Deep Phenotyping of 3D Data for Candidate Gene Selection from Kids First Studies

对 3D 数据进行深度表型分析，用于从 Kids First 研究中选择候选基因

• 批准号: 10355998
• 负责人: Ali Murat Maga
• 金额: $ 32.99万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355998
• 关键词: 3-Dimensional; Affect; Anatomy; Animal Model; Bilateral; Bioinformatics; Biological; Candidate Disease Gene; Complex; Computer Analysis; Computer software; Congenital Abnormality; Congenital Disorders; Data; Data Set; Development; Diagnostic; Disease susceptibility; Embryo; Environmental Risk Factor; Family; Family member; Fetal Alcohol Syndrome; Funding; Genes; Genetic; Genomics; Genotype; Genotype-Tissue Expression Project; Goals; Human; Image; Image Analysis; Individual; Knock-out; Knockout Mice; Knowledge; Latin American; Light; Link; Measures; Methods; Mouse Strains; Mus; Organ; Outcome Study; Parents; Pediatric Research; Phenotype; Play; Population; Population Control; Predisposition; Procedures; Process; Publishing; Research; Research Project Grants; Resolution; Risk; Role; Scanning; Schizophrenia; Standardization; Statistical Models; Structural Congenital Anomalies; Structure; Testing; Therapeutic Intervention; Three-Dimensional Image; Three-Dimensional Imaging; Three-dimensional analysis; Tissues; Translating; Validation; Variant; autism spectrum disorder; biological systems; cohort; craniofacial; craniofacial microsomia; developmental disease; disorder risk; experience; fetal; gene function; genetic variant; genome sequencing; genomic data; improved; microCT; mouse genome; mouse model; nervous system disorder; open source; open source tool; orofacial cleft; phenotypic data; programs; rare variant; risk prediction; shape analysis; whole genome

Abstract/Project Summary This project will pilot a process to explore the role of genes contributing to abnormal asymmetry in developmental disorders by combining knowledge of genotype/phenotype interactions derived from the Common Fund Knockout Mouse Phenotyping Program (KOMP2) and the Genotype-Tissue Expression (GTEx) project with family cohort data from two Gabriella Miller Kids First Pediatric Research Projects (KF): Genomic Studies of Orofacial Cleft Birth Defects and Genomics of Orofacial Cleft Birth Defects in Latin American Families. Asymmetry is a key feature of numerous developmental disorders including major structural birth defects as well as neurological disorders. A better understanding of the genetic basis of asymmetry and its relationship to disease susceptibility will help unravel the complex genetic and environmental factors and their interactions that increase risk in a wide range of developmental disorders. The KOMP2 project aims to provide comprehensive mouse knockout phenotype data, including 3D fetal imaging of sub-viable and lethal lines that are likely to play a significant role in development. In this project, automated, dense quantification of asymmetry of 3D embryonic microCT images will be used to build statistical models of asymmetry in normal development. Knockout strains will be screened for phenotypes with asymmetric structures or organs with the goal of detecting genes associated with abnormally heightened asymmetry. The functional significance of the selected genes will be validated by comparing regions impacted in knockout strain phenotypes from the KOMP2 dataset to tissue expression data from the GTEx project. Candidate genes identified using biological information from the KOMP2 and GTEx datasets will be explored f or association with the KF whole genome sequencing data from OFC parent-case trios with the aim of identifying genetic variants that are enriched in these groups compared to a control population. Identification of these variants will help shed light on the mechanisms linking congenital asymmetry and OFC risk. The outcomes of this study will include (1) statistical models of normal anatomy and asymmetry from the KOMP2 fetal 3D imaging data, (2) an open -source software to produce detailed phenotype descriptions from dense morphometric analysis of 3D images from the KOMP2 dataset, (3) correlations between phenotype descriptions from the KOMP2 knockout strains and tissue expression data from the GTEx project, and (4) analysis of the contribution of rare variants on candidate genes towards OFC risk.

摘要/项目摘要 该项目将试验一个过程，以探索基因的作用，有助于异常不对称性， 通过结合基因型/表型相互作用的知识， 共同基金敲除小鼠表型分析程序（KOMP 2）和基因型-组织表达（GTEx） 来自两个Gabriella米勒儿童第一儿科研究项目（KF）的家庭队列数据项目：基因组 拉丁美洲口面裂出生缺陷及其基因组学研究 家庭不对称性是许多发育障碍的关键特征，包括主要结构性出生 缺陷以及神经系统疾病。更好地理解不对称的遗传基础及其 与疾病易感性的关系将有助于揭示复杂的遗传和环境因素及其 这些相互作用会增加各种发育障碍的风险。KOMP 2项目旨在提供 全面的小鼠敲除表型数据，包括亚存活和致死品系的3D胎儿成像， 可能在发展中发挥重要作用。在这个项目中， 3D胚胎microCT图像的不对称性将用于建立正常胚胎中不对称性的统计模型。 发展将筛选敲除菌株的具有不对称结构或器官的表型， 目标是检测与异常高度不对称相关的基因。的功能意义 将通过比较来自基因组的敲除菌株表型中受影响的区域来验证所选基因。 KOMP 2数据集与来自GTEx项目的组织表达数据。使用生物学方法鉴定候选基因 将探索KOMP 2和GTEx数据集的信息与KF全基因组的关联 来自OFC亲本病例三人组的测序数据，目的是鉴定富含以下基因的遗传变异： 与对照人群相比。识别这些变体将有助于阐明 先天性不对称与眶额肌痛风险之间的联系机制。本研究的结果将包括（1）统计学 模型的正常解剖和不对称的KOMP 2胎儿三维成像数据，（2）一个开源的 软件，以产生详细的表型描述，从密集的形态测量分析的3D图像，从 KOMP 2数据集，（3）来自KOMP 2敲除菌株的表型描述与组织 来自GTEx项目的表达数据，以及（4）分析罕见变异对候选基因的贡献 OFC风险。