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

人类的特点是两条腿直立行走的能力和耐力跑步的能力。这种行为的部分原因是人类骨骼肌的耐力，与黑猩猩相比，骨骼肌更适合保持身体直立，并长期活动而不疲劳。然而，由于化石记录中没有人类骨骼肌的这一特性，而且在遗传水平上对肌肉纤维发育的了解有限，因此人类骨骼肌的这一特性是如何进化的尚不清楚。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遗传开关。通过这样做，这项研究将增加关于肌肉纤维发育背后的复杂遗传格局的新信息，并阐明一种独特的人类特征的进化史，该特征可能在两足动物的进化中发挥了关键作用。该项目将支持高级分子方法和生物信息学方面的研究生培训。此外，这位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研究成果。最后，这项研究产生的数据将有助于在基因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。理解在人类进化过程中何时、为什么以及如何发生向两足行走的转变是生物人类学中的一个基本问题。作为一个物种，人类的特征是一套被描述得很好的解剖学适应能力，支持高效的长距离两足动物运动。虽然这些特征中的许多都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)则更难检测到。人类后肢肌肉中抗疲劳的慢抽动肌肉纤维比例很高，这使它们最适合进行基于紧张性和耐力的活动，并表明这一特征有助于实现长距离的两足运动。然而，控制这一特征的遗传机制还没有被很好地理解。为了解决这一知识差距，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史。这项研究的中心假设是，自然选择选择了影响肌肉纤维类型的基因组区域中人类特有的变异，增加了人类后肢骨骼肌中慢抽动纤维的数量，并提高了两足动物的运动效率。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的、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的一个子集的功能，这些区域具有人类特有的变异。通过这样做，这个项目将通过识别人类基因组中与两足行走高度相关的特征的生物学形成区域来丰富人类学对人类进化的理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.