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: 9765417
• 负责人: Jonathan Sebat
• 金额: $ 69.17万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765417
• 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; 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.

项目总结