Abstract
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 (~ 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.
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Availability of data and material
The data used in the current study are as follows: Nanopore MinION long-read sequencing data for sample RK067 are available from the Japanese Genotype–phenotype Archive (JGA) database (https://ddbj.nig.ac.jp/jga/viewer/view/studies) under accession number JGAS00000000180. Nanopore MinION long-read sequencing data for sample NA18943 are available from the DNA Data Bank of Japan (DDBJ) Sequence Read Archive (DRA) (https://www.ddbj.nig.ac.jp/dra/index-e.html) under accession number DRA008482. The reference panel used for the imputation in the current study is not publicly available due to the risk of compromise of participants’ privacy but is available from the corresponding author on reasonable request. Other web resources or tools used in this study are as follows: IMSindel software: https://github.com/NCGG-MGC/IMSindel; PLINK: https://www.cog-genomics.org/plink2; IMPUTE2: http://mathgen.stats.ox.ac.uk/impute/impute_v2.html; MatrixeQTL: http://www.bios.unc.edu/research/genomic_software/Matrix_eQTL/; CAVIAR: http://genetics.cs.ucla.edu/caviar/. RepeatMasker software developed by A.F.A. Smit, R. Hubley, and P. Green; see http://www.repeatmasker.org/. All statistical tests were conducted in R (ver3.5.0): https://www.r-project.org/. GTEx portal database: http://gtexportal.org/home/. Gene expression data for 82 Japanese HapMap samples used for the eQTL association analysis were obtained from EMBL-EBI ArrayExpress under accession E-MTAB-264 (Montgomery). Published GWAS association results are available from NHGRI-EBI Catalogue of published GWAS: https://www.ebi.ac.uk/gwas/home. Super-enhancer regions data are available from dbSUPER (http://asntech.org/dbsuper/). CTCF-binding site data are available from CTCFBSDB2.0 (http://insulatordb.uthsc.edu/). Ensembl regulatory regions data were obtained using BioMart for Ensembl Release 93 (https://grch37.ensembl.org/info/index.html). UCSC phastCons genome conservation scores are available from the UCSC genome browser (http://hgdownload.cse.ucsc.edu/goldenpath/hg19/phastCons46way/).
Code availability
Source code is available from https://github.com/Saeideh-Ashouri/Intermediate-Sized-Insertions
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The super-computing resource was provided by Human Genome Center, the Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html).
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This research was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 19km0405207h0004 (to AF), 20km04052 (to AF), and 20km0405205 (to KT).
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All the authors contributed to the study conception and design. Akihiro Fujimoto designed the study. Saeideh Ashouri performed the computational analyses and the experiments. Saeideh Ashouri, Jing Hao Wong, Hidewaki Nakagawa, Mihoko Shimada, Katsushi Tokunaga, and Akihiro Fujimoto interpreted the results. Saeideh Ashouri, Jing Hao Wong, and Akihiro Fujimoto wrote the first draft of manuscript, and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.
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Ashouri, S., Wong, J.H., Nakagawa, H. et al. Characterization of intermediate-sized insertions using whole-genome sequencing data and analysis of their functional impact on gene expression. Hum Genet 140, 1201–1216 (2021). https://doi.org/10.1007/s00439-021-02291-2
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DOI: https://doi.org/10.1007/s00439-021-02291-2