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.

项目概要 在过去的十年中，在了解自闭症谱系的遗传基础方面取得了重大进展 疾病（自闭症谱系障碍）。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 的遗传结构由具有重大影响的罕见突变组成，包括结构变异 (SV) 和从头点突变影响基因，以及常见多基因的显着贡献 变化。然而，自闭症谱系障碍的大部分遗传风险仍然无法解释。失踪人口比例 自闭症谱系障碍（ASD）的遗传性可能归因于遗传变异，而这种变异在当今的高水平人群中仍然无法获得 通量测序平台，包括大多数结构变异 (SV) 和序列变异， 发生在基因组的重复序列中。对这些新的遗传类别的系统分析 变异可以弥补我们对自闭症谱系障碍遗传学知识的重大差距。新单机的开发 分子测序平台现在可以对长 DNA 片段（平均读长）进行直接测序 >5,000 bp）。这些技术使得能够在复杂且复杂的环境中进行序列组装和变体调用。 基因组的重复区域，并显着增加了结构和串联的比例 可以通过全基因组测序（WGS）捕获的重复（TR）变异。长读的应用 全基因组测序（WGS）到自闭症谱系障碍（ASD）家庭样本可以极大地扩展对自闭症遗传原因的了解。这项研究将 结合长读和 短读技术。 (1) 我们将表征初级样本中遗传变异的全局模式 ASD 家庭（N = 373 例，127 名兄弟姐妹对照及其父母），使用 Pacific Biosciences 进行全基因组测序 (SEQUEL) 平台，这些数据将与 Illumina 短读长的现有 WGS 数据集相结合 相同的样品。 (2) 我们将研究基因中新型SV和TR的遗传关联 以及控制基因表达的调控元件，新的发现将在 Illumina WGS 中得到复制 来自 Simons Simplex Collection (SSC) 的 2600 个 ASD 家庭的数据 (3) 然后我们将调查影响 新的风险等位基因对家庭临床表型的影响，并通过实验证实突变对 基因功能。我们提出的研究将扩大我们对自闭症谱系障碍遗传结构的了解，并确定 疾病风险背后的新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.

推断氨基酸变体与MUTPRED2的分子和表型影响。

• 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