Somatic mutations in neurodevelopment and disease

项目总结 体细胞合子后突变越来越被认为是导致神经系统疾病的原因，包括 从癫痫到自闭症再到神经变性。在胎儿时期，体细胞突变随着每一次细胞分裂而积累， 尚未完全确定规模和机制的发展过程，阻碍了对疾病的解释 各州。这项研究的第一部分实施了临床上适用的体细胞感知算法来识别早期 导致癫痫和脑畸形的体细胞突变。后者应用于尖端的单一- 用细胞DNA技术对人胎脑进行研究，以确定驱动脑积聚的速率和机制 神经元在正常发育过程中的体细胞突变。这项研究的洞察力有可能 影响临床实践中躯体疾病的检测和诊断，并定义了正常的范围 神经元中的大脑发育嵌合体作为未来神经疾病研究的框架。 候选人的职业目标是成为一名独立的内科科学家，为 儿童神经科合子后突变的遗传和功能意义 精神错乱。应聘者接受过儿童神经遗传学方面的临床培训，具有丰富的研究经验，包括 细胞和分子生物学和统计分析，在癌症领域获得。在接受指导的培训期间 在此期间，候选人将优先考虑将技能从癌症背景转移到人类遗传学和 神经科学：专门研究人类原始死后组织、单细胞分析方法和 评估躯体疾病中的基因-表型关系，此外，为向 独立。候选人将由著名神经生物学家克里斯托弗·沃尔什博士指导，他曾 指导了数十名成功的独立调查人员，并将得到一个咨询团队的支持 在癫痫、神经科学和生物信息学方面的专业知识。拟议的研究和培训计划将在 在隶属于哈佛医学院的波士顿儿童医院(BCH)沃尔什博士的实验室里 而霍华德·休斯医学研究所，嵌入了波士顿世界级的生命科学界- 剑桥地区。候选人将从杰出的资源和知识界中受益 除了BCH神经科和BCH神经科内紧密联系的社区外，这个巨大的网络 遗传学分部。

PROJECT SUMMARY Somatic post-zygotic mutations are increasingly recognized as a cause of neurologic disorders ranging from epilepsy to autism to neurodegeneration. Somatic mutations accumulate with each cell division during fetal life, a developmental process of not yet fully defined scale and mechanism, hampering interpretation of disease states. The first part of this study implements a clinically applicable somatic-aware algorithm to identify early somatic mutations that lead to epilepsy and brain malformations. The latter aspect applies cutting-edge single- cell DNA technology to human fetal brain in order to define the rates and mechanisms driving accumulation of somatic mutations in neurons during normal development. The insights from this study have the potential to impact the detection and diagnosis of somatic disorders in clinical practice, and defines the scope of normal brain developmental mosaicism in neurons to serve as a framework for future studies of neurological disease. The candidate’s career goal is to become an independent physician-scientist contributing to the understanding of genetic and functional implications of post-zygotic mutations in childhood neurological disorders. The candidate trained clinically in child neurogenetics with deep research experience, including in cellular and molecular biology and statistical analysis, acquired in the cancer field. During the mentored training period, the candidate will prioritize activities to transition skills from a cancer background to human genetics and neuroscience: specifically working with primary human postmortem tissue, single cell analytical methods, and evaluating genotype-phenotype relationships in somatic disorders, and additionally, preparing for a transition to independence. The candidate will be mentored by Dr. Christopher Walsh, a renowned neurobiologist who has mentored dozens of successful independent investigators and will be supported by an advisory team with expertise in epilepsy, neuroscience, and bioinformatics. The proposed research and training plan will take place in the laboratory of Dr. Walsh at Boston Children’s Hospital (BCH), which is affiliated with Harvard Medical School and Howard Hughes Medical Institute, embedded within a world-class life sciences community of the Boston- Cambridge area. The candidate will benefit from both the outstanding resources and intellectual community of this tremendous network in addition to the close-knit communities within the BCH Department of Neurology and Division of Genetics.