The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

种系突变和父母年龄在自闭症谱系障碍中的作用

基本信息

批准号：
9039401
负责人：
Jonathan Sebat
金额：
$ 15.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039401
关键词：
16p11.2 Address Affect Age Alleles Architecture Autistic Disorder Blood Characteristics Computer software Copy Number Polymorphism Custom DNA DNA Sequence DNA Structure Data Data Set Detection Dideoxy Chain Termination DNA Sequencing Disease Environment Environmental Exposure Exons Family Fathers Frequencies Funding Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Genets Genome Genomic Instability Genomic Segment Genomics Germ-Line Mutation Goals Grant Human Human Genome Knowledge Mutation Nature Neurons Nucleotides Parental Ages Parents Paternal Age Pattern Phase Pilot Projects Play Point Mutation Process Property Recurrence Relative (related person)Risk Role Sampling Sampling Studies Science Scientific Advances and Accomplishments United States National Institutes of Health Untranslated RNA Variant age effect autism spectrum disorder base density disorder risk exome exome sequencing genome sequencing genome-wide high risk insight neuropsychiatry novel offspring risk variant sex sperm cell success tool

项目摘要

DESCRIPTION (provided by applicant): The genetic etiology of Autism Spectrum Disorders (ASDs) reflects of the nature of genome instability. Based in part on studies of copy number variation (CNV) from the first phase of this project, it is now widely recognized that de novo or recent mutations in the germline are important contributors to risk for ASDs. Mutations that confer high risk for autism are located within regions of hypermutability (ROHs). Examples include large >500 kb regions at 1q21.1, 15q11-13 and 16p11.2, where local genomic architecture predisposes to frequent recurrent rearrangements. All told, de novo CNVs contribute in approximately 5-10% of cases. It is likely that other classes of de novo mutation (DNM), in exons and in non-coding regions, contribute to ASD. As a field, we have a limited knowledge of global patterns of germline mutation in humans, and we have an incomplete understanding of how DNM contributes to risk for disease. Based on the knowledge above, and based on key findings that have emerged from our preliminary genome sequencing studies in autism, we hypothesize that, regions of hypermutability (ROHs), primarily consisting of nucleotide substitution hotspots, play a major role in ASDs. In the new phase of our project, we will apply a whole genome sequencing-based approach to determine the role of ROHs in ASD. We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in a sample of 120 trios (60 ASD and 60 controls) and determine the parent of origin of DNMs. Specific Aim 2 will investigate the role of ROHs in ASD. We will identify ROHs based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of ROHs with ASD in the discovery sample and in exome and CNV datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

描述（由申请人提供）：自闭症谱系疾病的遗传病因（ASD）反映了基因组不稳定性的性质。部分基于该项目第一阶段的拷贝数变化（CNV）的研究，现在广泛认识到种系中的新开始或最近的突变是导致ASDS风险的重要促进者。赋予自闭症的高风险的突变位于超显性区域（ROHS）内。示例包括在1q21.1、15q11-13和16p11.2处的大> 500 kb区域，其中局部基因组架构易于经常进行重新排列。总而言之，从新CNV造成了大约5-10％的病例。外显子和非编码区域中的其他从头突变（DNM）可能会导致ASD。作为一个领域，我们对人类种系突变的全球种系突变的了解有限，并且我们对DNM如何促进疾病的风险有不完整的了解。基于上面的知识，并基于我们自闭症初步基因组测序研究所产生的关键发现，我们假设，主要由核苷酸替代热点组成的高过度性（ROHS）区域在ASD中起主要作用。在我们项目的新阶段，我们将采用整个基于基因组测序的方法来确定ROHS在ASD中的作用。我们将研究本质的内在性超显性和外在力，例如父亲年龄，影响种系突变的速率。我们将通过以下特定目标来实现这些目标：特定目标1将通过家庭中的整个基因组测序来表征新生突变（DNM）。这些研究将在120个三重点（60个ASD和60个对照）样本中识别并验证约8,000个从头突变和结构变异，并确定DNM的起源父母。具体目标2将研究ROHS在ASD中的作用。我们将根据基因组中DNM的区域密度鉴定ROHS，并确定DNA序列特征对突变速率的影响。我们将在发现样本中的ROH与ASD的关联以及来自2700例和2700个对照的独立样本中的外显子和CNV数据集的关联。具体目标3将表征包括父母年龄和环境在内的外部因素对全基因组突变率的影响。我们将量化父亲年龄对精子中致病性和中性等位基因的影响，并研究某些DNM是否赋予种系选择性优势。这项研究的发现将提供对自闭症风险遗传基础的基本见解以及观察到的父母年龄影响ASD的遗传机制。我们将确定给自闭症带来重大风险的基因，并确定基因组的内在特性如何与外部力相互作用以确定后代疾病的风险。