Illuminating the distribution of extreme evolutionary constraint in the human genome from fetal demise to severe developmental disorders

阐明人类基因组中从胎儿死亡到严重发育障碍的极端进化限制的分布

• 批准号: 10601318
• 负责人: Lily Wang
• 金额: $ 4.05万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601318
• 关键词: Atlases; Automobile Driving; Autopsy; Biological; Birth; Cells; Childhood; Chromatin; Clinical; Code; Data; Data Set; Development; Developmental Process; Discipline; Disease; Disease model; Doctor of Philosophy; Etiology; Exhibits; Family member; Fellowship; Fertility; Fetal Death; Fetus; First Pregnancy Trimester; Gene Dosage; Gene Frequency; General Population; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Human; Human Development; Human Genome; Individual; Inherited; Institution; International; Laboratories; Maternal-fetal medicine; Measures; Mentors; Mentorship; Mus; Mutation; Natural Selections; Neurodevelopmental Disorder; Outcome; Parents; Pathway interactions; Pattern; Play; Point Mutation; Population; Positioning Attribute; Property; Publishing; Recurrence; Regulatory Element; Research; Research Support; Resources; Risk Factors; Role; Sampling; Source; Statistical Models; Structural defect; Testing; Training; Untranslated RNA; Variant; Work; base; career; cell type; cohort; congenital anomaly; developmental disease; exome; fetal; fetal loss; gene discovery; gene function; genetic architecture; genome sequencing; genome-wide; genomic variation; hands on research; insertion/deletion mutation; insight; laboratory experience; loss of function; novel; programs; protein protein interaction; purge; reproductive; sex; skill acquisition; stillbirth; symposium; tool; training opportunity; whole genome

Abstract Natural selection purges deleterious mutations from populations in genomic regions impacting survival or reproductive capacity. Recent genetic studies of massive population cohorts have revealed a continuous distribution across the human genome of this constraint on deleterious mutations. Large-scale association studies have found mutations in strongly constrained genomic regions to be major risk factors in many childhood developmental disorders (DDs), suggesting that highly constrained sequences are likely to play key roles in development. However, genetic studies of fetal demise after the first trimester (FD), an extreme outcome of DDs, have thus far been limited in scope and size. The establishment by my mentors of an international Fetal Genomics Consortium to sequence 10,500 samples (3,500 FD cases and their family members) ascertained for FD of suspected genetic etiology now offers an unprecedented opportunity to illuminate the most extreme consequences of mutation across individual genes and dosage sensitive genomic segments critical for human development. In this fellowship, I will integrate whole-genome sequencing and autopsy data from this cohort together with data from previously established DD cohorts to discover and functionally characterize mutationally intolerant loci in the human genome. I will first define patterns of genetic variation in FD across constraint metrics (loss-of-function, missense, and noncoding) and genomic variation classes (point mutations, indels, structural variants, and repeat expansions), and investigate biases in these patterns with respect to fetal sex and mutational parent-of-origin. I will then adapt a statistical framework for disease association capable of integrating evidence from all coding and noncoding variant classes with prioritization of constrained regions, which I will apply to perform novel gene discovery in FD (Aim 1). I will leverage these findings to generate functional predictions of mutationally intolerant loci by defining the biological networks of activity and the cell types in which they are likely to operate early in development (Aim 2). Finally, I will test these functional hypotheses across DDs that do not result in FD, including liveborn fetal structural abnormalities, neurodevelopmental disorders, and congenital anomalies (Aim 3). In parallel with these research aims, an exceptional team of six mentors and advisors across multiple disciplines, career stages, and institutions will provide didactic training, hands-on research support, regular opportunities for presentation in seminars and conferences, and a variety of soft skill development sessions that directly align with my career objectives during my PhD training. Collectively, the aims outlined in this proposal will take advantage of unique tools and resources to yield novel insights into the etiology of the extremes along the continuum of developmental anomalies and evolutionary constraint, and will serve as an outstanding training opportunity for me in computational, statistical, and functional disease genomics.

抽象的 自然选择清除基因组区域中影响生存或种群的有害突变 生殖能力。最近对大量人群的遗传学研究揭示了连续的 这种对有害突变的限制在人类基因组中的分布。大型协会 研究发现，强烈受限的基因组区域的突变是许多儿童的主要危险因素 发育障碍（DD），表明高度受限的序列可能在发育障碍中发挥关键作用 发展。然而，对妊娠早期 (FD) 后胎儿死亡（DD 的一种极端结果）的遗传学研究， 迄今为止，其范围和规模都受到限制。我的导师建立了一个国际胎儿 基因组学联盟将对 10,500 个样本（3,500 个 FD 病例及其家庭成员）进行测序，以确定 疑似遗传病因的 FD 现在提供了前所未有的机会来阐明最极端的情况 对人类至关重要的单个基因和剂量敏感基因组片段突变的后果 发展。在这项研究金中，我将整合该队列的全基因组测序和尸检数据 与先前建立的 DD 队列的数据一起发现突变并对其进行功能表征 人类基因组中的不耐受基因座。我将首先定义跨约束指标的 FD 遗传变异模式 （功能丧失、错义和非编码）和基因组变异类别（点突变、插入缺失、结构性变异） 变体和重复扩展），并研究这些模式在胎儿性别和突变方面的偏差 父母的起源。然后我将调整一个能够整合证据的疾病关联统计框架 来自所有编码和非编码变体类，并优先考虑受约束区域，我将应用到 在 FD 中发现新基因（目标 1）。我将利用这些发现来生成功能预测 通过定义活性的生物网络和它们可能所处的细胞类型来突变不耐受的位点 在开发早期进行运营（目标 2）。最后，我将在不支持的 DD 中测试这些功能假设 导致 FD，包括活产胎儿结构异常、神经发育障碍和先天性 异常（目标 3）。与这些研究目标同时，一个由六名导师和顾问组成的杰出团队 多个学科、职业阶段和机构将提供教学培训、实践研究支持、 定期在研讨会和会议上发表演讲的机会以及各种软技能发展 在我的博士培训期间，课程与我的职业目标直接相关。总体而言，中概述的目标 该提案将利用独特的工具和资源，对疾病的病因学产生新的见解 沿着发展异常和进化限制的连续体的极端，并将作为 为我提供了计算、统计和功能疾病基因组学方面的绝佳培训机会。