Expanding the accessible genetic architecture of autism by single molecule sequencing

通过单分子测序扩展自闭症的可访问遗传结构

• 批准号: 10216962
• 负责人: Jonathan Sebat
• 金额: $ 85.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216962
• 关键词: Biological Sciences; Brain; Clinical; Collection; Complex; Custom; DNA; Data; Data Set; Detection; Development; Family; Frequencies; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genomic Segment; Genotype; Glean; Goals; Haplotypes; Heritability; High-Throughput Nucleotide Sequencing; Human; Human Genome; Hybrids; Impairment; Inherited; Investigation; Knowledge; Length; Measures; Mosaicism; Mutation; Neurobiology; Parents; Pattern; Point Mutation; Production; Regulatory Element; Repetitive Sequence; Risk; Sampling; Severities; Shapes; Siblings; Structure; Tandem Repeat Sequences; Technology; Testing; Validation; Variant; analysis pipeline; autism spectrum disorder; base; clinical phenotype; cohort; de novo mutation; disorder risk; exome sequencing; gene function; genetic architecture; genetic association; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide; improved; novel; novel sequencing technology; prediction algorithm; risk variant; sequencing platform; single molecule; social; technological innovation; trait; whole genome

Project Summary Within the last decade, major progress has been made in understanding the genetic basis of Autism Spectrum Disorders (ASDs). Based on exome sequencing studies and microarray-based genotyping, it is recognized that the genetic architecture of ASD consists of rare mutations of large effect, including structural variants (SVs) and de novo point mutations that impact genes, as well as a significant contribution from common polygenic variation. However, a majority of the genetic risk for ASD remains unexplained. A proportion of the missing heritability of ASD could be attributable to genetic variation that remains inaccessible to today’s high throughput sequencing platforms including a majority of structural variants (SVs) and sequence variation that occurs within repetitive sequences in the genome. A systematic analysis of these novel classes of genetic variation could close a significant gap in our knowledge of ASD genetics. The development of new single- molecule sequencing platforms now enables direct sequencing of long DNA fragments (average read lengths >5,000 bp). These technologies have enable sequence assembly and variant calling within complex and repetitive regions of the genome and have dramatically increased the proportion of structural and tandem repeat (TR) variation that can be captured by whole genome sequencing (WGS). The application of long read WGS to ASD family samples could greatly expand knowledge of the genetic causes of autism. This study will investigate the contribution of complex genetic variants to risk for ASD using a combination of long-read and short-read technologies. (1) We will characterize global patterns of genetic variation in a primary sample of ASD families (N=373 cases, 127 sibling controls and their parents) by WGS using the Pacific Biosciences (SEQUEL) platform, and these data will be combined with an existing WGS dataset of Illumina short reads on the same samples. (2) We will investigate the genetic association of novel classes of SVs and TRs in genes and in regulatory elements that control gene expression, and novel findings will be replicated in Illumina WGS data on 2600 ASD families from the Simons Simplex Collection (SSC) (3) We will then investigate the influence of novel risk alleles on clinical phenotype in families and experimentally confirm the effects of mutations on gene function. Our proposed study will expand our knowledge of the genetic architecture of ASD and identify novel risk alleles and genetic mechanisms underlying disease risk.

项目摘要 在过去的十年中，在理解自闭症谱系的遗传基础方面取得了重大进展 疾病（ASD）。基于外显子组测序研究和基于微阵列的基因分型，人们认识到 ASD的遗传结构由稀有效果的罕见突变组成，包括结构变体（SVS） 以及影响基因的从头突变，以及共同多基因的重要贡献 变化。但是，大多数ASD遗传风险仍然未知。失踪的一部分 ASD的遗传力可能归因于遗传变异，而遗传变异仍然无法访问当今的高 吞吐量测序平台，包括大多数结构变体（SV）和序列变化， 发生在基因组中的重复序列中。对这些新型通用类别的系统分析 变异可能会缩小我们对ASD遗传学知识的显着差距。新单一的发展 现在，分子测序平台可以直接对长DNA片段进行直接测序（平均读取长度 > 5,000 bp）。这些技术在复杂和 基因组的重复区域，并显着增加了结构和串联的比例 可以通过整个基因组测序（WGS）捕获的重复（TR）变异。长阅读的应用 WGS到ASD家庭样本可以大大扩展对自闭症遗传原因的了解。这项研究会 研究复杂遗传变异对ASD风险的贡献，结合了长期阅读和 短阅读技术。 （1）我们将在主要样本中表征遗传变异的全局模式 WGS使用Pacific Biosciences，ASD系列（n = 373例，127个同胞控制及其父母） （续集）平台，这些数据将与现有的Illumina简短读取的现有WGS数据集相结合 相同的样本。 （2）我们将研究基因中新型SV和TR的遗传关联 在控制基因表达的调节元素中，新发现的发现将在Illumina WG中复制 Simons单纯征（SSC）的2600个ASD家族的数据（3）我们将研究影响 新型风险等位基因对家族临床表型的风险等位基因，并通过实验确认突变对 基因功能。我们提出的研究将扩大我们对ASD遗传结构的了解，并确定 疾病风险的新型风险等位基因和遗传机制。

项目成果

A reference haplotype panel for genome-wide imputation of short tandem repeats.

• DOI: 10.1038/s41467-018-06694-0
• 发表时间: 2018-10-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Saini S;Mitra I;Mousavi N;Fotsing SF;Gymrek M
• 通讯作者: Gymrek M

Inferring the molecular and phenotypic impact of amino acid variants with MutPred2.

• DOI: 10.1038/s41467-020-19669-x
• 发表时间: 2020-11-20
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Pejaver V;Urresti J;Lugo-Martinez J;Pagel KA;Lin GN;Nam HJ;Mort M;Cooper DN;Sebat J;Iakoucheva LM;Mooney SD;Radivojac P
• 通讯作者: Radivojac P