Jahic Amir, Erichsen Anne K, Deufel Thomas, Tallaksen Chantal M, Beetz Christian
Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Eur J Hum Genet. 2016 Aug;24(9):1371-4. doi: 10.1038/ejhg.2016.20. Epub 2016 Mar 2.
Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite- and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.
与Alu衍生序列插入相关的大片段缺失代表了一类罕见但可能独特的改变。它们是通过一步机制形成，还是通过一个初级插入步骤后接着一个独立的次级缺失步骤形成，目前尚不清楚。我们通过长距离PCR解析了两个与疾病相关的SPAST缺失，它们涉及不同的外显子。在这两种情况下，断点之间均观察到Alu衍生序列。代表潜在涉及的Alu逆转录转座事件靶点的内含子区域相互重叠。基于微卫星和单核苷酸多态性的单倍型分析表明，这两个缺失均起源于同一个奠基者等位基因。我们的数据表明，这些缺失最好用两步插入-缺失情况来解释，其中单个Alu逆转录转座事件代表共同的初级步骤。然后，这个Alu通过非同源末端连接介导了其中一个缺失，另一个缺失则通过非等位基因同源重组介导。因此，我们的发现有力地支持了Alu插入相关缺失中插入和缺失的时间分离。它们还表明，某些Alu整合会导致局部基因组不稳定性普遍增加，这就解释了为什么在它们介导的重排之前可能很短的时间内通常检测不到它们。
