Polyploidy (PLD) is a common event in development and aging [1]. Also, it may be induced by physiological and pathological stresses [2]. Currently, PLD attracts much attention because of its links to regeneration, tumor initiation and drug resistance [3-5]. Aim: To understand the evolutionary nature of these links, we investigated the effects of PLD on transcriptome in homologous human and mouse tissues differed by PLD (heart, liver and placenta). Methods: The methods of bioinformatic data analysis and analysis of principal components (PCA), cross-species transcriptome comparison (TC), phylostratigraphy, protein interaction network (PIN) and gene module investigation were used. Results: We show that polyploidy exerts common effects on various cell types. The main PLD-related effects were the up-regulation of gene modules and PIN clusters increasing adaptation and transformation, including oncogene signaling, growth, development, drug metabolism, adaptation to stress and hypoxia and epithelial to mesenchymal transition. PLD-inhibited gene modules were involved mainly in differentiation and immunity. To find out whether PLD activates molecular programs of unicellular organisms that can trigger cancer, we applied the method of phylostratigraphy. The analysis revealed the enrichment of PLD-induced genes with genes from evolutionary ancient phylostrates (from procaryota, eucaryota, and opistokontha). In particular, these genes were implicated in drug resistance and ABC transporters. Accordingly, PLD-inhibited genes were enriched in evolutionary young phylostrates (bilateria, chordata, amniota and mammalia). These genes participated mostly in immunity, multicellular organism processes and differentiation. Conclusion: PLD causes de-speciation by restructuring transcription towards the up-regulation of the early phylogenetic unicellular strates (cellular organisms to opistokonta) and down-regulation of the multicellularian complexity strates from (bilateralia to mammalia) indicating together with literature data concerning cancer [1, 2, 3] that cancer-induced phylogenetic shift is associated with polyploidy component. References: [1] Vinogradov AE. 2010. Genomics. 95:345-354. [2] Trigos AS, et al. 2017. Proc Natl Acad Sci U S A.114:6406-6411. [3] Erenpreisa, et al. 2018. Cancer Hypothesis. 1: 1-20