Gabriel Martínez-Gálvez, Suji Lee, Ryo Niwa, Knut Woltjen
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引用次数: 0
摘要
随着长读数测序在基因组分析中越来越普遍,与人类性状和疾病相关的缺失变异的数量预计将继续增长,其增长速度可能远远超过新型单核苷酸变异(SNV)发现的增长速度。这种模式的转变将导致对基因编辑技术的需求增加,这种技术可以在诱导多能干细胞(iPS)等人类模型系统中进行功能分析。基因编辑的结果最终由细胞修复途径决定,并可通过周围的 DNA 序列进行预测。由于多项研究揭示了天然缺失变体边缘的微观同源性,因此诱导微观同源性介导的末端连接(MMEJ)是创建特异性缺失的可靠方法。在这篇综述中,我们将讨论人类基因组变异发现的变化趋势,简要回顾 DNA 修复过程和相关预测算法,展示 MMEJ 在产生功能缺失和功能增益等位基因方面的实用性,最后推测这些进展对人类功能基因组学未来的影响。
On the edge of deletion: Using natural and engineered microhomology to edit the human genome
As long read sequencing becomes more commonplace in genome analysis, the number of deletion variants associated with human traits and disease are anticipated to continue growing at a rate that may well outpace the increase in novel single nucleotide variant (SNV) discoveries. Such a paradigm shift will be met with an increased demand for gene editing technologies that enable functional analyses in a human model system such as induced pluripotent stem (iPS) cells. The outcome of gene editing is ultimately determined by cellular repair pathways and can be predicted by the surrounding DNA sequence. As multiple studies have revealed microhomology at the edges of natural deletion variants, eliciting microhomology mediated end joining (MMEJ) presents a reliable approach to create specific deletions. In this review, we discuss the shifting trends in human genome variant discovery, briefly review DNA repair processes and the associated prediction algorithms, demonstrate the utility of MMEJ in generating both loss- and gain-of-function alleles, and finally speculate on the impact these advances will have on the future of human functional genomics.