Allelic recombination and de novo deletions in sperm in the human β-globin gene region
Allelic recombination and de novo deletions in sperm in the human β-globin gene region
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DOI：
10.1093/hmg/ddl025
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Jeffreys, AJ
中科院分区：
文献类型：
--
作者：
Holloway, K;Lawson, VE;Jeffreys, AJ
减数分裂重组在人类基因组中创造单倍型多样性具有重要意义，并有可能通过重复序列之间的异位重组和重组启动事件引发的其他变化而导致基因组重排。然而，人类生殖系中等位基因重组和基因组不稳定性之间的关系仍不清楚。因此，我们分析了Delta-，β-珠蛋白基因区域的重组和DNA不稳定性及其相关的重组热点。精子分型首次准确地定义了热点，并表明它是迄今描述的最活跃的常染色体交叉热点，尽管在非交换基因转换中异常不活跃。这个热点只是延伸到一个由β-珠蛋白和β-珠蛋白基因共享的同源区块中，在这个区块内，异位交换可以产生HB LEPOLE缺失。我们开发了一种物理选择方法来恢复和验证人类DNA中极其罕见的从头缺失，并用它来表征精子中这些HB Lepol缺失以及其他不是由同源DNA序列之间的异位交换引起的缺失的动态。令人惊讶的是，这两类缺失都显示出避开了β-珠蛋白热点的断裂点，证明了它具有显著的保真度，并且在触发这些DNA重排方面没有发挥重大作用。这项研究还首次对人类生殖系中的从头缺失进行了直接分析，并指出在β-珠蛋白基因中可能存在一个与交叉热点分离的缺失控制元件。
Meiotic recombination is of fundamental importance in creating haplotype diversity in the human genome and has the potential to cause genomic rearrangements by ectopic recombination between repeat sequences and through other changes triggered by recombination-initiating events. However, the relationship between allelic recombination and genome instability in the human germline remains unclear. We have therefore analysed recombination and DNA instability in the delta-, beta-globin gene region and its associated recombination hotspot. Sperm typing has for the first time accurately defined the hotspot and shown it to be the most active autosomal crossover hotspot yet described, although unusually inactive in non-exchange gene conversion. The hotspot just extends into a homology block shared by the delta- and beta-globin genes, within which ectopic exchanges can generate Hb Lepore deletions. We developed a physical selection method for recovering and validating extremely rare de novo deletions in human DNA and used it to characterize the dynamics of these Hb Lepore deletions in sperm as well as other deletions not arising from ectopic exchanges between homologous DNA sequences. Surprisingly, both classes of deletion showed breakpoints that avoided the beta-globin hotspot, establishing that it possesses remarkable fidelity and does not play a significant role in triggering these DNA rearrangements. This study also provides the first direct analysis of de novo deletion in the human germline and points to a possible deletion-controlling element in the beta-globin gene separate from the crossover hotspot.