The detection of covariation of mRNA levels of large sets of genes across multiple human populations

In this study we report that, measured in human lymphoblastoid cell lines (LCLs), different individuals exhibit correlated changes in the mRNA levels of multiple groups of genes; the largest group of genes such variation contains 2168 members and over 52% of all genes expressed in these cell lines are members of one or more groups. We show that these gene groups are replicable across different human populations and across different methods of analysis, supporting the view that the covariation is caused by biological and not experimental batch effects. This view is also supported by enrichment in the covarying genes of single and combinations of transcription factors (TFs) binding to cognate promoter regions, enrichment of genes shown to be sensitive to the knockdown of individual TFs and by enrichment of functional pathways and finally of protein-protein interactions. The properties of the groups of genes are therefore most readily explained by the influence of cumulative variations in the effectors of gene expression that act in trans on cognate genes. We suggest that covariation has functional outcomes by showing that covariation of 83 genes involved in the spliceosome pathway accounts for 21-43% of the variation in the alternative splicing patterns of genes expressed in human LCLs.