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

1.项目总结 反转与疾病病因、物种形成和适应的相关性广泛而显著。 虽然流行率尚不清楚，但已被确认。在人类中，从头开始的倒置与先天性 约9.6%的患者出现异常。然而，尽管倒置具有生物学相关性，但它们的分子特征， 携带者的形成机制、对基因组结构的影响及其对临床的贡献 表型，还没有进一步研究。反转通常被归类为平衡的互惠事件 由异位重组产生，尽管最近的研究揭示了一个明显的图景，即反转 起源于伴随产生拷贝数变体(CNV)的机制。令人惊讶的是，那些 复杂的倒置是神经发育缺陷相关CNV的30%的基础。假说 这种应用的特点是：I.倒置通常是由异位以外的机制从头开始产生的 重组；ii.相关的部分倒位与复杂的基因组重排有关 (CGRs)在散发性疾病中经常被忽视，以及倒置是一种“隐藏的”结构类型 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。这些假设将通过以下具体目标进行检验：i)确定 不同的DNA修复机制对反转形成的相对贡献；ii)确定 CGR是倒置的基因组签名；以及iii)调查从头倒置的贡献规模 到零星疾病。为了克服每种方法的局限性，多基因组的组合策略 工具将被应用于表征倒置和相关的基因组改变，包括整个基因组 测序(WGS)短读和长读、基因组图谱经典细胞遗传学、阵列CGH和/或SNP 数组。在本申请中获得的结果将导致术语反转的更广泛的定义，启用 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，它还将识别受影响的候选基因 该结构变异用于进一步的遗传和功能验证。总之，这一应用程序将对 我们对人类生物学过程和疾病机制的理解与反转有关 对出生缺陷、人类发育、不孕和癌症的诊断具有广泛的意义。此应用程序将 还建立了共同的基础，将罕见和常见疾病、人类进化和人口研究联系起来 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.