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

1.项目摘要 倒位与疾病成因、物种形成和适应的相关性是广泛而显著的 尽管患病率尚不清楚，在人类中，新生倒位与先天性 约9.6%的患者出现异常。然而，尽管倒位具有生物学意义，但它们的分子特征， 形成机制、对携带者基因组结构的影响以及对临床的贡献 表型，尚未进一步探索。反转通常被归类为平衡的相互事件 产生的异位重组，虽然最近的研究揭示了一个独特的图片， 来源于伴随产生拷贝数变异（CNVs）的机制。令人惊讶的是，这些 复杂的倒位是多达30%的神经发育缺陷相关的CNVs的基础。的假设 本申请的主要目的是：i.倒位通常是通过异位以外的机制重新产生的， 重组; ii.倒位的相关部分与复杂的基因组重排有关 （CGRs）在散发性疾病中经常被忽视，和iii.反转是一种"隐藏"的结构类型， 由于缺乏对临床表型贡献的评估， 合适的检测工具。这些假设将通过以下具体目标进行测试：i）定义 不同的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;以及iii）调查从头倒位的贡献规模 到散发性疾病。为了克服每种方法的局限性，多基因组联合策略 工具将被应用于表征倒位和相关的基因组改变，包括全基因组 测序（WGS）短读段和长读段、基因组作图经典细胞遗传学、阵列CGH和/或SNP 阵在本申请中获得的结果将导致术语反演的更广泛的定义， 估计有丝分裂和减数分裂DNA修复机制的贡献，它们的形成，并揭示 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， 这种结构变体用于进一步的遗传和功能验证。总而言之，这一应用将对 我们对人类生物学过程和疾病机制的理解与逆转有关， 对诊断出生缺陷、人类发育、不孕症和癌症具有广泛意义。此应用程序将 还建立共同基础，以弥合罕见和常见疾病，人类进化和人口的研究 遗传学

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.