Annotation and interpretation of loss-of-function polymorphisms in human genomes

人类基因组功能丧失多态性的注释和解释

• 批准号: 9069447
• 负责人: Daniel G MacArthur
• 金额: $ 32.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069447
• 关键词: Algorithms; Alternative Splicing; Base Sequence; Cataloging; Catalogs; Clinical; Code; Collaborations; Complex; Crohn' s disease; Custom; Cystic Fibrosis; Data; Data Set; Databases; Detection; Development; Disease; Drug Targeting; Etiology; Frequencies; Funding; Gene Expression; Genes; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genotype; Genotype-Tissue Expression Project; Goals; Haplotypes; Health; Human; Human Genome; Individual; Informatics; Intervention; Mediating; Modeling; Morphologic artifacts; Muscular Dystrophies; Mutation; Natural Selections; Nucleotides; Patients; Pharmacologic Substance; Phenotype; Play; Population; Probability; Proteins; RNA; RNA Splicing; Research Personnel; Risk; Role; Sampling; Science; Site; Spliced Genes; Statistical Methods; Structure; Surveys; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Transcript; United States National Institutes of Health; Validation; Variant; Weight; Work; analytical tool; base; clinical sequencing; cohort; cost; cost effective; design; disease-causing mutation; disorder risk; empowered; exome; exome sequencing; gene function; genetic variant; genome sequencing; human disease; human genome sequencing; improved; insertion/deletion mutation; interest; loss of function; loss of function mutation; mRNA Decay; next generation sequencing; novel; predictive modeling; research study; risk variant; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): Loss-of-function (LoF) mutations in human protein-coding genes are known to play a major role in severe diseases such as cystic fibrosis and muscular dystrophy, and have also recently been shown to influence the risk of complex diseases such as type 1diabetes and Crohn's disease. We have recently conducted the largest systematic survey to date of human LoF variants, as part of the 1000 Genomes Project, which has confirmed the value of LoF variants for human disease studies and also identified key chalenges for the detection and interpretation of these variants. We propose to overcome these challenges by constructing robust, accurate tools for the annotation, characterization and high-throughput genotyping of LoF variants. Firstly, we will develop an integrated informatic pipeline (Annotation of LoF Transcripts, ALoFT) for the identification and filtering of all classes of LoF variant, including single nucleotide substitutions (SNPs), insertions and deletions. Secondly, we will exploit data from RNA sequencing experiments and disease mutation databases to create more accurate predictive models of the efects of genetic variants on gene expression and splicing, and of their probability of disease causation. Finally, we will apply the ALoFT pipeline and the predictive models described above to over 30,000 human exomes and genomes sequenced as part of other NIH-funded projects, using the resulting annotation as the basis for a publicly accessible database of validated LoF variants, dbLoF. We will use our functional annotation to develop a weighted association test and apply this to the discovery of novel disease risk variants in these sequenced individuals. In addition, we will use the catalogue of LoF variants identified in these samples to design a custom genotyping array permitting rapid, cost-effective interrogation of the majority of common human LoF variants in human cohorts, allowing the phenotypic effects of these variants to be assessed in separately funded association studies. This study will provide powerful tools for discovering and characterizing natural loss-of-function variants, and for exploring their potential association with human disease risk.

描述（由申请人提供）：已知人类蛋白质编码基因的功能丧失（LoF）突变在严重疾病如囊性纤维化和肌营养不良中起主要作用，最近还显示其影响复杂疾病如1型糖尿病和克罗恩病的风险。作为1000个基因组计划的一部分，我们最近对人类LoF变异进行了迄今为止最大规模的系统调查，该调查证实了LoF变异对人类疾病研究的价值，并确定了检测和解释这些变异的关键挑战。我们建议克服这些挑战，通过构建强大的，准确的工具，注释，表征和高通量基因分型的LoF变体。首先，我们将开发一个集成的信息管道（LoF转录本注释，ALoFT），用于识别和过滤所有类别的LoF变体，包括单核苷酸取代（SNP），插入和缺失。其次，我们将利用来自RNA测序实验和疾病突变数据库的数据，建立更准确的预测模型，预测遗传变异对基因表达和剪接的影响，以及它们致病的可能性。最后，我们将把ALoFT管道和上述预测模型应用于作为NIH资助的其他项目的一部分测序的超过30，000个人类外显子组和基因组，使用所得注释作为经验证的LoF变体dbLoF的公共访问数据库的基础。我们将使用我们的功能注释来开发加权关联检验，并将其应用于发现这些测序个体中的新疾病风险变体。此外，我们将使用在这些样本中鉴定的LoF变体目录来设计定制的基因分型阵列，允许对人类队列中的大多数常见人类LoF变体进行快速、具有成本效益的询问，允许在单独资助的关联研究中评估这些变体的表型效应。这项研究将为发现和表征自然功能丧失变体以及探索其与人类疾病风险的潜在关联提供强有力的工具。

项目成果

Health and population effects of rare gene knockouts in adult humans with related parents.

稀有基因敲除的健康和人口影响与相关父母的成年人。

• DOI: 10.1126/science.aac8624
• 发表时间: 2016-04-22
• 期刊: Science (New York, N.Y.)
• 作者: Narasimhan VM;Hunt KA;Mason D;Baker CL;Karczewski KJ;Barnes MR;Barnett AH;Bates C;Bellary S;Bockett NA;Giorda K;Griffiths CJ;Hemingway H;Jia Z;Kelly MA;Khawaja HA;Lek M;McCarthy S;McEachan R;O'Donnell-Luria A;Paigen K;Parisinos CA;Sheridan E;Southgate L;Tee L;Thomas M;Xue Y;Schnall-Levin M;Petkov PM;Tyler-Smith C;Maher ER;Trembath RC;MacArthur DG;Wright J;Durbin R;van Heel DA
• 通讯作者: van Heel DA