Understanding how structural mutations and individual RNA isoforms are involved in human health and disease

了解结构突变和个体 RNA 亚型如何参与人类健康和疾病

• 批准号: 10307270
• 负责人: Mark T W Ebbert
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307270
• 关键词: Understanding; how; structural; mutations; individual

PROJECT SUMMARY/ABSTRACT In today’s efforts to personalize medicine, it does not seem reasonable to personalize medicine without constructing and utilizing an individual’s genome structure for both haplotypes. Current standards force the reference genome’s structure on each individual. The same principle applies to understanding the function for individual RNA isoforms. Structural variants are involved in, or directly cause, a broad range of diseases including cancer, autism, schizophrenia, neurodegenerative diseases, and Crohn’s disease, among others. We seek to better understand how structural variants affect disease by helping characterize structural variants and their downstream effects, combining this information with RNA isoform sequencing (IsoSeq). The histocompatibility complex, which contains the human leukocyte antigen (HLA) genes, is a particular region of interest for my lab because this region has been implicated in dozens of diseases. Similarly, we seek understand the role for individual RNA isoforms for all genes. Protein-coding human genes average seven RNA isoforms, resulting in unique protein products. For practical reasons, standard short-read RNA sequencing studies treat all isoforms as a single ‘gene’—an oversimplification of the underlying biology; this is also true when considering sex differences in human health and disease. While females and males have many similarities, both sexes have unique biology with clear differences in disease prevalence, therapeutic needs, and responses. Females, in particular, have not received adequate attention in human health and disease research. A next critical step in all of biology research, especially in disease research, will be to determine individual isoform function, and how that changes between sexes. We want to contribute to this effort, and propose to employ long-read sequencing technologies to accomplish these goals.

项目摘要/摘要 在当今个性化医学的努力中，个性化医学似乎是不合理的 不为两个单倍型构建和使用个人的基因组结构。当前的 标准迫使参考基因组的结构对每个人。相同的原则适用 了解单个RNA同工型的功能。结构变体参与或 直接引起多种疾病，包括癌症，自闭症，精神分裂症， 神经退行性疾病和克罗恩病等。我们试图更好地理解 结构变异如何通过帮助表征结构变体及其其影响疾病 下游效应，将这些信息与RNA同工型测序（ISOSEQ）结合在一起。这 组织相容性复合物包含人白细胞抗原（HLA）基因，是一个 我实验室的特定感兴趣区域，因为该区域已在数十个 疾病。同样，我们寻求了解所有基因的单个RNA同工型的作用。 蛋白质编码的人基因平均七个RNA同工型，从而产生独特的蛋白质产物。 出于实际原因，标准的短阅读RNA测序研究将所有同工型视为单个同工型 “基因” - 基础生物学的过度简化；考虑性时也是如此 人类健康和疾病的差异。女性和男性都有许多相似之处 性别具有独特的生物学，在疾病患病率，治疗需求和 回答。尤其是女性，在人类健康和 疾病研究。所有生物学研究，尤其是疾病研究中的下一个关键步骤， 将是确定个体同工型功能，以及性别之间的变化。我们想要 为这项努力做出贡献，并向员工长阅读测序技术提出建议 实现这些目标。