Detecting Transcriptomic Structural Variants in Heterogeneous Contexts via the Multiple Compatible Arrangements Problem


Transcriptomic structural variants (TSVs) — structural variants that affect expressed regions — are common, especially in cancer. Detecting TSVs is a challenging computational problem. Sample heterogeneity (including differences between alleles in diploid organisms) is a critical confounding factor when identifying TSVs. To improve TSV detection in heterogeneous RNA-seq samples, we introduce the extsc{Multiple Compatible Arrangement Problem} (MCAP), which seeks k genome rearrangements to maximize the number of reads that are concordant with at least one rearrangement. This directly models the situation of a heterogeneous or diploid sample. We prove that MCAP is NP-hard and provide a 14-approximation algorithm for k=1 and a 34-approximation algorithm for the diploid case (k=2) assuming an oracle for k=1. Combining these, we obtain a 316-approximation algorithm for MCAP when k=2 (without an oracle). We also present an integer linear programming formulation for general k. We completely characterize the graph structures that require k>1 to satisfy all edges and show such structures are prevalent in cancer samples. We evaluate our algorithms on 381 TCGA samples and 2 cancer cell lines and show improved performance from the state-of-the-art TSV-calling tool, SQUID.

19th International Workshop on Algorithms in Bioinformatics (WABI 2019) 18:1–18:19 (2019); journal version in Alg Mol Bio (2020)