Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with Large NF1 Deletions Mediated by Nonallelic Homologous Recombination
Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with Large NF1 Deletions Mediated by Nonallelic Homologous Recombination
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DOI：
10.1002/humu.22473
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发表时间：
2014-02-01
期刊：
影响因子：
3.9
通讯作者：
Kehrer-Sawatzki, Hildegard
中科院分区：
文献类型：
--
作者：
Bengesser, Kathrin;Vogt, Julia;Kehrer-Sawatzki, Hildegard
NF1的大缺失是由非等位基因同源重组介导的。深入分析了NF1大缺失的断点侧翼区域的基因转换，以调查在NAHR交叉期间不连续基因转换的比率是否增加，正如之前在NAHR介导的重排中所指出的那样。分析的所有20个种系1型NF1缺失都是由与断点侧翼区域内连续基因转换相关的NAHR介导的。在31/32个2型NF1缺失中也观察到持续的基因转换。与减数分裂1型NF1缺失相比，2型NF1缺失主要发生在合子后。因此，我们的研究结果表明，NF1大缺失的有丝分裂和减数分裂NAHR中间体通过长补片错配修复（MMR）进行处理，从而确保基因转换通道的连续性，而不是短补片修复特征的不连续基因转换。然而，不表现连续基因转换的单个2型NF1缺失在没有MMR的情况下进行处理，产生两条不同的携带缺失的染色体，它们在断点位置上是可区分的。我们的研究结果表明，在NAHR期间MMR失败，随后是减数分裂后/有丝分裂分离，有可能通过产生断点异质性在人类基因组重排中引起体细胞嵌合体。(C) 2013 Wiley期刊公司
Large NF1 deletions are mediated by nonallelic homologous recombination (NAHR). An in-depth analysis of gene conversion operating in the breakpoint-flanking regions of large NF1 deletions was performed to investigate whether the rate of discontinuous gene conversion during NAHR with crossover is increased, as has been previously noted in NAHR-mediated rearrangements. All 20 germline type-1 NF1 deletions analyzed were mediated by NAHR associated with continuous gene conversion within the breakpoint-flanking regions. Continuous gene conversion was also observed in 31/32 type-2 NF1 deletions investigated. In contrast to the meiotic type-1 NF1 deletions, type-2 NF1 deletions are predominantly of post-zygotic origin. Our findings therefore imply that the mitotic as well as the meiotic NAHR intermediates of large NF1 deletions are processed by long-patch mismatch repair (MMR), thereby ensuring gene conversion tract continuity instead of the discontinuous gene conversion that is characteristic of short-patch repair. However, the single type-2 NF1 deletion not exhibiting continuous gene conversion was processed without MMR, yielding two different deletion-bearing chromosomes, which were distinguishable in terms of their breakpoint positions. Our findings indicate that MMR failure during NAHR, followed by post-meiotic/mitotic segregation, has the potential to give rise to somatic mosaicism in human genomic rearrangements by generating breakpoint heterogeneity. (C) 2013 Wiley Periodicals, Inc.