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

5万年前，现代人从非洲迁徙到欧洲和亚洲，遇到了现在已经灭绝的人类亲戚，比如尼安德特人，并与他们杂交。因此，来自尼安德特人的遗传变异存在于人类基因库中，但这种变异对人类生物学的影响尚不清楚。在这个博士论文项目中，研究人员将进行大规模的实验室遗传实验，以测试尼安德特人的变异是否会影响基因在人类免疫细胞中的活跃程度。通过识别这些变异并公开实验的原始数据，研究人员将进一步了解进化史和遗传变异对活人免疫系统的影响。鉴于科学新闻经常以尼安德特人的故事为特色，研究人员将利用人们对这一领域的普遍兴趣来证明研究人类进化史的生物学和医学相关性。他们还将与两家博物馆合作举办一个展览，进一步突出这一研究领域的实际重要性。此外，这个项目将有助于促进妇女参与科学，因为这项研究将主要由一名女研究生承担，她致力于在科学方面培训其他妇女，并一直活跃于她所在大学的科学工程研究生妇女组织。尽管在过去的二十年里，基因研究取得了巨大的进步，但由于大多数人类基因组的特定功能仍然未知，研究人员在试图将大多数特定的基因突变与其对生物学的影响联系起来时面临着困难。为了帮助这一发现，已经产生了允许遗传变异和生物表型之间存在相关性的数据集。然而，由于彼此接近的遗传变异通常是一起遗传的，因此很难确定哪种遗传变异负责生物效应，从而限制了真正理解其机制的能力。在现存人类中存在的尼安德特人基因序列的情况下尤其如此，这些基因序列大多位于基因组中鲜为人知的部分，这些部分通常被认为是调节基因表达的。尽管如此，相关证据表明，这种尼安德特人的遗传变异可能会影响人类的免疫系统功能。研究人员将进行一项实验，他们将同时测试数千种尼安德特人遗传变异及其人类对应基因在免疫系统中调节基因表达的能力，以便分离出影响人类免疫系统生物学的特定尼安德特人遗传变异。这将使研究人员将未来的工作重点放在这些重要遗传变异的特定功能测试上。此外，通过直接将相关发现与实验室实验结果进行比较，本研究将加深对这些常用遗传数据集的理解。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。

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.