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

基本信息

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
项目类别：
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

项目摘要

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点一个过程，探索导致异常不对称的基因的作用。通过结合源自基因型/表型相互作用的知识来治疗发育障碍共同基金敲除小鼠表型计划 (KOMP2) 和基因型组织表达 (GTEx) 项目使用来自两个 Gabriella Miller Kids First 儿科研究项目 (KF) 的家庭队列数据：基因组拉丁美洲口面部裂出生缺陷及口面部裂出生缺陷基因组学研究家庭。不对称是包括主要结构出生在内的许多发育障碍的一个关键特征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影响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影响相互作用会增加多种发育障碍的风险。 KOMP2 项目旨在提供全面的小鼠敲除表型数据，包括亚存活系和致死系的 3D 胎儿成像很可能在发展中发挥重要作用。在这个项目中，自动化、密集量化 3D 胚胎 microCT 图像的不对称性将用于建立正常情况下不对称性的统计模型发展。敲除菌株将筛选具有不对称结构或器官的表型检测与异常高度不对称性相关的基因的目标。的功能意义将通过比较受敲除菌株表型影响的区域来验证选定的基因来自 GTEx 项目的 KOMP2 数据集到组织表达数据。利用生物学方法鉴定候选基因将探索来自 KOMP2 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，目的是识别富含这些群体与对照组人群进行比较。识别这些变体将有助于揭示先天性不对称与 OFC 风险之间的联系机制。本研究的结果将包括（1）统计来自 KOMP2 胎儿 3D 成像数据的正常解剖结构和不对称模型，(2) 开源软件通过对 3D 图像进行密集形态测量分析来生成详细的表型描述 KOMP2 数据集，(3) KOMP2 敲除菌株和组织的表型描述之间的相关性来自 GTEx 项目的表达数据，以及（4）稀有变异对候选基因的贡献分析 OFC 风险。