Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes
Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes
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DOI：
10.1101/gr.111609.110
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发表时间：
2011-01-01
期刊：
影响因子：
7
通讯作者：
Cheung, Sau W.
中科院分区：
文献类型：
--
作者：
Ou, Zhishuo;Stankiewicz, Pawel;Cheung, Sau W.
分析了4个具有相同der（4）t（4;11）（p16.2;p15.4）不平衡易位的无关家系。通过aCGH和SNP阵列分析，4p16.2和11p15.4中的两个断裂点区域分别变窄到类似于359-kb和类似于215-kb低拷贝重复（LCR）簇的大。DNA测序能够映射一个易位到24 bp的断裂点内的染色体间旁系同源LCR的长度类似于130 kb和94.7%的DNA序列同一性位于嗅觉受体基因簇，表明非等位基因同源重组（NAHR）的易位形成的机制。为了研究染色体间LCR在复发性染色体易位形成中的潜在参与，我们进行了计算全基因组分析，并鉴定了1143个染色体间LCR底物对，其大小>5 kb，序列同一性>94%，可以潜在介导染色体易位。通过对另一个复发性易位der（8）t（8;12）（p23.1;p13.31）的断点进行测序，提供了染色体间NAHR介导易位形成的额外证据。NAHR位点定位在55 bp内，与7.8 kb旁系同源亚基的序列同一性为95.3%，位于与579 kb（chr 8）和287 kb（chr 12）LCR簇相似的位置。我们证明，NAHR介导经常宪法易位t（4;11）和t（8;12）和潜在的许多其他染色体间易位整个人类基因组。此外，我们提供了一个计算确定的全基因组“经常性易位图。''
Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large similar to 359-kb and similar to 215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of similar to 130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in similar to 7.8-kb paralogous subunits of 95.3% sequence identity located in the similar to 579-kb (chr 8) and similar to 287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map.''