities. Given recent advances in high throughput functional testing, the researchers will conduct experiments in which they investigate tens of thousands of Neandertal genetic variants and their human counterparts for their ability to regulate the expression of genes in a variety of human cell types. The researchers will follow up key findings from this approach by performing additional functional experiments on genetic base-pairs in specific cell types, to examine the functional effects of Neandertal genetic variants on gene expression and cell biology. Furthermore, by directly comparing previous correlational findings to the results acquired in a laboratory experimental context, this research will deepen the understanding of these commonly used genetic datasets. This project is supported by NSF Biological Anthropology with Human Networks & Data Science co-funds.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.