Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3
Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3
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DOI：
10.1093/hmg/ddv146
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发表时间：
2015-07-15
影响因子：
3.5
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
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作者：
Gu, Shen;Yuan, Bo;Lupski, James R.
已知Alu重复元件通过产生Alu介导的拷贝数变异（CNVs）是基因组不稳定的主要贡献者。大多数报道的alu介导的CNVs是简单的缺失和重复，alu - alu介导的重排机制归因于非等位基因同源重组（NAHR）。位于p13.3基因组区的17号染色体缺乏广泛的低拷贝重复结构；然而，它高度富集了Alu重复元件，在人类参考基因组中注释了总序列的30%，而在全基因组中注释了10%，在17号染色体上注释了18%。我们通过高密度寡核苷酸阵列比较基因组杂交对17p13.3 CNVs进行了机制研究，特别是以类似于150 bp /探针密度的17p13.3区域进行了查询；通过聚合酶链反应和Sanger测序，将CNV断点连接定位为核苷酸分辨率。研究的重排包括5个间质缺失、14个串联重复、7个末端缺失和13个复杂基因组重排。在17p13.3区域，80%的间隙缺失、46%的串联重复和50%的cgr中发现了alu - alu介导的重排，这表明该机制是断点连接形成的主要因素。我们的研究表明，Alu重复元件促进了17号染色体p13.3处非复发性CNVs、cgr和其他结构畸变的形成。在cgr中常见的alu介导的重排和断点连接序列分析进一步表明，这种类型的机制不太可能归因于NAHR，而可能是由于重组偶联的DNA复制修复过程。
Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu-mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30% of total sequence annotated in the human reference genome, compared with the 10% genome-wide and 18% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with similar to 150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80% of the interstitial deletions, 46% of the tandem duplications and 50% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.