NIPBL, Cohesin and Related Structural Birth Defects

在过去三年里，在了解这些问题的性质和模式方面取得了相当大的进展。 人类物种内的单核苷酸变异。与此相反，全面了解人类 包括缺失、插入和倒位多态性的结构变异远远落后。的 大多数这些事件的结构、频率和表型影响尚不清楚。然而，最近的研究， 这表明基因组结构变异在正常人群中很常见， 与人类疾病/疾病易感因素相关。本方案项目 开发了一种系统的方法来描述人类基因组中常见的结构变异。的 该建议的具体目标是：1）鉴定九个基因组中的所有倒位、缺失和插入（大小> 6 kb）， 使用末端序列对映射策略对人类样品进行测序; 2）对这些序列中的每一个的结构进行测序， （n=~2000种变异），包括断点;和3）开发基因分型测定，以评估其在 人类人口。这是一项合作努力，汇集了基因组测序方面的专业知识， 克隆特征和结构变异。这项工作的结果将产生第一个高质量的 参考一组测序的结构变体，提供对潜在分子机制的深入了解 这些事件，并开发基因分型平台，将需要评估表型 对人类疾病和适应的影响。

In the last three years there has been considerable progress in understanding the nature and pattern of single nucleotide variation within the human species. By contrast, a comprehensive understanding of human structural variation which includes deletion, insertion and inversion polymorphisms lags far behind. The structure, frequency and phenotypic impact of most of these events are not known. Recent studies, however, suggest that genome structural variation is common in the normal population, alters structure and copy number of genes and is associated with human disease/disease susceptibility factors. This program project develops a systematic approach to characterize common structural variation within the human genome. The specific aims of this proposal are 1) to identify all inversions, deletions and insertions (> 6 kb in size) in nine human samples using an end-sequence-pair mapping strategy; 2) to sequence the structure of each of these (n=~2000 variants) including breakpoints; and 3) to develop genotyping assays to assess their frequency in the human population. It is a collaborative effort which brings together expertise in genome sequencing, clone characterization and structural variation. The results of this work will generate the first high quality reference set of sequenced structural variants, provide insight into the molecular mechanisms underlying these events, and develop the genotyping platforms that will be needed to assess the phenotypic consequences in terms of human disease and adaptation.