Phylostratic shift of whole‐genome duplications in normal mammalian tissues towards unicellularity is driven by developmental bivalent genes and reveals a link to cancer

Abstract

Tumours were recently revealed to undergo a phylostratic and phenotypic shift to unicellularity. As well, aggressive tumours are characterized by an increased proportion of polyploid cells. In order to investigate a possible shared causation of these two features, we performed a comparative phylostratigraphic analysis of ploidy‐related genes, obtained from transcriptomic data for polyploid and diploid human and mouse tissues using pairwise cross-species transcriptome comparison and principal component analysis. Our results indicate that polyploidy shifts the evolutionary age balance of the expressed genes from the late metazoan phylostrata towards the upregulation of unicellular and early metazoan phylostrata. The up-regulation of unicellular metabolic and drug‐resistance pathways and the downregulation of pathways related to circadian clock were identified. This evolutionary shift was associated with the enrichment of ploidy with bivalent genes (p < 10−16). The protein interactome of activated bivalent genes revealed the increase of the connectivity of unicellulars and (early) multicellulars, while circadian regulators were depressed. The mutual polyploidy‐c‐MYC‐bivalent genes-associated protein network was organized by gene‐hubs engaged in both embryonic development and metastatic cancer including driver (proto)‐oncogenes of viral origin. Our data suggest that, in cancer, the atavistic shift goes hand‐in‐hand with polyploidy and is driven by epigenetic mechanisms impinging on development‐related bivalent genes.