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首页> 外文期刊>Nucleic Acids Research >Chromosomal position effects on AAV-mediated gene targeting
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Chromosomal position effects on AAV-mediated gene targeting

机译：染色体位置对AAV介导的基因靶向的影响

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The effects of chromosomal position and neighboring genomic elements on gene targeting in human cells remain largely unexplored. To study these, we used a shuttle vector system in which murine leukemia virus (MLV)-based proviral targets present at different chromosomal locations and containing mutations in the neomycin phosphotransferase (neo) gene were corrected by adeno-associated virus (AAV)-mediated gene targeting. Sixteen identical target loci present in HT-1080 human sarcoma cells were all successfully corrected by gene targeting. The gene targeting frequencies varied by as much as 10-fold, and there was a clear bias for correction of one of the targets in clones containing two target sites. The targeting frequency at each site was correlated to the proximity and density of various genomic elements, and we found a significant association of higher targeting frequencies at loci near a subset of dinucleotide microsatellite repeats (r = -0.55, P < 0.05), in particular GT repeats (r = -0.87, P < 0.0001). Additionally, there was a correlation between meiotic recombination rates and targeting frequencies at the target loci (r = 0.52, P < 0.05). There was no correlation between surrounding chromosomal transcription units and targeting frequencies. Our results indicate that certain chromosomal positions are preferred sites for gene targeting in human cells.
机译：染色体位置和邻近基因组元件对人类细胞基因靶向的影响尚待探索。为了研究这些，我们使用了穿梭载体系统，其中腺相关病毒（AAV）介导的基于鼠白血病病毒（MLV）的原病毒靶标存在于不同的染色体位置并在新霉素磷酸转移酶（neo）基因中包含突变。基因靶向。通过基因靶向成功纠正了HT-1080人肉瘤细胞中存在的16个相同的靶基因座。基因靶向频率的变化幅度高达10倍，在包含两个靶位点的克隆中，对靶标之一的校正存在明显偏差。每个位点的靶向频率与各种基因组元件的接近度和密度相关，我们发现在双核苷酸微卫星重复子集附近的基因座上较高的靶向频率有显着关联（r = -0.55，P <0.05） GT重复（r = -0.87，P <0.0001）。另外，减数分裂重组率与靶位点的靶定频率之间存在相关性（r = 0.52，P <0.05）。周围的染色体转录单位与靶向频率之间没有相关性。我们的结果表明，某些染色体位置是人类细胞中基因靶向的首选位点。

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