Characterization of intermediate-sized insertions using whole-genome sequencing data and analysis of their functional impact on gene expression
Characterization of intermediate-sized insertions using whole-genome sequencing data and analysis of their functional impact on gene expression
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DOI：
10.1007/s00439-021-02291-2
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发表时间：
2021-05-12
期刊：
影响因子：
5.3
通讯作者：
Fujimoto, Akihiro
中科院分区：
文献类型：
--
作者：
Ashouri, Saeideh;Wong, Jing Hao;Fujimoto, Akihiro
中等大小的插入是有助于基因组多样性的结构变异之一。然而，由于鉴定它们的技术困难，它们在疾病致病性和基因表达调控中的重要性仍然不清楚。我们使用174个日本样本的全基因组测序数据，使用高精度插入调用方法（IMSindel软件和联合调用恢复）来表征中等大小的插入，并获得了4254个插入的目录。我们构建了一个由所有样本的插入和SNV组成的插补小组，并对82个公开的日本样本进行了中等大小插入的插补。使用Nanopore长读取测序数据评估的插补的阳性预测值为97%。随后的eQTL分析预测128（类似于3.0%）插入作为基因表达水平变化的原因。基因组调控元件的因果插入的富集分析显示与CTCF结合位点、超级增强子和启动子显著相关。在与GWAS命中相同的因果集中发现的17个因果插入中，有与癌症相关基因（如BRCA 1，ZNF 222和ABCB 10）表达变化相关的插入。对插入序列的分析表明，461个插入片段是常见于基因组早期复制区的短串联重复。此外，在我们以前的研究中，在同一样本集中检测到的中等大小的插入和中等大小的缺失的功能重要性的比较表明，插入更频繁的基因区域，和功能候选人的比例较小的插入。在这里，我们描述了一组高置信度的中等大小的插入，并指出它们在基因表达调控中的重要性。我们的研究结果强调了在性状关联研究中考虑中等大小插入的重要性。
Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Positive Predictive Value of imputation, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (similar to 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early-replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.