Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline
Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline
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DOI：
10.1093/hmg/ddr073
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发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Cuppen, Edwin
中科院分区：
文献类型：
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作者：
Kloosterman, Wigard P.;Guryev, Victor;Cuppen, Edwin
各种突变机制塑造了人类基因组的动态结构，并偶尔导致先天性缺陷和疾病。在这里，我们使用全基因组长配偶对测序来系统地筛选遗传和新生结构变异，包括一个患有严重先天性异常的儿童。我们确定了4321个遗传结构变异和17个从头重排。我们将从头开始的结构变化表征为碱基对水平，揭示了一系列复杂的平衡染色体间和染色体内重排，包括涉及染色体1、4和10的12个断点。对断点区域的详细检查表明，一系列同时发生的双链DNA断裂导致了染色体的局部破碎。所产生的染色体片段的融合涉及非同源末端连接，因为连接点显示有限或没有同源性和小的插入和缺失。我们在这里观察到的染色体片段的随机连接模式与最近在精神错乱的癌细胞中描述的体细胞重排模式非常相似，这种模式被称为染色体分裂。我们得出的结论是，类似的机制也可能驱动种系从头结构变异的形成。
A variety of mutational mechanisms shape the dynamic architecture of human genomes and occasionally result in congenital defects and disease. Here, we used genome-wide long mate-pair sequencing to systematically screen for inherited and de novo structural variation in a trio including a child with severe congenital abnormalities. We identified 4321 inherited structural variants and 17 de novo rearrangements. We characterized the de novo structural changes to the base-pair level revealing a complex series of balanced inter- and intra-chromosomal rearrangements consisting of 12 breakpoints involving chromosomes 1, 4 and 10. Detailed inspection of breakpoint regions indicated that a series of simultaneous double-stranded DNA breaks caused local shattering of chromosomes. Fusion of the resulting chromosomal fragments involved non-homologous end joining, since junction points displayed limited or no homology and small insertions and deletions. The pattern of random joining of chromosomal fragments that we observe here strongly resembles the somatic rearrangement patterns-termed chromothripsis-that have recently been described in deranged cancer cells. We conclude that a similar mechanism may also drive the formation of de novo structural variation in the germline.