Discovery of tandem and interspersed segmental duplications using high-throughput sequencing

Abstract

Motivation Several algorithms have been developed that use high-throughput sequencing technology to characterize structural variations (SVs). Most of the existing approaches focus on detecting relatively simple types of SVs such as insertions, deletions and short inversions. In fact, complex SVs are of crucial importance and several have been associated with genomic disorders. To better understand the contribution of complex SVs to human disease, we need new algorithms to accurately discover and genotype such variants. Additionally, due to similar sequencing signatures, inverted duplications or gene conversion events that include inverted segmental duplications are often characterized as simple inversions, likewise, duplications and gene conversions in direct orientation may be called as simple deletions. Therefore, there is still a need for accurate algorithms to fully characterize complex SVs and thus improve calling accuracy of more simple variants. Results We developed novel algorithms to accurately characterize tandem, direct and inverted interspersed segmental duplications using short read whole genome sequencing datasets. We integrated these methods to our TARDIS tool, which is now capable of detecting various types of SVs using multiple sequence signatures such as read pair, read depth and split read. We evaluated the prediction performance of our algorithms through several experiments using both simulated and real datasets. In the simulation experiments, using a 30× coverage TARDIS achieved 96% sensitivity with only 4% false discovery rate. For experiments that involve real data, we used two haploid genomes (CHM1 and CHM13) and one human genome (NA12878) from the Illumina Platinum Genomes set. Comparison of our results with orthogonal PacBio call sets from the same genomes revealed higher accuracy for TARDIS than state-of-the-art methods. Furthermore, we showed a surprisingly low false discovery rate of our approach for discovery of tandem, direct and inverted interspersed segmental duplications prediction on CHM1 (<5% for the top 50 predictions). Availability and implementation TARDIS source code is available at https://github.com/BilkentCompGen/tardis, and a corresponding Docker image is available at https://hub.docker.com/r/alkanlab/tardis/. Supplementary information Supplementary data are available at Bioinformatics online.

Population Structure, Stratification and Introgression of Human Structural Variation

“…The reasoning for this is the possible misclassification of variant class (e.g. insertion vs duplication, in addition some inversions identified in the 1KG have since been shown to be inverted 730 duplications and deletions (Soylev et al, 2019)). This analysis shows 78% of variants in our callset not to be present in either the 1000G or SGDP callsets.…”

VALOR2: characterization of large-scale structural variants using linked-reads

“…We tested VALOR2 using both simulated and real data sets to compare the precision and recall rates of VALOR2 with the state-of-the-art tool that use linkedread sequencing (Long Ranger [29]), three tools that use only short-read WGS data sets (DELLY [40] LUMPY [11], TARDIS [12,35]), and one that uses long read WGS data sets (Sniffles [41]). For LUMPY, we used the smoove wrapper as recommended by the authors.…”

“…Note that it is still possible to identify increase in SD copy number using read depth signature [33,34]; however, no linked-read-based method yet exists to anchor a new SD (i.e., find their insertion locations). We note that the TARDIS algorithm [35] can locate new SDs; however, it is developed for short-read sequencing data only; therefore, it can find only short duplications (up to 10 kbp) copied to a distance of up to 50 kbp.…”

Towards a better understanding of the low recall of insertion variants with short-read based variant callers

“…Another alternative, less described, could be the use of dedicated tools for each type of insertion, instead of using only generalpurpose SV callers. Among them, Expansion Hunter has been designed to detect tandem repeats, Pamir and Popins for novel insertions and TARDIS for large duplications [28,29,30,31].…”