Doctoral Dissertation Research: Investigating the genomic underpinnings of the human hand and foot

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Humans use their feet almost exclusively in locomotion (walking, running, etc.) while our hands are used for a range of activities involving precise, powerful movements of individual fingers, such as typing on a computer, playing the piano, or throwing a baseball. The ability to perform these tasks requires that the bones of the hand and foot have an appropriate size and shape. Human hand and foot bones have some key differences in structure from our closest living primate relative and these differences are encoded in the genome by DNA sequences which differ between the two species. In this doctoral dissertation project, thousands of human and non-human primate DNA sequences are screened to identify underlying genomic regions that are likely to encode the differences observed. The project advances knowledge about the developmental genetics of the hand and foot in the context of human evolution and supports undergraduate and graduate training, including students from groups underrepresented in STEM.Numerous studies have identified thousands of genomic regions with an excess of human-specific DNA changes. Many of these regions were likely under positive selection over the course of human evolution, but tying specific genetic changes to phenotypic change remains a challenge akin to finding a needle in a haystack. To identify genetic changes underlying uniquely human features of the hand and foot skeleton, this proposal uses the massively parallel reporter assay (MPRA) system to simultaneously screen the human and chimp versions of thousands of genomic regions known to be involved in the developing human hand or foot for differential activity between the two species in cartilage cells. This research can shed light on the genetic architecture patterning individual elements of the hand and foot skeleton, which can inform our understanding of human evolution, development, and disease.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.