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

博士论文研究：研究人类手脚的基因组基础

• 批准号: 2337516
• 负责人: Terence Capellini
• 金额: $ 4.23万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2337516&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Investigating; genomic

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.

人类几乎完全在机动（步行，跑步等）中使用脚，而我们的手则用于一系列活动，这些活动涉及精确，有力的单个手指动作，例如在计算机上打字，弹钢琴或投掷棒球。执行这些任务的能力要求手和脚的骨头具有适当的尺寸和形状。人的手和脚骨与我们最接近的灵长类动物亲戚之间的结构有一些关键差异，这些差异是通过DNA序列在基因组中编码的，而DNA序列之间的差异是两种物种之间的不同。在这个博士学位论文项目中，筛选了数千个人类和非人类灵长类动物DNA序列，以识别可能编码观察到的差异的基本基因组区域。该项目在人类进化的背景下对手和脚的发育遗传学的知识提高了知识，并支持本科和研究生培训，包括来自STEM中代表性不足的群体的学生。许多研究已经确定了成千上万的基因组区域，其人类特异性DNA的变化过多。在人类进化过程中，其中许多区域可能处于积极的选择，但是将特定的遗传变化与表型变化联系在一起仍然是类似于在干草堆中找到针头的挑战。为了确定手和脚骨架的独特人类特征的遗传变化，该提案使用大量平行的记者测定法（MPRA）系统同时筛选已知基因组区域的人类和黑猩猩版本，这些基因组区域的人和黑猩猩版本涉及在软骨细胞中这两个物种之间的人体或脚部的发展中的人体或脚部。这项研究可以阐明遗传结构，使手和脚骨架的个体元素模仿了我们对人类进化，发展和疾病的理解。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响审查标准通过评估来进行评估的。