Functional tests of non-coding DNA variants associated with risk for orofacial clefting.

与口面部裂风险相关的非编码 DNA 变异的功能测试。

基本信息

  • 批准号:
    10614747
  • 负责人:
  • 金额:
    $ 47.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-01 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Orofacial clefting (primarily cleft lip and/or cleft palate) is a relatively common structural birth defect with environmental and genetic contributions to etiology. Genome wide association studies (GWAS) and linkage studies have identified many gene variants that are associated with elevated risk for isolated oral facial clefting (OFC). However, our understanding of the pathogenic mechanisms underlying this disease remains poor because, one, we have yet to distinguish DNA variants that directly influence risk for OFC (i.e., causal variants) from those that are merely in linkage disequilibrium with them, and two, the functions of the regulatory molecules encoded y OFC-associated genes in craniofacial development are largely unknown. At each locus, there are multiple identified multiple SNPs that are statistically associated with OFC – and all of these reside in non-coding DNA. In Aim 1, we will prioritize the SNPs for functional tests by performing fine mapping of GWAS data, and identifying de novo mutations in new whole genome sequence data from 800 case-parent trios. In Aim 2 we propose to identify the OFC-associated SNPs that are functional (causal). We hypothesize that pathogenic SNPs reside in enhancers that drive expression in oral tissues, and that risk alleles of such SNPs quantitatively affect activity of the enhancers. To test this hypothesis, we will amplify genomic DNA containing risk-associated SNPs and test them for allele-dependent enhancer activity in vitro (cell-based reporter assays). We will also test the tissue specificity of the enhancers (zebrafish and mouse-based reporter assays). In Aim 3, we will determine the effect that altering the allele of pathogenic SNPs has on expression of the relevant OFC-risk gene (genome engineering with CRISPR/Cas9 in vitro). Finally, we apply chromatin immuno precipitation and chromatin configuration capture in the oral epithelium cell line to deduce the mechanism by which functional SNPs change expression of the OFC-risk genes. The expected outcome of the proposed experiments is identification of the mechanisms by which genetic risk variants cause a common birth defect.
口面裂(主要是唇裂和/或腭裂)是一个相对常见的结构出生 与环境和遗传因素有关的缺陷。全基因组关联 研究(GWAS)和连锁研究已经确定了许多基因变异, 孤立性口面裂(OFC)的风险增加。然而,我们对 这种疾病的致病机制仍然很差,因为,一,我们还没有 区分直接影响OFC风险的DNA变异(即,因果变量) 第二,监管机构的职能, 在颅面发育中编码γ OFC相关基因的分子在很大程度上是未知的。 在每个基因座处,存在多个鉴定的多个SNP,其与以下各项在统计学上相关: 所有这些都存在于非编码DNA中。在目标1中,我们将优先考虑SNP, 通过对GWAS数据进行精细映射,并识别 来自800个病例父母三人组的新的全基因组序列数据。在目标2中,我们建议确定 OFC相关的SNP是功能性的(因果性的)。我们假设致病性SNP 存在于驱动口腔组织中表达的增强子中,并且存在这种SNP的风险等位基因 定量地影响增强子的活性。为了验证这一假设,我们将扩增基因组 含有风险相关SNP的DNA,并测试它们在基因组中的等位基因依赖性增强子活性。 体外(基于细胞的报告基因测定)。我们还将测试增强剂的组织特异性 (基于斑马鱼和小鼠的报告基因测定)。在目标3中,我们将确定 改变致病性SNP的等位基因会影响相关OFC风险基因的表达 (体外用CRISPR/Cas9进行基因组工程)。最后,我们应用染色质免疫 沉淀和染色质构型捕获在口腔上皮细胞系,以推断 功能性SNP改变OFC风险基因表达的机制。预期 拟议的实验的结果是确定遗传风险的机制, 变异导致常见的出生缺陷。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Generating Zebrafish RNA-Less Mutant Alleles by Deleting Gene Promoters with CRISPR/Cas9.
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Robert Aaron Cornell其他文献

Robert Aaron Cornell的其他文献

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{{ truncateString('Robert Aaron Cornell', 18)}}的其他基金

Genetic underpinnings of craniofacial disorders explored with spatial sequencing
通过空间测序探索颅面疾病的遗传基础
  • 批准号:
    10712635
  • 财政年份:
    2023
  • 资助金额:
    $ 47.28万
  • 项目类别:
Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
AP2 转录因子家族对黑素细胞谱系的调节
  • 批准号:
    10607024
  • 财政年份:
    2022
  • 资助金额:
    $ 47.28万
  • 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
  • 批准号:
    10589307
  • 财政年份:
    2022
  • 资助金额:
    $ 47.28万
  • 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
  • 批准号:
    10521268
  • 财政年份:
    2022
  • 资助金额:
    $ 47.28万
  • 项目类别:
Cornell- Common Fund Data Supplement Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
康奈尔大学共同基金数据补充 AP2 转录因子家族对黑素细胞谱系的调节
  • 批准号:
    9985505
  • 财政年份:
    2019
  • 资助金额:
    $ 47.28万
  • 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
  • 批准号:
    9900769
  • 财政年份:
    2019
  • 资助金额:
    $ 47.28万
  • 项目类别:
Dissecting the transcriptional network governing differentiation of periderm
剖析控制周皮分化的转录网络
  • 批准号:
    10058264
  • 财政年份:
    2019
  • 资助金额:
    $ 47.28万
  • 项目类别:
Functional tests of non-coding DNA variants associated with risk for orofacial clefting
与口面部裂风险相关的非编码 DNA 变异的功能测试
  • 批准号:
    9924262
  • 财政年份:
    2018
  • 资助金额:
    $ 47.28万
  • 项目类别:
Regulation of the melanocyte lineage by the AP2 transcription factor family
AP2 转录因子家族对黑素细胞谱系的调节
  • 批准号:
    8832130
  • 财政年份:
    2014
  • 资助金额:
    $ 47.28万
  • 项目类别:
Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family
AP2 转录因子家族对黑素细胞谱系的调节
  • 批准号:
    10229547
  • 财政年份:
    2013
  • 资助金额:
    $ 47.28万
  • 项目类别:

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