Exceptions to Broad Tissue-Specific Transcriptomic Interdependence: Searching for Independence in Expression of Genes.

Correlation of genes within tissues has attracted much attention. In contrast, genes that are INDependent In Expression (INDIE) remain poorly understood, even though they may represent tissue admixtures, reflect new regulatory mechanisms, either transcriptional or post-transcriptional, and contribute to biomarkers or machine learning algorithms. We hypothesised that INDIE genes can be found, may remain uncorrelated across tissues, and replicate within tissues in external datasets. Biweight midcorrelation was calculated for each gene against all other genes with sufficiently high expression in the given tissue from the GTEx dataset v8, along with the means of absolute values of obtained correlation coefficients. The threshold for gene designation as INDIE was both absolute (r) and relative (Z-score), while the threshold for external validation in the whole blood (four datasets) and the ileum (two datasets) was relative. Only one gene, RPL13P12, was INDIE in all the analysed GTEx tissues, but it did not replicate in the external datasets. In contrast, HIST1H2AD and TMEM176B were not only INDIE in GTEx whole blood but also replicated in all four external datasets, despite their heterogeneity. Moreover, ACAT2 replicated in both external ileal datasets. The haemoglobin gene HBB belonged to most widespread INDIE genes in various GTEx tissues and was validated in an external ileal dataset, pointing towards the importance of tissue heterogeneity in bulk samples. A set of genes exhibiting independent expression patterns across various tissues of GTEx was described. Results for each tissue are made available. Even though many findings can be explained by tissue heterogeneity, some results point towards interesting mechanisms of gene expression regulation.