Precision Genomic Medicine in The Plain Communities and its Impact on The Plain and General Population

摘要 平原种群(亚米希人和门诺派)起源于创始人种群，随后的遗传 瓶颈和遗传漂移；导致多样性的丧失和遗传疾病负担的改变。西式 宾夕法尼亚平原人是美国最不具遗传特征的平原社区之一。此应用程序 建议使用全外显子组测序(WES)来识别该人群中的新的遗传疾病。由于 平原种群丧失了种群基因组的复杂性、近亲交配和社会隔离，许多 由于纯合子突变，遗传性疾病以常染色体隐性方式遗传。这一基因 化妆和大家庭将有助于WES分析，以找到潜在的候选变异 疾病的致病原因。平原人群中有多种遗传性疾病的特征， 这项拟议的研究将确定其他疾病，使以社区为中心的个性化医疗成为可能 基于个体遗传风险的护理方法。此外，关于遗传性疾病的知识最初 通过对平原种群的研究开发出来的，随后可以应用于一般人群。这个 中心假设是亚米希人和门诺派社区将允许识别新的基因 与平原社区相关的疾病/致病变异体，最终与普通人群相关。这个 提出了以下目标：(1)在平原地区识别新的遗传性疾病/致病变异 社区。这个假设是，对使用WES的西部PA平原人的遗传学研究将允许 继续表征新的遗传性疾病/致病变异体，这些新的遗传病/致病变异体与平原和 普通人群。(2)对一种引起扩张性疾病的新型遗传性疾病进行功能研究 心肌病(DCM)。假设MTCL1变异体(c.82C和gt；G；p.His28Asp)是致病的 MTCL1基因突变是DCM的新病因。应聘者坚定地致力于翻译事业 基因组学研究及其对普通人群和普通人群的影响。她已经在 平原社区，证明了她有能力与这些文化截然不同的人联系并进行研究 组。这些联系，以及她的研究重点是使用WES作为诊断工具的翻译研究 在需要的时候进行功能研究，已经发现了几种线粒体疾病和 AK2基因突变是导致免疫缺陷的原因，在阿米什人中具有新的表型。初级阶段 赞助商是世界公认的遗传学领域的专家，具有出色的培训记录和 与应聘者建立了良好的工作关系。这位候选人已经发展了一个全面的职业生涯。 发展计划，以提高她的生物信息学和WES分析技能，并将学习执行功能 与心肌病相关的研究。

Abstract The Plain populations (Amish and Mennonites) originated from founder populations with subsequent genetic bottlenecks and genetic drift; leading to a loss of diversity and an altered genetic disease burden. The Western PA Plain people are among the least genetically characterized Plain communities in the US. This application proposes to use Whole Exome Sequencing (WES) to identify novel genetic disorders in this population. Due to the Plain Populations loss of population genomic complexity, inbreeding, and sociologic isolation, many of the genetic disorders are inherited in autosomal recessive fashion due to homozygous mutations. This genetic makeup as well as the large families will facilitate WES analysis to find candidate variants that can potentially be pathogenic causes of diseases. A multitude of genetic diseases are characterized in the Plain population, and this proposed study will identify additional diseases, enabling a community-centric personalized medicine approach to care based on individual genetic risk. In addition, knowledge of genetic disorders originally developed through study of the Plain Populations, can subsequently be applied in the general population. The central hypothesis is that the Amish and Mennonite communities will allow the identification of novel genetic disorders/pathogenic variants of relevance to the Plain communities, and ultimately the general population. The following aims are proposed: (1) Identification of novel genetic disorders/ disease-causing variants in the Plain communities. The hypothesis is that genetics studies of the Western PA Plain people using WES will allow for continued characterization of novel genetic disorders/pathogenic variants that are relevant to both the Plain and general populations. (2) Performing functional studies for a novel genetic disorder causing dilated cardiomyopathy (DCM). The hypothesis is that the MTCL1 variant (c.82C>G;p.His28Asp) is pathogenic and MTCL1 gene mutations are novel cause of DCM. The candidate is firmly committed to a career in translational genomics research and its implications on the Plain and General populations. She has already worked within the Plain communities, proving her ability to connect with and perform research within these culturally distinct groups. These connections, and her research focus on translational research using WES as a diagnosis tool with functional studies when needed, have already led to the discovery of several mitochondrial disorders and an AK2 gene mutation as a cause of an immunodeficiency with a novel phenotype in the Amish. The primary sponsor is a world recognized expert in the field of Genetics with an outstanding track record of training and with a great working relationship with the candidate. The candidate has developed a comprehensive career development plan to improve her bioinformatics and WES analysis skills, and will learn to perform functional studies related to cardiomyopathy.