Joint analysis of sQTL and Hi-C reveals spatial proximity between sQTLs and target genes in cancer tissues.

Gene expression and regulation with or without alternative splicing are crucial for tissues and cells to function correctly. They have been studied from three almost independent perspectives at the genome level: 1- Recognition of splicing quantitative trait loci (sQTLs), 2- Expression quantitative trait loci (eQTLs) recognition, and 3- Recognition of longer-range physical chromatin interactions between genome segments which model 3D dynamics of cells and tissues. Even though the associations between eQTLs and longer-range chromatin interactions have been previously studied, a similar relationship between sQTLs and chromatin interactions has yet to be analyzed. In this case, examining whether sQTLs control the alternative splicing of their target genes' mRNA via physically interacting genome segments is crucial. We have jointly analyzed high-throughput chromatin conformation capture (Hi-C) and sQTL datasets over eight human cancer tissues. We have discovered a positive association between the number of genes having sQTLs and chromatin interaction frequency. Such a positive association still exists when we also control for eQTLs. Additionally, sQTLs and their target genes generally exist inside identical topologically associating domains (TADs). These findings are observed over the whole set of analyzed cancer types and functional subsets of the sQTL dataset, such as survival-related sQTLs. Furthermore, tissue-specific sQTLs are statistically enriched in tissue-specific frequently interacting regions (FIREs) in 6 out of 8 human cancer tissues (Chronic Myeloid Leukemia, Colon Adenocarcinoma, Acute Myeloid Leukemia, Lung Adenocarcinoma, Prostate Cancer, Sarcoma). Our sQTL and Hi-C datasets have shown the existence of closer spatial distance between sQTLs and their target genes with possible alternative splicing across several different cancer types in humans. Such a closer spatial distance also exists, independent of whether we integrate eQTLs into the analysis. We found that sQTLs regulate alternative splicing through chromatin interactions. Source code of the analysis in this research is available on https://github.com/seferlab/sqtlhic .