Whole-genome sequencing with long reads reveals complex structure and origin of structural variation in human genetic variations and somatic mutations in cancer.
Whole-genome sequencing with long reads reveals complex structure and origin of structural variation in human genetic variations and somatic mutations in cancer.
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DOI：
10.1186/s13073-021-00883-1
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发表时间：
2021-04-29
期刊：
影响因子：
12.3
通讯作者：
Shimada M
中科院分区：
文献类型：
--
作者：
Fujimoto A;Wong JH;Yoshii Y;Akiyama S;Tanaka A;Yagi H;Shigemizu D;Nakagawa H;Mizokami M;Shimada M
种系变异和体细胞突变的鉴定是人类遗传学中的一个主要问题。然而，由于DNA测序技术和计算算法的限制，我们对遗传变异和体细胞突变的理解还远远不够。在本研究中，我们使用长读测序技术（Oxford Nanopore）对11例日本肝癌进行了全基因组测序，并匹配了先前为国际癌症基因组联盟（ICGC）测序的正常样本。我们构建了长读数据的分析管道，并确定了种系和体细胞结构变异（SV）。在多态性生殖系SV中，我们的分析确定了8004个插入，6389个缺失，27个倒位和32个染色体内易位。通过与黑猩猩基因组的比较，我们正确地推断出导致插入和缺失的事件，并发现大多数插入是由转座子引起的，Alu是最主要的来源，而其他类型的插入，如串联重复和加工假基因，是罕见的。我们推断了缺失世代的机制，发现大多数非等位基因同源重组（NAHR）事件是由西内斯中的重组错误引起的。对肝癌体细胞突变的分析表明，长读段可以检测到比以前的短读段研究更多的SV，并且癌症SV产生的机制与种系缺失不同。我们的分析提供了一个全面的目录多态性和体细胞SV，以及他们可能的原因。我们的软件可在https://github.com/afujimoto/CAMPHOR和https://github.com/afujimoto/CAMPHORsomatic上获得。
Identification of germline variation and somatic mutations is a major issue in human genetics. However, due to the limitations of DNA sequencing technologies and computational algorithms, our understanding of genetic variation and somatic mutations is far from complete. In the present study, we performed whole-genome sequencing using long-read sequencing technology (Oxford Nanopore) for 11 Japanese liver cancers and matched normal samples which were previously sequenced for the International Cancer Genome Consortium (ICGC). We constructed an analysis pipeline for the long-read data and identified germline and somatic structural variations (SVs). In polymorphic germline SVs, our analysis identified 8004 insertions, 6389 deletions, 27 inversions, and 32 intra-chromosomal translocations. By comparing to the chimpanzee genome, we correctly inferred events that caused insertions and deletions and found that most insertions were caused by transposons and Alu is the most predominant source, while other types of insertions, such as tandem duplications and processed pseudogenes, are rare. We inferred mechanisms of deletion generations and found that most non-allelic homolog recombination (NAHR) events were caused by recombination errors in SINEs. Analysis of somatic mutations in liver cancers showed that long reads could detect larger numbers of SVs than a previous short-read study and that mechanisms of cancer SV generation were different from that of germline deletions. Our analysis provides a comprehensive catalog of polymorphic and somatic SVs, as well as their possible causes. Our software are available at https://github.com/afujimoto/CAMPHOR and https://github.com/afujimoto/CAMPHORsomatic.
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通讯作者：
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通讯作者：
Kellis M
影响因子：
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作者：
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通讯作者：
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