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 自然选择清除了影响生存或 生殖能力。最近对大量人群队列的遗传研究表明 对有害突变的这种约束的人类基因组的分布。大规模协会 研究发现，在许多童年时期，强烈约束基因组区域的突变是主要危险因素 发育障碍（DDS），表明高度约束的序列可能在 发展。然而，孕期（FD）后胎儿灭亡的遗传研究，DDS的极端结果， 到目前为止，范围和大小受到限制。我的国际胎儿导师的建立 序列的基因组学联盟10,500个样本（3,500 FD病例及其家人）确定 现在，可疑遗传病因的FD提供了前所未有的机会来照亮最极端的 跨个体基因和剂量敏感基因组段突变的后果对人至关重要 发展。在此奖学金中，我将整合此队列中的全基因组测序和尸检数据 以及来自先前建立的DD队列的数据，以发现并在功能上表征突变 人类基因组中不宽容的基因座。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，indels，结构性 变体和重复扩展），并研究这些模式中有关胎儿性别和突变的偏见 父母。然后，我将适应能够整合证据的疾病协会的统计框架 来自所有编码和非编码变体类，并优先考虑受限区域，我将适用于 在FD中执行新颖的基因发现（AIM 1）。我将利用这些发现来产生功能预测 通过定义活性的生物网络和可能的细胞类型，在突变不宽容的基因座 在开发初期运作（AIM 2）。最后，我将在DDS跨DDS测试这些功能假设 FD导致FD，包括Live Born胎儿结构异常，神经发育障碍和先天性 异常（目标3）。与这些研究目的同时，由六位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，动手研究支持， 定期在研讨会和会议上演示的机会，以及各种软技能开发 在我的博士学位培训期间直接与我的职业目标保持一致的会议。共同概述了 该提案将利用独特的工具和资源来产生对病因的新颖见解 沿着发展异常和进化约束的连续性极端，并将作为一个 我在计算，统计和功能性疾病基因组学方面的杰出培训机会。