Doctoral Dissertation Research: Uncovering the regulatory landscape of myofiber type in the context of human evolution

人类以两条腿直立行走和耐力跑步的能力而著称。这种行为部分可以用人类骨骼肌的耐力来解释，与黑猩猩相比，人类骨骼肌更适合保持身体直立，并且在不疲劳的情况下长时间活动。然而，人类骨骼肌的这种特性是如何进化的尚不清楚，因为化石记录中没有它，而且在遗传水平上对肌肉纤维发育的理解有限。这个博士论文项目将使用一套尖端的分子方法来识别控制肌肉纤维发育的基因开关。在此过程中，这项研究将为肌纤维发育背后复杂的遗传景观提供新的信息，并阐明可能在两足动物进化中发挥关键作用的一种独特人类特征的进化史。该项目将支持高级分子方法和生物信息学的研究生培训。此外，研究人员还将通过举办“科学跑”外展活动与公众分享他们的发现。最后，从这项研究中产生的数据将有助于在遗传水平上表征肌肉生物学，因此有可能帮助针对一系列神经肌肉疾病进行更有效的治疗。了解人类在进化过程中何时、为何以及如何向两足动物过渡是生物人类学的一个基本问题。作为一个物种，人类的特点是一套良好的解剖适应，支持高效，远距离的两足运动。虽然这些特征中的许多可以在化石记录中观察到（例如，骨骼形态），但其他特征（例如，骨骼肌的特性）更难检测到。人类后肢肌肉中高比例的抗疲劳慢肌纤维使它们能够进行强直、耐力为基础的活动，并表明这一特征有助于长距离双足运动。然而，控制这一特性的遗传机制尚不清楚。为了解决这一知识缺口，该项目将确定肌肉纤维发育的遗传机制，并重建这些机制在灵长类动物中的进化历史。本研究的中心假设是，自然选择选择了影响肌纤维类型的基因组区域的人类特异性变异，增加了人类后肢骨骼肌中慢肌纤维的数量和两足运动的效率。为了验证这一假设，研究人员将首先使用定制的ATACseq方法来识别在哺乳动物肌肉组织中活跃并与肌肉纤维类型相关的基因组部分。接下来，他们将测试这些区域中具有人类特异性变异的子集的功能。在此过程中，该项目将通过确定人类基因组的区域来丰富对人类进化的人类学理解，这些区域塑造了与两足动物高度相关的特征的生物学。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 are distinguished by their ability to walk upright on two legs and their capacity for endurance running. This behavior is explained in part by the endurance capabilities of human skeletal muscle, which, in comparison to chimpanzees, are better suited for holding bodies upright and being active for prolonged periods without fatiguing. However, it is unknown how this property of human skeletal muscle evolved due to its absence from the fossil record and a limited understanding of muscle fiber development at the genetic level. This doctoral dissertation project will identify the genetic switches controlling muscle fiber development using a suite of cutting-edge molecular methods. In doing so, this research will add novel information about the complex genetic landscape underlying muscle fiber development and illuminate the evolutionary history of a unique human trait that may have played a key role in bipedal evolution. This project will support graduate training in advanced molecular methods and bioinformatics. Additionally, the researcher will share their findings with the public by hosting a “science run” outreach event. Finally, data generated from this research will help characterize muscle biology at the genetic level and therefore has the potential to help target more efficient treatments for a range of neuromuscular diseases.Understanding when, why and how the transition to bipedalism occurred over the course of human evolution is a fundamental question in biological anthropology. As a species, humans are characterized by a suite of well-described anatomical adaptations that support efficient, long-distance bipedal locomotion. While many of these traits are observable in the fossil record (e.g., bone morphology), others (e.g., properties of skeletal muscle) are more difficult to detect. The high proportion of fatigue-resistant slow-twitch muscle fibers in human hind limb muscles optimizes them to perform tonic, endurance-based activities, and suggests that this trait helps enable long-distance bipedal locomotion. Yet, the genetic mechanisms controlling this trait are not well understood. To address this gap in knowledge, this project will identify the genetic mechanisms underlying muscle fiber development and reconstruct the evolutionary history of these mechanisms across primates. The central hypothesis of this research is that natural selection has selected for human-specific variation in regions of the genome that influence muscle fiber type, increasing the amount of slow-twitch fibers in human hind limb skeletal muscles and the efficiency of bipedal locomotion. To test this hypothesis, the researcher will first use a tailored ATACseq approach to identify those parts of the genome that are active in mammalian muscle tissues and associated with muscle fiber type. Next, they will test the function of a subset of these regions with human-specific variation. In doing so, this project will enrich anthropological understandings of human evolution by identifying regions of the human genome that have shaped the biology of a trait highly relevant to bipedalism.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.