Positive Selection on Gene Regulation and the Evolution of the Human Brain

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Although humans and chimpanzees share approximately 98% of the same genes, they have very different brains. Scientists hypothesize that regions of the genome that turn gene expression on and off are critically important for understanding this difference. This project uses evolutionary and experimental methods to examine how natural selection has shaped gene expression in the human brain. The investigators will analyze regions of the genome showing evidence for adaptations unique to the human lineage, to better understand the advent, nature, and importance of neural differentiation between humans and non-human primates. The project will provide student-led educational experiences using a next-generation sequencing platform for hands-on training. The critical big-data skill set that students will gain is translatable both to graduate training and careers in biotech. Additionally, outreach to local elementary school students will be provided through a partnership with the Eureka! Program for STEM retention of women, which runs every summer at UMass Amherst. This project will find functional links between adaptation across the genome and changes in neural cells. Using a curated bioinformatics catalog of putative enhancers, this project will test the hypothesis that there are functional links between adaptation in the genome and changes in neural phenotypes that occurred during human evolution. In order to understand the functional consequences of mutations particular to human regulatory regions, changes in gene expression associated with particular gene regulatory sequences will be measured. This will be done in neural progenitor cells and in mature neurons, in both human and chimpanzee cell lines. To functionally test these regions, cutting-edge high-throughput enhancer assays will be used to measure significant differences in how these ~10,000 implicated regulatory regions are driving differential gene expression in neural progenitor cells and mature neurons. Both of these cell types will be derived from induced pluripotent stem cell (iPSC) lines, which have the capacity to be driven to many different cell types. The results will reveal information about the functional links between adaptation and human-specific changes in a tightly controlled experimental environment.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.