Doctoral Dissertation Research: Identifying Positively-Selected Introgressed Genetic Variants with Regulatory Effects in Humans

博士论文研究：识别对人类具有调节作用的积极选择的基因渗入基因变异

• 批准号: 1847287
• 负责人: Terence Capellini
• 金额: $ 3.34万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1847287&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Identifying; Positively

Fifty thousand years ago, modern humans dispersing out of Africa to Europe and Asia met now-extinct human relatives, such as Neanderthals, and interbred with them. As a result, genetic variation from Neanderthals exists in the human gene pool, but the effects of this variation on human biology are not well understood. In this doctoral dissertation project, the researcher will conduct a large-scale laboratory-based genetic experiment to test whether Neanderthal variants can affect the degree to which a gene is active in human immune cells. By identifying these variants and making publicly available the raw data from this experiment, the researchers will advance knowledge about the effects of evolutionary history and genetic variation on the immune system of living humans. Given that science news often features stories about Neanderthals, the researchers will utilize popular interest in this area to demonstrate the biological and medical relevance of studying human evolutionary history. They will also work with two museums to develop an exhibit that will additionally highlight the practical importance of this field of research. Furthermore, this project will help promote women in science given that the research will largely be undertaken by a female graduate student who is committed to training other women in science and has been active in the organization for Graduate Women in Science Engineering at her university. Although the last two decades have seen great strides in genetic research, because the specific function of most of the human genome is still unknown, researchers face difficulty when trying to connect most specific genetic mutations to their effect on biology. To aid in this discovery, datasets have been produced that allow correlations between the presence of genetic variation and biological phenotypes. However, because genetic variants near each other are often inherited together, it can be difficult to determine which genetic variant is responsible for the biological effect, limiting the ability to truly understand the mechanism. This is especially true in the case of Neanderthal genetic sequences present in living humans, which mostly lay in poorly understood parts of the genome that are thought generally to regulate the expression of genes. Nonetheless, correlational evidence suggests that this Neanderthal genetic variation may be affecting human immune system function. The researchers will conduct an experiment in which they simultaneously test thousands of Neanderthal genetic variants and their human counterparts for their ability to regulate the expression of genes in the immune system, in order to isolate the specific Neanderthal genetic variants that affect the biology of the human immune system. This will allow researchers to focus future work on specific functional testing of these important genetic variants. Furthermore, by directly comparing correlational findings to the results in a laboratory experiment, this research will deepen the understanding of these commonly used genetic datasets.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.

五万年前，现代人类从非洲分散到欧洲和亚洲，遇到了现在灭绝的人类亲戚，例如尼安德特人，并与他们交往。结果，人类基因库中存在来自尼安德特人的遗传变异，但是这种变异对人类生物学的影响尚不清楚。在这个博士学位论文项目中，研究人员将进行大规模的基于实验室的基因实验，以测试尼安德特人的变体是否会影响基因在人类免疫细胞中活性的程度。通过识别这些变体并使该实验中的原始数据公开可用，研究人员将提高有关进化史和遗传变异对生命人类免疫系统的影响的知识。鉴于科学新闻经常以有关尼安德特人的故事为特色，研究人员将利用这一领域的大众兴趣来证明研究人类进化史的生物学和医学相关性。他们还将与两个博物馆合作，开发一个展览，还将强调这一研究领域的实际重要性。此外，鉴于该研究将在很大程度上由一位致力于培训其他科学妇女的女性研究生进行，并一直活跃于她的大学的科学工程研究生，因此该项目将有助于促进科学妇女。尽管过去二十年来在遗传研究方面取得了长足的进步，但由于大多数人基因组的特定功能仍然未知，因此研究人员试图将大多数特定的遗传突变与对生物学的影响联系起来时面临困难。为了帮助这一发现，已经产生了数据集，以允许遗传变异和生物表型之间存在相关性。但是，由于彼此接近的遗传变异通常是共同遗传在一起的，因此很难确定哪种遗传变异造成了生物学效应，从而限制了真正理解机制的能力。在活着的人类中存在的尼安德特人遗传序列的情况下，这尤其如此，这些遗传序列通常位于基因组的部分知识中，通常认为这些部分以调节基因的表达。尽管如此，相关证据表明，这种尼安德特人遗传变异可能会影响人类免疫系统功能。研究人员将进行一项实验，在该实验中，他们同时测试了数千种尼安德特人遗传变异和人类对应物，以调节免疫系统中基因表达的能力，以隔离影响人类免疫系统生物学的特定尼安德特人遗传变异。这将使研究人员能够将未来的工作集中在这些重要遗传变异的特定功能测试上。 此外，通过将相关结果与实验室实验的结果直接进行比较，这项研究将加深对这些常用遗传数据集的理解。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛的影响标准通过评估来获得支持的。