Insights to Noncoding Disease Variants using Mosaic Diseases

使用花叶病洞察非编码疾病变异

• 批准号: 10244405
• 负责人: Bryan Sun
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244405
• 关键词: Affect; Chromatin; Code; Development; Disease; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Human; Mosaicism; Mutation; Natural regeneration; Organoids; Patients; Population; Proteins; Regulator Genes; Research; Technology; Tissues; Untranslated RNA; Variant; common treatment; disease-causing mutation; genome sequencing; innovation; insight; multimodality; multiple omics; mutant; next generation sequencing; rare genetic disorder; skin disorder; whole genome

Next-generation sequencing technologies have revolutionized the ability to identify genetic changes associated with disease. Historically, it was expected that most disease-causing mutations would affect the parts of the genome encoding proteins, but accumulating evidence indicates the importance of mutations in non-protein coding genome regions. Compared to proteins, the disease significance of non-coding regions is still poorly understood. This goal of this proposal is to better understand the non-protein coding genomic regulators of skin disease by focusing on subjects with uncommon mosaic forms of disease using a multimodal approach that combines chromatin profiling and whole genome sequencing. Genetic variations will be functionally characterized by regenerating candidate mutant disease genotypes in human organoids, as well as by rescuing disease organoid tissues by genetic correction of the underlying noncoding mutation. At the end of this proposal, we aim to better understand non-coding genomic regulators of tissue development by innovating a combined strategy of rare mosaic disease research and multi-omics approaches.

下一代测序技术彻底改变了识别基因的能力 与疾病相关的变化。从历史上看，预计大多数致病 突变会影响基因组编码蛋白质的部分，但证据不断积累 表明非蛋白质编码基因组区域突变的重要性。相比 蛋白质中，非编码区的疾病意义仍知之甚少。 该提案的目标是更好地了解非蛋白质编码基因组调节因子 通过使用一种方法来关注患有不常见的马赛克形式疾病的受试者 结合染色质分析和全基因组测序的多模式方法。遗传 变异将通过再生候选突变疾病来进行功能表征 人类类器官的基因型，以及通过遗传拯救疾病类器官组织 纠正潜在的非编码突变。在本提案的最后，我们的目标是更好地 通过创新组合来了解组织发育的非编码基因组调节因子 罕见花叶病研究策略和多组学方法。