Uncovering inversion formation in the human genome and its impact to disease.

揭示人类基因组中倒位的形成及其对疾病的影响。

• 批准号: 10390192
• 负责人: Claudia Carvalho Fonseca
• 金额: $ 8.26万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390192
• 关键词: Affect; Architecture; Biological; Biological Process; Candidate Disease Gene; Chromosome Structures; Complex; Congenital Abnormality; Copy Number Polymorphism; Cytogenetics; DNA Repair; DNA Sequence Alteration; DNA Sequence Rearrangement; Defect; Detection; Diagnosis; Disease; Etiology; Event; Evolution; Frequencies; Gene Expression Regulation; Genetic; Genetic Recombination; Genome; Genome Mappings; Genomics; Human; Human Biology; Human Development; Human Genome; Infertility; Malignant Neoplasms; Meiosis; Methodology; Mitotic; Molecular; Pathogenicity; Patients; Population Genetics; Prevalence; SNP array; Structure; Testing; Validation; Variant; clinical phenotype; comparative genomic hybridization; congenital anomaly; disease diagnosis; genome sequencing; genomic signature; genomic tools; public health relevance; structural genomics; tool; whole genome

1. Project Summary The relevance of inversions for disease causation, speciation and adaptation, is broadly and prominently recognized although the prevalence is unknown. In humans, de novo inversions are associated with congenital anomalies in ~9.6% of patients. Yet, despite the biological relevance of inversions, their molecular features, formation mechanism, impact to the genomic structure in carriers, as well as their contribution to clinical phenotypes, have not been further explored. Inversions are typically classified as a balanced reciprocal event generated by ectopic recombination, although recent studies reveal a distinct picture whereby inversions originate from mechanisms that concomitantly generate copy number variants (CNVs). Surprisingly, those complex inversions underlie as much as 30% of neurodevelopmental defect-associated CNVs. The hypothesis of this application are: i. inversions are often generated de novo by mechanisms other than ectopic recombination; ii. a relevant fraction of inversions are associated with complex genomic rearrangements (CGRs) often overlooked in sporadic diseases, and iii. inversions are a “hidden” type of structural variation for which contribution to a clinical phenotype has been under assessed due to the lack of appropriate detection tools. These hypotheses will be tested by virtue of the following specific aims: i) to define the relative contributions of distinct DNA repair mechanisms to the formation of inversions; ii) to establish whether CGRs are genomic signature of inversions; and iii) to investigate the scale of contribution of de novo inversions to sporadic diseases. To overcome the limitations of each methodology, a combined strategy of multiple genomic tools will be applied to characterize inversions and associated genomic alterations, consisting of whole genome sequencing (WGS) short-and long-reads, genome mapping classical cytogenetics, array CGH and/or SNP arrays. The results obtained in this application will lead to a more broadly definition for the term inversion, enable estimate of the contribution of mitotic and meiotic DNA repair mechanisms of their formation and reveal the frequency of origin and underlying genomic architecture. Moreover, it will identify candidate genes affected by that structural variant for further genetic and functional validation. In summary, this application will strongly impact our understanding of human biological processes and disease mechanisms associated with inversions with broad implications for diagnosis of birth defects, human development, infertility and cancer. This application will also establish common grounds to bridge studies of rare and common diseases, human evolution and population genetics.

一、项目概要 倒转与疾病因果关系、物种形成和适应的相关性广泛且显着 尽管患病率未知，但已得到认可。在人类中，从头倒转与先天性相关 约 9.6% 的患者出现异常。然而，尽管倒位具有生物学相关性，但它们的分子特征， 形成机制、对携带者基因组结构的影响及其对临床的贡献 表型，尚未进一步探讨。反转通常被归类为平衡倒数事件 由异位重组产生，尽管最近的研究揭示了一种独特的情况，即倒位 起源于同时产生拷贝数变异（CNV）的机制。令人惊讶的是，那些 多达 30% 的神经发育缺陷相关 CNV 是由复杂的倒位引起的。假设 该申请的内容是： i．倒位通常是通过异位以外的机制从头产生的 重组；二.倒位的相关部分与复杂的基因组重排有关 （CGR）在散发性疾病中经常被忽视，以及 iii．倒置是一种“隐藏”类型的结构 由于缺乏对临床表型的贡献而被低估的变异 适当的检测工具。这些假设将根据以下具体目标进行检验： i) 定义 不同 DNA 修复机制对倒位形成的相对贡献； ii) 确定是否 CGR 是倒位的基因组特征； iii) 研究从头反转的贡献规模 到散发性疾病。为了克服每种方法的局限性，多种基因组的组合策略 将应用工具来表征倒位和相关的基因组改变，包括全基因组 测序 (WGS) 短读长和长读长、基因组作图经典细胞遗传学、阵列 CGH 和/或 SNP 数组。本应用中获得的结果将为术语反演提供更广泛的定义，使 估计有丝分裂和减数分裂 DNA 修复机制对其形成的贡献，并揭示 起源频率和潜在的基因组结构。此外，它将识别受以下影响的候选基因 该结构变体用于进一步的遗传和功能验证。总而言之，该应用程序将强烈影响 我们对与倒转相关的人类生物过程和疾病机制的理解 对出生缺陷、人类发育、不孕不育和癌症的诊断具有广泛的影响。该应用程序将 还建立共同点来连接罕见和常见疾病、人类进化和人口的研究 遗传学。