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

人类几乎只用脚来运动（走路、跑步等），而我们的手则用于一系列活动，包括单个手指的精确、有力的运动，比如在电脑上打字、弹钢琴或扔棒球。完成这些任务的能力要求手和脚的骨头有适当的大小和形状。人类的手和脚的骨骼在结构上与我们最近的灵长类亲戚有一些关键的差异，这些差异是由两个物种之间不同的DNA序列编码在基因组中。在这个博士论文项目中，筛选了数千个人类和非人类灵长类动物的DNA序列，以确定可能编码所观察到的差异的潜在基因组区域。该项目在人类进化背景下推进了关于手足发育遗传学的知识，并支持本科生和研究生的培训，包括来自STEM中代表性不足群体的学生。许多研究已经确定了数千个基因组区域存在过量的人类特异性DNA变化。在人类进化过程中，这些区域中的许多可能处于积极选择之下，但是将特定的遗传变化与表型变化联系起来仍然是一个类似于大海捞针的挑战。为了确定人类手和足骨骼独特特征的遗传变化，本研究建议使用大规模平行报告试验（MPRA）系统同时筛选人类和黑猩猩的数千个已知与人类手或足发育有关的基因组区域，以确定两种物种在软骨细胞中的差异活性。这项研究可以揭示手和脚骨骼的单个元素的遗传结构模式，这可以告诉我们对人类进化，发育和疾病的理解。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。

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.