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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dynamics and processes of copy number instability in human γ-globin genes
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Dynamics and processes of copy number instability in human γ-globin genes

机译：人γ-珠蛋白基因拷贝数不稳定的动力学和过程

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摘要

Copy number variation in the human genome is prevalent but relatively little is known about the dynamics of DNA rearrangement. We therefore used the duplicated γ-globin genes as a simple system to explore de novo copy number changes. Rearrangements that changed gene number were seen in both germline and somatic DNA, and mainly arose by unequal sister chromatid exchange between homologous sequences, with evidence from recurrent mosaic rearrangements that many, if not all, of these events in sperm arise before meiosis. Unequal exchange frequencies are apparently controlled primarily by the degree of sequence identity shared by the duplicate genes, leading to substantial variation between haplotypes in copy number instability. Additional, more complex rearrangements generated by mechanisms not involving homologous recombination, and in some cases showing DNA transfer between chromosomes, were also detected but were rare. Sequence changes were also seen in γ-globin DNA molecules, with strong evidence that some were genuine de novo base substitutions. They were present in sperm at a frequency far higher than predicted from current estimates of germline mutation rates, raising interesting questions about base mutation dynamics in the male germline.
机译：人类基因组中的拷贝数变异很普遍，但对DNA重排的动力学知之甚少。因此，我们使用重复的γ-珠蛋白基因作为一个简单的系统来探索从头复制数量的变化。在种系和体细胞DNA中都发现了改变基因数目的重排，并且主要是由于同源序列之间姐妹染色单体交换不平等所引起的，并有复发性镶嵌重排的证据表明，精子中的许多（如果不是全部）这些事件是在减数分裂之前发生的。交换频率的不平等显然主要受重复基因共享的序列同一性程度控制，从而导致单倍型之间拷贝数不稳定的实质性差异。此外，还检测到由不涉及同源重组的机制所产生的更复杂的重排，并且在某些情况下显示了染色体之间的DNA转移，但这种情况很少见。在γ-珠蛋白DNA分子中也发现了序列变化，有力的证据表明某些是真正的从头碱基取代。它们存在于精子中的频率远高于目前对种系突变率的估计所预测的频率，这引发了有关雄性种系中碱基突变动态的有趣问题。

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