Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Nat Biotechnol. 2013 Dec;31(12):1119-25. doi: 10.1038/nbt.2727. Epub 2013 Nov 3.
Genomes assembled de novo from short reads are highly fragmented relative to the finished chromosomes of Homo sapiens and key model organisms generated by the Human Genome Project. To address this problem, we need scalable, cost-effective methods to obtain assemblies with chromosome-scale contiguity. Here we show that genome-wide chromatin interaction data sets, such as those generated by Hi-C, are a rich source of long-range information for assigning, ordering and orienting genomic sequences to chromosomes, including across centromeres. To exploit this finding, we developed an algorithm that uses Hi-C data for ultra-long-range scaffolding of de novo genome assemblies. We demonstrate the approach by combining shotgun fragment and short jump mate-pair sequences with Hi-C data to generate chromosome-scale de novo assemblies of the human, mouse and Drosophila genomes, achieving--for the human genome--98% accuracy in assigning scaffolds to chromosome groups and 99% accuracy in ordering and orienting scaffolds within chromosome groups. Hi-C data can also be used to validate chromosomal translocations in cancer genomes.
从头组装的基因组与人类和关键模式生物的完成染色体相比，相对来说是高度碎片化的，这些完成染色体是由人类基因组计划产生的。为了解决这个问题，我们需要可扩展、具有成本效益的方法来获得具有染色体级连续性的组装。在这里，我们表明全基因组染色质相互作用数据集，如 Hi-C 产生的数据集，是分配、排序和定向基因组序列到染色体的丰富的长程信息来源，包括在着丝粒处。为了利用这一发现，我们开发了一种算法，该算法利用 Hi-C 数据进行从头组装基因组的超远程支架搭建。我们通过将鸟枪法片段和短跳配对序列与 Hi-C 数据相结合，展示了该方法在人类、小鼠和果蝇基因组的染色体级从头组装中的应用，该方法实现了——在人类基因组中——将支架分配到染色体组的准确率为 98%，在染色体组内对支架进行排序和定向的准确率为 99%。Hi-C 数据还可用于验证癌症基因组中的染色体易位。
