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: 10217870
• 负责人: Claudia Carvalho Fonseca
• 金额: $ 63.75万
• 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/10217870
• 关键词: Affect; Architecture; Biological; Biological Process; Candidate Disease Gene; Chromosomal Instability; Chromosome Structures; Chromosomes; Complex; Congenital Abnormality; Copy Number Polymorphism; Cytogenetics; DNA; DNA Repair; DNA Sequence; DNA Sequence Alteration; DNA Sequence Rearrangement; Data; Defect; Detection; Diagnosis; Disease; Etiology; Event; Evolution; Frequencies; Gene Expression Regulation; Generations; Genetic; Genetic Diseases; Genetic Recombination; Genome; Genome Mappings; Genomic Segment; Genomics; Goals; Haplotypes; Human; Human Biology; Human Development; Human Genome; Individual; Infertility; Inherited; Lead; Malignant Neoplasms; Mediating; Meiosis; Methodology; Mitosis; Mitotic; Molecular; Molecular Abnormality; Optics; Pathogenicity; Patients; Pattern; Phase; Phenotype; Population Genetics; Prevalence; Primates; Procedures; Production; Role; SNP array; Sampling; Series; Structure; Subgroup; Techniques; Testing; Validation; Variant; Work; base; clinical phenotype; comparative genomic hybridization; congenital anomaly; disease diagnosis; ds-DNA; genetic disorder diagnosis; genome sequencing; genomic signature; genomic tools; high risk; nanopore; next generation sequencing; offspring; proband; public health relevance; reference genome; repaired; reproductive; structural genomics; tool; trait; 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.

1。项目摘要 反转与疾病原因，规范和适应的相关性是广泛而显着的 尽管流行率尚不清楚。在人类中，从头逆与先天性有关 约9.6％的患者异常。但是，对反转的生物学相关性，它们的分子特征， 形成机制，对载体基因组结构的影响及其对临床的贡献 表型，尚未进一步探索。反转通常被归类为平衡的倒数事件 通过生态重组产生 起源于同时生成拷贝数变体（CNV）的机制。令人惊讶的是，那些 复杂的反转是多达30％的神经发育相关的CNV。假设 此应用程序是：i。反转通常是通过Echopic以外的其他机制产生的 重组； ii。相关的反转部分与复杂的基因组重排有关 （CGRS）经常在零星疾病和III中被忽略。反转是一种“隐藏”的结构类型 由于缺少 适当的检测工具。这些假设将通过以下特定目的进行检验：i）定义 不同的DNA修复机制对反转形成的相对贡献； ii）确定是否 CGR是反转的基因组特征。 iii）调查从头反转的贡献规模 偶发性疾病。为了克服每种方法的局限性，多种基因组的组合策略 工具将用于表征反转和相关的基因组改变，由整个基因组组成 测序（WGS）短读，基因组映射经典细胞遗传学，阵列CGH和/或SNP 数组。在本应用程序中获得的结果将导致该术语的更广泛的定义，启用 估计其形成有丝分裂和减数分裂DNA修复机制的贡献，并揭示了 起源频率和潜在的基因组结构。此外，它将确定受影响的候选基因 该结构变体用于进一步的遗传和功能验证。总而言之，此应用程序将对 我们对与与逆转有关的人类生物过程和疾病机制的理解 对诊断出生缺陷，人类发育，不育和癌症的广泛影响。此应用程序将 还为桥梁研究罕见和常见疾病，人类进化和人群的研究建立共同点 遗传学。