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

博士论文研究：揭示人类进化背景下肌纤维类型的调控景观

• 批准号: 1945809
• 负责人: Kirstin Sterner
• 金额: $ 2.94万
• 依托单位: University of Oregon Eugene
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1945809&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Uncovering; regulatory

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.

人类的特征在于他们用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，人类骨骼肌更适合保持身体直立，长时间活动而不疲劳。然而，人类骨骼肌的这种特性是如何进化的尚不清楚，因为它没有化石记录，而且在遗传水平上对肌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确定控制肌纤维发育的遗传开关。在这样做的过程中，这项研究将增加有关肌纤维发育背后的复杂遗传景观的新信息，并阐明一种独特的人类特征的进化历史，这种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，研究人员将通过举办“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基因水平上描述肌肉生物学，因此有可能帮助更有效地治疗一系列神经肌肉疾病。了解人类进化过程中何时，为什么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，人类的特点是一套描述良好的解剖适应，支持有效的，长距离的双足运动。虽然这些特征中有许多在化石记录中可以观察到（例如，骨形态学），其它（例如，骨骼肌的特性）更难以检测。人类后肢肌肉中高比例的抗疲劳慢缩肌纤维使它们能够优化进行紧张性的、基于耐力的活动，并表明这种特征有助于实现长距离双足运动。然而，控制这种特征的遗传机制还没有得到很好的理解。为了解决这一知识差距，该项目将确定肌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。这项研究的中心假设是，自然选择选择了影响肌纤维类型的基因组区域中的人类特异性变异，增加了人类后肢骨骼肌中慢缩纤维的数量和双足运动的效率。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纤维类型相关的基因组部分。接下来，他们将测试这些具有人类特异性变异的区域子集的功能。在此过程中，该项目将通过识别人类基因组中塑造与两足动物高度相关的特征生物学的区域，丰富人类学对人类进化的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。