Characterizing a spectrum of mosaic variation in the population and across neurological disorders

表征人群和跨神经系统疾病的一系列马赛克变异

• 批准号: 10224952
• 负责人: Elise Valkanas
• 金额: $ 3.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224952
• 关键词: Address; Age; Algorithms; Alleles; Alzheimer' s Disease; Area; Autopsy; Benchmarking; Blood; Brain; Cell physiology; Cells; Computational Biology; Computing Methodologies; Copy Number Polymorphism; DNA; Data; Data Set; Databases; Detection; Development; Disease; Doctor of Philosophy; Family; Fellowship; General Population; Genetic; Genome; Genomics; Incidence; Individual; Laboratories; Life; Maps; Measurable; Mentorship; Methods; Mind; Modeling; Molecular; Mosaicism; Mutation; Mutation Detection; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Onset of illness; Parents; Performance; Point Mutation; Population; Population Genetics; Prevalence; Process; Publishing; Resolution; Resources; Risk; Sampling; Sensitivity and Specificity; Series; Single Nucleotide Polymorphism; Somatic Mutation; Statistical Models; Structure; Testing; Tissues; Training; Variant; Work; age related; autism spectrum disorder; autistic children; base; chromosome Y loss; cloud based; cohort; disorder risk; early onset; early onset disorder; exome; exome sequencing; gene function; genome sequencing; genomic variation; human disease; in silico; insertion/deletion mutation; insight; laboratory experience; male; nervous system disorder; neuropsychiatric disorder; single cell sequencing; tool; transcriptome; transcriptome sequencing; whole genome

Project Summary Post-zygotic mutations, both those arising early in life (mosaic) and acquired in somatic tissues throughout life, are present in a sub-population of cells and have been implicated in a variety of disorders, but the prevalence of these mutations in the general population is largely unknown due to limitations in tools and reference datasets. Recent studies have suggested that post-zygotic mutations can have a profound impact on disease, particularly neuropsychiatric and neurodegenerative disorders. From these prior studies, it is clear that post-zygotic mutations are prevalent in the population and could represent a significant contribution to human disease, but systematic analyses in very large reference sets using tightly benchmarked tools are needed. Prior studies have been limited in scope, focusing solely on single nucleotide variants (SNVs) and small indels, or a narrow class of mega-base scale structural variation (SV). The emergence of population-scale whole-genome sequencing (WGS) in controls, and tens of thousands of case cohorts, offers the first opportunities to interrogate a mutational spectrum of mosaic variation including SV, SNVs, and indels at WGS-resolution. In this fellowship, I propose that post-zygotic mutations are abundant in the population across the size spectrum, increase with age, and can have a measurable impact on gene function. To further describe this cryptic class of variation in the population, across ages, and in disease cohorts, I plan to first optimize and benchmark recently developed mosaic SV detection algorithms, then, using these tools, derive allelic fraction thresholds to distinguish mosaic variation from somatic variation (Aim 1). I will then apply these tools and annotations to a population-scale WGS reference dataset in the genome aggregation database (gnomAD). These analyses will determine the incidence and prevalence of post-zygotic mutations at sequence resolution and determine the variance explained by age in the accumulation of somatic mutations in the population (Aim 2). Finally, I will directly test prior hypotheses that post-zygotic mutations influence disease risk from WGS data in an early onset neurodevelopmental disorder (autism) cohort and a late onset neurodegenerative disorder (Alzheimer’s disease) cohort, as well as matched controls, to determine the differential influence of early mosaic variation and the accumulation of somatic variation on disease risk and brain function (Aim 3). Collectively, the aims outlined in this proposal will leverage unique tools and resources to further characterize this underappreciated class of genomic variation and its influence on human disease, as well as provide outstanding mentorship in each of my targeted areas of development during my PhD training.

项目摘要 合子后突变，无论是出现在生命早期(镶嵌)的，还是在整个生命过程中在体细胞组织中获得的， 存在于细胞亚群中，并与各种疾病有关，但 由于工具和参考数据集的限制，普通人群中的这些突变在很大程度上是未知的。 最近的研究表明，合子后突变可以对疾病产生深远的影响，尤其是 神经精神病学和神经退行性疾病。从这些先前的研究中可以清楚地看出，后受精症 突变在人群中很普遍，可能对人类疾病有重大贡献，但 需要在非常大的参考集中使用严格的基准工具进行系统分析。先前的研究已经 在范围上受到限制，只专注于单核苷酸变体(SNV)和小INDELs，或一小类 兆基尺度的结构变化(SV)。种群规模全基因组测序的出现 (WGS)在对照和数以万计的病例队列中，提供了第一次审问突变的机会 WGS分辨率下的马赛克变异光谱，包括SV、SNV和INDELS。在这个团契里，我建议 合子后突变在不同体型的人群中都很丰富，随着年龄的增长而增加，并且可以 对基因功能有可测量的影响。为了进一步描述种群中这种神秘的变异类别， 在各个年龄段，在疾病队列中，我计划首先优化和基准最近开发的马赛克SV 然后，检测算法使用这些工具得出等位基因比例阈值来区分马赛克变异 来自体细胞变异(目标1)。然后，我会将这些工具和注解应用于人口规模的WGS参考 基因组聚合数据库(GnomAD)中的数据集。这些分析将确定发病率和 在序列解析时合子后突变的流行率，并确定年龄解释的差异 在种群中积累体细胞突变(目标2)。最后，我将直接检验先前的假设 来自WGS数据的合子后突变影响早发性神经发育障碍的疾病风险 (自闭症)队列和迟发性神经退行性疾病(阿尔茨海默病)队列，以及匹配的 对照，以确定早期花叶变异和体细胞积累的差异影响 疾病风险和脑功能的变化(目标3)。总体而言，本提案中概述的目标将利用 独一无二的工具和资源，以进一步描述这类被低估的基因组变异及其 对人类疾病的影响，以及在我的每个目标领域提供出色的指导 在我的博士培训期间，我的发展。