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

项目摘要/摘要 在医学个性化的今天，将医学个性化似乎是不合理的 而不为两种单倍型构建和利用个体的基因组结构。当前 标准将参考基因组的结构强加给每个人。同样的原理也适用于 以了解单个RNA异构体的功能。结构变体涉及，或 直接导致的疾病，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异及其对疾病的影响 将这一信息与RNA异构体测序(IsoSeq)相结合。这个 组织相容性复合体含有人类白细胞抗原(人类白细胞抗原)基因，是一种 我的实验室感兴趣的特定区域，因为这个区域牵涉到数十起 疾病。类似地，我们试图了解单个RNA亚型对所有基因的作用。 编码蛋白质的人类基因平均有七种RNA异构体，产生独特的蛋白质产物。 出于实际原因，标准的短读RNA测序研究将所有异构体视为单一的 ‘基因’--对潜在生物学的过分简单化；在考虑性别时也是如此 人类健康和疾病的差异。虽然女性和男性有很多相似之处，但两者 性别具有独特的生物学特征，在疾病患病率、治疗需求和 回应。尤其是女性，在人类健康方面没有得到足够的重视， 疾病研究。所有生物学研究，特别是疾病研究的下一个关键步骤， 将决定个体的异构体功能，以及这种功能在性别之间如何变化。我们要 为这一努力做出贡献，并建议采用长阅读测序技术来 完成这些目标。

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.