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.

人类的区别是他们的能力直立在两条腿上和耐力的能力。人类骨骼肌的耐力能力部分解释了这种行为，与黑猩猩相比，它更适合保持身体直立并长时间活跃而不会疲劳。但是，由于缺乏化石记录以及对遗传水平上肌肉纤维发育的有限理解，人类骨骼肌的这种特性如何发展。该博士学位论文项目将使用一套尖端的分子方法来确定控制肌肉纤维发育的遗传开关。在此过程中，这项研究将添加有关肌肉纤维发育的复杂遗传景观的新颖信息，并阐明了独特的人类特征的进化史，该历史可能在两体性进化中起着关键作用。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，研究人员将通过举办“科学跑步”活动与公众分享他们的发现。最后，这项研究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的更有效的治疗方法。理解何时，为什么以及如何在人类进化过程中出现过渡到双皮亚主义的过渡是生物人类人类人类学的基本问题。作为一个物种，人类的特征是一套很好地描述的解剖适应，以支持有效的长距离两足动力。尽管这些特征在化石记录（例如骨形态）中可以观察到，但其他特征（例如，骨骼肌的特性）更难检测到。人后肢肌肉中高比例的抗疲劳慢速肌肉纤维优化了它们以执行基于耐耐力的活动，并表明这种特征有助于实现长途双皮运动。然而，控制这种特征的遗传机制尚不清楚。为了解决知识的这一差距，该项目将确定肌肉纤维发育的遗传机制，并重建整个主要原理的这些机制的进化历史。这项研究的核心假设是，已经选择了自然选择以用于影响肌肉纤维类型的基因组区域的人类特异性变异，从而增加了人后肢骨骼骨骼肌肉中慢扭纤维纤维的量和双皮德运动的效率。为了检验这一假设，研究人员将首先使用量身定制的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的那些部分。接下来，他们将通过人类特异性变异来测试这些区域的子集的功能。这样一来，该项目将通过确定人类基因组的区域来丰富人类学对人类学的理解，这些区域塑造了与双皮亚主义高度相关的特征的生物学。该奖项反映了NSF的法定使命，并认为通过基金会的知识和更广泛的影响审查审查批评，被认为是值得通过评估的支持。