Comparative Transcriptomics Suggests that Breast Secretory Epithelium Reuses Gene Repertoires Conserved Across...

The emergence of novel organs is often attributed to lineage-specific innovation; however, accumulating evidence suggests that many complex traits arise through the regulatory redeployment of conserved molecular components. From a molecular evolutionary perspective, an unresolved question is how preexisting gene repertoires are reorganized to generate tissue-specific functions. Here, we examine the molecular evolutionary organization of gene expression programs in human breast tissue by situating its transcriptome within a comparative framework of epithelial tissues with secretory functions. Using bulk RNA-seq data from the GTEx project, combined with co-expression network analysis, single-cell reference integration, and cross-vertebrate orthology assessment, we identify gene expression modules that are broadly shared across epithelial secretory tissues, relatively enriched in breast tissue, or biased toward female breast samples. We show that genes enriched in breast tissue are largely evolutionarily conserved across vertebrates and are embedded within transcriptional modules shared with other epithelial secretory organs. Co-expression analysis revealed partial overlap between breast modules and those of other epithelial secretory tissues, particularly in pathways related to secretion, vesicle trafficking, and extracellular matrix organization. Together, these results support a model in which breast secretory epithelium achieves tissue specialization through integration of conserved vertebrate gene repertoires, rather than through extensive emergence of mammal-specific genes.