Genomic investigations of the auditory system

背景：我们解释世界的方式受到我们处理声音的能力的影响。这个基本过程涉及听觉系统中的复杂系统，遗传因素在控制内耳的正常功能方面发挥着重要作用。然而，这些因素的研究受到了与准确表征大型人群队列中的听力和捕获不同内耳细胞中基因表达谱相关的挑战的阻碍。此外，虽然已知男性和女性感知声音的方式存在差异，并且超过三分之一的基因在特定组织中的基因表达中表现出性别偏见的差异，但我们对这些差异背后的基因组和生物学机制的理解存在差距。 目的：我的研究计划的长期目标是利用基因组学来了解听力的生物学途径。我的计划的短期目标是：（i）发现新的基因和参与人类听力的途径;（ii）确定小鼠耳蜗基因表达谱的性别特异性差异。研究方法：为了确定对听力重要的生物学途径，我们将使用机器学习算法根据听力的变化对健康老年人群进行分类。我们将使用这些数据进行基因组分析，以确定与这些不同的听力模式相关的遗传变异和基因。一旦这些基因被识别，我们将使用单细胞RNA测序数据来研究这些基因的表达模式。这些数据将提供与参与不同听力过程的基因相关的独特表达模式相关的信息。这些不同的基因表达特征可以反过来用于识别显示类似表达模式的其他基因，因此可能也参与听力。我们将在这些分析的基础上研究小鼠内耳细胞中观察到的基因表达模式的性别特异性差异。这些数据将大大增加我们对听觉重要途径的了解，重要的是，这些途径在两性衰老过程中如何变化。影响：该项目产生的数据将解决有关听力性别和年龄相关变异性所涉及的基因组途径知识的关键空白。这些数据将为未来的研究铺平道路，通过额外的组学分析和进化比较，将提高我们对听力基础的复杂生物机制的理解。这项发现补助金将为三名研究生和两名本科生提供计算和分子生物学方面的培训机会。最先进的技术和分析的结合将在自然科学领域开辟多样化的职业机会。

Background: The way in which we interpret the world is influenced by our ability to process sound. This fundamental process involves complex systems in the auditory system, with genetic factors playing an important role in controlling the normal functioning of the inner ear. However, investigation of these factors has been hampered by challenges associated with accurately characterizing hearing in large population cohorts and capturing gene expression profiles in the diverse inner ear cells. Further, while it is known that there are differences in the way in which males and females perceive sound, and more than one-third of genes exhibit sex-biased differences in gene expression in specific tissues, there are gaps in our understanding of the genomic and biological mechanisms underlying these differences. Objectives: The long-term objective of my research program is to use genomics to understand the biological pathways underlying hearing. The short-term objectives for my program are to: (i) Uncover novel genes and pathways involved in hearing in humans; and (ii) Identify sex-specific differences in murine cochlear gene expression profiles. Methods: To identify biological pathways that are important for hearing, we will use machine learning algorithms to classify individuals from the healthy elderly population according to their variability in hearing. We will use these data to perform genomic analyses to identify genetic variants and genes that are associated with these distinct patterns of hearing. Once these genes have been identified, we will use single cell RNA sequencing data to investigate the expression patterns of these genes. These data will provide information relating to the unique expression patterns that are associated with genes that are involved in different hearing processes. These distinct gene expression signatures can in turn be used to identify additional genes that display similar expression patterns and are thus likely to also be involved in hearing. We will build on these analyses to investigate sex-specific differences in gene expression patterns observed in murine inner ear cells. These data will substantially add to our knowledge regarding the pathways that are important to hearing, and importantly, how these pathways change during the aging process in both sexes. Impact: The data generated from this program will address key gaps in knowledge regarding the genomic pathways involved in sex- and age- related variability in hearing. These data will pave the way for future research, which through additional omics analyses and evolutionary comparisons, will improve our understanding of the complex biological mechanisms that underlie hearing. This discovery grant will provide training opportunities in computational and molecular biology for three graduate students and two undergraduate students. The incorporation of state-of-the art techniques and analyses will open diverse career opportunities in the natural sciences.