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

Harvard University, Cambridge MA

Investigators

Abstract

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.