Structural Variation analysis of Orofacial Cleft associated genomic regions in African and Asian populations

非洲和亚洲人群口面部裂相关基因组区域的结构变异分析

• 批准号: 10643334
• 负责人: DASHZEVEG BAYARSAIHAN
• 金额: $ 17.08万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643334
• 关键词: Affect; African; African ancestry; Alleles; Asian ancestry; Asian population; BMP4; Base Pairing; Bite; Child; Cleft Lip; Communities; Complement; Congenital Abnormality; Copy Number Polymorphism; DNA sequencing; Data; Data Analyses; Data Set; Deposition; Development; Diagnostic; Disease; Enhancers; Etiology; Family; Fostering; Genes; Genome; Genomic Segment; Genomics; Human; Human Genome; Impairment; Individual; Intercistronic Region; Knowledge; Language; Literature; Live Birth; MAPK3 gene; Malignant Childhood Neoplasm; Nucleotides; Outcome; Parents; Pathway Analysis; Pathway interactions; Pediatric Research; Phenotype; Publishing; Reporting; Research; Role; Sampling; Structural Congenital Anomalies; Surveys; Therapeutic; Untranslated RNA; Variant; Work; analysis pipeline; cohort; data portal; data resource; data sharing; diagnostic value; functional disability; genomic data; genomic locus; improved; orofacial cleft; paralogous gene; phase 3 study; phenotypic data; programs; transcription factor; whole genome

Project Summary Cleft lip is the 4th most common birth defect in the U.S. and is known to affect annually one in 800 babies worldwide. The Kids First program aims to uncover the etiology of these diseases and foster data sharing within the pediatric research community. Expert-Driven Small Projects to Strengthen Gabriella Miller Kids First Discovery (RFA-RM-22-006) is intended to “engage experts in a variety of activities that will enhance the utility of childhood cancer and/or structural birth defects genomic datasets generated by the Kids First program and/or associated phenotypic datasets and resources”. In this proposal we specifically propose to analyze in-depth the Kids First curated datasets assembled for the cohort Orofacial Cleft: African and Asian Ancestry (253 Families) currently available through the framework CAVATICA at the Kids First data portal. Currently single nucleotide variation (SNV) analysis in syndromic and non-syndromic OFC has found functional impairments in genes such as IRF6, BMP4, MAPK3, etc. However, considering that Structural Variations (SVs) account for more total base-pair variation in human genomes than SNVs, we argue that this topic is an important and missing component of this Kids First project. Exploring the role of SVs in the manifestation of the OFC phenotype will require a search beyond gene regions, since intergenic SVs can cause impairment to normal enhancers and transcription factors. We will explore three main SV types: deletion, duplication and inversions by looking for common and individual SV alleles that differ from the parents. We will also look at the OFC associated genes along with the related transcription factors, paralogs and associated intergenic regions to fully characterize potentially causative SVs. Using a set of preidentified 39 gene loci including IRF6, we will closely survey the 244 triads and use a healthy human cohort to filter the results (1000 Genome Project Phase 3 study, 2504 samples). This analysis will complement the SNV analysis for this data that has already been completed and will provide additional context for the total genomic landscape. We will disseminate our work to the scientific community and compare our results with previous copy number variation (CNV) literature and share the SV triad workflows we develop to enable a similar analysis on other Gabriella Miller Kids First Pediatric Research Program (Kids First) datasets.

项目概要 唇裂是美国第四大最常见的出生缺陷，据了解，全球每年 800 名婴儿中就有 1 人患有唇裂。 “儿童优先”计划旨在揭示这些疾病的病因并促进数据共享 儿科研究社区。专家驱动的小型项目，以加强 Gabriella Miller Kids First Discovery。 (RFA-RM-22-006) 旨在“让专家参与各种活动，以提高 由 Kids First 计划生成的儿童癌症和/或结构性出生缺陷基因组数据集和/或 相关的表型数据集和资源”。在本提案中，我们特别建议进行深入分析。 Kids First 为口颌裂队列收集的精选数据集：非洲和亚洲血统 (253 家庭）目前可通过 Kids First 数据门户的 CAVATICA 框架获得。 目前对综合征型和非综合征型 OFC 的单核苷酸变异 (SNV) 分析发现 IRF6、BMP4、MAPK3 等基因的功能损伤。然而，考虑到结构 变异（SV）比 SNV 更能解释人类基因组中碱基对的总变异，我们认为这 主题是“探索 SV 在儿童第一”项目中的重要且缺失的组成部分。 OFC 表型的表现需要基因区域之外的搜索，因为基因间 SV 可以 对正常增强子和转录因子造成损害我们将探讨三种主要的 SV 类型： 通过寻找与 SV 等位基因不同的常见和个体 SV 等位基因来进行删除、重复和倒位 我们还将研究 OFC 相关基因以及相关转录因子、旁系同源物。 和相关的基因间区域，以使用一组预先确定的 SV 来充分表征潜在的致病性 SV。 包括IRF6在内的39个基因位点，我们将密切调查244个三联体，并使用健康人类队列来筛选 结果（1000 项基因组计划第 3 阶段研究，2504 个样本）该分析将补充 SNV 分析。 该数据已经完成，将为总基因组提供额外的背景信息 我们将向科学界传播我们的工作，并将我们的结果与以前的结果进行比较。 拷贝数变异 (CNV) 文献并分享我们开发的 SV 三联体工作流程，以实现类似的 对其他 Gabriella Miller Kids First 儿科研究计划（Kids First）数据集的分析。