It’s a TAD Complicated: Detecting Genomic Structural Alterations Using TAD Delineated Gene Expression Data

ABSTRACT Genomes are biologically complex entities where an alteration in structure can yield no effect, or have a devastating effect on many pathways. Most of the focus has been on translocations that generate fusion proteins. However, this is only one of many outcomes. Recent work suggests alterations in topologically associated domains (TADs) can lead to changes in gene expression. It is hypothesized that alterations in genome structure can disrupt TADs leading to an alteration in the variability of gene expression within the contained gene expression neighborhood defined by the TAD. To test this hypothesis, variability of gene expression for genes contained within TADs between 37 cancer cell lines from the NCI-60 cell line panel was compared with normal expression data for the corresponding tissues of origin. Those results were correlated with the data on structural events within the NCI-60 cell lines that would disrupt a TAD. It was observed that 2.4% of the TADs displayed altered variance in gene expression when comparing cancer to normal tissue. Using array CGH data from the cancer cell lines to map breakpoints within TADS, it was discovered that altered variance is always associated with a TAD disrupted by a breakpoint, but a breakpoint within a TAD does not always lead to altered variance. TADs with altered variance in gene expression were no different in size than those without altered variance. There is evidence of recurrent pan-cancer alteration in variance for eleven genes within two TADs on two chromosomes (Chromosome 10 & 19) for all 37 cell lines. The genes located within these TADs are enriched in pathways related to RNA processing. This study supports altered variance as a signal of a breakpoint with a functional consequence.