ABSTRACT

Causative mutations for human genetic disorders have mainly been identified in exonic regions that code for amino acid sequences. Recently, however, it has been reported that mutations in deep intronic regions can also cause certain human genetic disorders by creating novel splice sites, leading to pseudo-exon activation. To investigate how frequently pseudo-exon activation events occur in normal individuals, we conducted in silico identification of such events using personal genome data and corresponding high-quality transcriptome data. With rather stringent conditions, on average, 2.6 pseudo-exon activation events per individual were identified. More pseudo-exon activation events were found in 5′ donor splice sites than in 3′ acceptor splice sites. Although pseudo-exon activation events have sporadically been reported as causative mutations in genetic disorders, it is revealed in this study that such events can be observed in normal individuals at a certain frequency. We estimate that human genomes typically contain on average at least 10 pseudo-exon activation events. The actual number should be higher than this, because we used stringent criteria to identify pseudo-exon activation events. This suggests that it is worth considering the possibility of pseudo-exon activation when searching for causative mutations of genetic disorders if candidate mutations are not identified in coding regions or RNA splice sites.

 抽象的

人类遗传疾病的致病突变主要是在编码氨基酸序列的外显子区域中发现的。然而，最近有报道称，深层内含子区域的突变也可以通过产生新的剪接位点，导致假外显子激活，从而导致某些人类遗传疾病。为了研究正常个体中伪外显子激活事件发生的频率，我们使用个人基因组数据和相应的高质量转录组数据对此类事件进行了计算机识别。在相当严格的条件下，平均每个个体识别出 2.6 个伪外显子激活事件。在 5' 供体剪接位点中发现的假外显子激活事件比在 3' 受体剪接位点中更多。尽管伪外显子激活事件偶尔被报道为遗传性疾病的致病突变，但本研究表明，此类事件可以在正常个体中以一定的频率观察到。我们估计人类基因组通常平均包含至少 10 个伪外显子激活事件。实际数字应该比这个更高，因为我们使用了严格的标准来识别伪外显子激活事件。这表明，如果在编码区或 RNA 剪接位点中未识别出候选突变，则在寻找遗传性疾病的致病突变时，值得考虑假外显子激活的可能性。