Computational methods for detecting patterns of complex genomic variation

 描述（由申请人提供）： 基因组通过不同的机制进化和多样化，包括小的点突变，但也有较大的结构变异（SV）。SV可以通过简单重复和基于微同源的重组（在本提议中称为“进行性SV”）来介导。然而，进行性SV机制不能解释所有形式的大的基因组变异;有时，需要更复杂的机制;例子包括断裂融合桥和Chromothripsis。此外，对导致复杂SV形成的基因组不稳定性的遗传机制知之甚少。据推测，病毒基因组随机插入基因组有时会破坏关键基因，导致基因组不稳定和超变异。为了解决这些问题，该提案将设计和实施计算方法，以（a）重建和验证病毒基因组插入的附加型结构;（B）确定从肿瘤基因组采样的基因组序列是否具有复杂变异的特征;以及（B）具有复杂SV（包括KIR和HLA）的相和亚型区域;随着基因组学的临床/转化应用的发展，复杂SV对个体表型的影响变得越来越重要。了解BFB和Chromothripsis的计算特征将有助于癌症的亚型和特征。对KIR/HLA亚型的认识将与免疫相关表型相关联，病毒附加体的重建将有助于阐明病毒介导的癌症的病因。因此，所提出的一套计算工具将直接影响基因组学的翻译/医学方面。

 DESCRIPTION (provided by applicant): Genomes evolve and diversify through different mechanisms, including small point mutations, but also larger, structural variations (SV). SVs can be mediated by simple repeats and microhomology based recombination (termed 'progressive SVs' in this proposal). However, progressive SV mechanisms cannot explain all forms of large genomic variation; sometimes, more 'complex mechanisms' are needed; examples include Breakage Fusion Bridge, and Chromothripsis. Moreover, there is little understanding of the genetic mechanisms of genome instability that lead to complex SV formation. It is suspected that random viral genome insertions into the genome can on occasion disrupt key genes, causing genome instability and hyper-variability. To address these problems, the proposal will design and implement computational methods to (a) reconstruct and validate episomal structures of viral genome insertions; (b) determine if genomic sequence sampled from tumor genomes has a signature of complex variation; and, (b) phase and sub-type regions with complex SV including KIR and HLA; As clinical/translational applications of genomics come to the forefront, the impact of complex SVs on the phenotype of an individual become increasingly important. Understanding the computational signatures of BFB and Chromothripsis will help sub-type and characterize cancers. The knowledge of KIR/HLA sub-type will be correlated with immune related phenotypes, and the reconstruction of viral episomes will help clarify the etiology of virus mediated cancers. Thus, the proposed set of computational tools will directly impact the translational/medical aspect of genomics.