Genomic investigations of the auditory system

背景：我们解读世界的方式受到我们处理声音能力的影响。这一基本过程涉及听觉系统的复杂系统，遗传因素在控制内耳的正常功能方面起着重要作用。然而，对这些因素的研究一直受到阻碍，因为在大量人群中准确表征听力和捕获不同内耳细胞中的基因表达谱相关的挑战。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仍存在差距。目标：我的研究项目的长期目标是利用基因组学来了解听力背后的生物学途径。我的项目的短期目标是：(1)发现与人类听力有关的新基因和途径；（ii）确定小鼠耳蜗基因表达谱的性别特异性差异。方法：为了识别对听力重要的生物通路，我们将使用机器学习算法根据听力的可变性对健康老年人进行分类。我们将使用这些数据进行基因组分析，以识别与这些不同听力模式相关的遗传变异和基因。一旦这些基因被确定，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，因此也可能与听力有关。我们将在这些分析的基础上研究在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力重要通路的认识，更重要的是，这些通路在两性衰老过程中是如何变化的。影响：从这个项目中产生的数据将解决关于听力中涉及性别和年龄相关变异的基因组途径的关键知识空白。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，将提高我们对听力背后复杂生物机制的理解。这项发现基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。结合最先进的技术和分析将在自然科学领域开辟多种职业机会。

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.