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

Abstract

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42×) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

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

“…eQTL mapping. We performed a cis-eQTL analysis using RNA sequencing data from iPSCs derived from 398 donors in the iPSCORE and HipSci projects along with a comprehensive map of genetic variation (37,296 SVs,588,189 STRs, and~48 M SNVs and indels (Supplementary Data 1)) generated using deep WGS from these same donors 4 . These variants include several classes of SVs including biallelic duplications and deletions; multi-allelic copy number variants (mCNVs); mobile element insertions (MEIs) including LINE1, ALU, and SVA; reference mobile element insertions (rMEI); inversions; and unspecified break-ends (BNDs).…”

“…Variant size influences eQTL associations. Given that SVs and STRs have size ranges that span orders of magnitude 4 , we sought to examine the relationship between variant length and the likelihood of being an eVariant across the different variant classes. We tested whether STRs or deletions, duplications, and mCNVs longer than a particular length threshold were more likely to be eVariants compared to variants shorter than the length threshold.…”

“…We anticipate that these properties of SV and STR eQTLs will be useful for identifying causal variants underlying eQTLs and delineating mechanisms by which structural variation can impact gene expression. The collection of eQTLs identified here, along with the catalog of high-quality SVs and STRs described in a companion paper 4 , provide a powerful resource for future studies examining how these variants regulate gene expression and contribute to variation in complex traits.…”

“…tructural variants (SVs) and short tandem repeats (STRs) are important categories of genetic variation that account for the majority of base pair differences between individual genomes and are enriched for associations with gene expression [1][2][3] . SVs and STRs are comprised of several diverse classes of variants (e.g., deletions, insertions, multi-allelic copy number variants (mCNVs), and mobile element insertions (MEIs)), and multiple algorithmic approaches and deep whole genome sequencing are required to accurately identify and genotype variants in these different classes 4 . Due to the complexity of calling SVs and STRs, previous genetic association studies have generally not identified a comprehensive set of these variants but rather have focused on one or a few of the class types, and therefore the genomic properties of SVs and STRs associated with gene expression and/or complex traits are not well characterized.…”

“…In this study, as part of the i2QTL Consortium, we use RNAsequencing data from induced pluripotent stem cells (iPSCs) from the iPSCORE and HipSci collections 7,16,17 along with a comprehensive call set of SVs and STRs from deep WGS data 4 to identify variants associated with iPSC gene expression and characterize the genomic properties of these SV and STR eQTLs. We observe that SVs are more likely to act as eQTLs than SNVs when in distal regions (> 100 kb from eGenes) and that duplications and mCNVs are more likely to have distal eQTLs and multiple eGenes compared to other SVs classes and STRs.…”