Properties of structural variants and short tandem repeats associated with gene expression and complex traits

Abstract

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits.

Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats

“…Furthermore, the gnomAD variants that wham and manta uniquely identified in the 75 iPSCORE samples were overwhelmingly deletions (429/583 SVs, 83.6%) rather than the small duplications that are missing from i2QTL relative to gnomAD. These results indicate that the i2QTL SV call set contains a large fraction of common SVs in Europeans discoverable using short read sequencing data as well as new, rare SVs, making it a valuable resource for examining functional differences between the SV classes 53 .…”

“…Given the large amount of GWAS and QTL studies performed using genotyping arrays, we next asked to what extent different classes of SVs and STRs are tagged by SNPs and indels. For each of the 42,921 common (NMAF > 0.05) SVs and STRs that were within 1 MB of an expressed gene, we calculated the maximum linkage disequilibrium (LD) in i2QTL Europeans with SNPs/indels within 50 kb (Methods) 53 . We found that 97.7% of STRs are tagged by an SNP or indel with R 2 > 0.8 while SVs classes ranged from 44.2% to 86.7% of variants tagged with R 2 > 0.8 (Fig.…”

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

“…These methods should have broad applications in various fields of research and medicine, from forensic medicine to population genetics for instance. STR length variations have notably been shown to influence gene expression and, similar to expression quantitative trait loci (eQTLs), several expression STR (eSTR) have been identified 46,47 . Their exact mode of action still remain largely elusive but, the majority of eSTRs appears to act by global mechanisms, in a tissue-agnostic manner 46 .…”

“…flanking sequences and directional transcription). Using transcription level of STRs, as predicted by our CNN models for instance, coupled with length variations 46,47 , may help to take into account the impact of genetic variants located in sequences surrounding STRs, and to refine eSTR computations.…”

“…Notably, to avoid any bias linked to CAGE noise signal observed along STRs, we decided to predict a signal normalized by the STR length. Therefore, our models do not allow to properly assess the contribution of STR length in transcription, although it clearly represents the most studied features of STRs 21,46,47 . Note that simply increasing the quality of the reads considered (using Q20 instead of Q3 filter) yielded sparse data and decreased the performance of our model.…”