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Using meta-analyses, we introduce a unicellular attractor (UCA) model integrating essential features of the 'atavistic reversal', 'cancer attractor', 'somatic mutation', 'genome chaos', and 'tissue organization field' theories. The 'atavistic reversal' theory is taken as a keystone. We propose a possible mechanism of this reversal, its refinement called 'gradual atavism', and evidence for the 'serial atavism' model. We showed the gradual core-to-periphery evolutionary growth of the human interactome resulting in the higher protein interaction density and global interactome centrality in the UC center. In addition, we revealed that UC genes are more actively expressed even in normal cells. The modeling of random walk along protein interaction trajectories demonstrated that random alterations in cellular networks, caused by genetic and epigenetic changes, can result in a further gradual activation of the UC center. These changes can be induced and accelerated by cellular stress that additionally activates UC genes (especially during cell proliferation), because the genes involved in cellular stress response and cell cycle are mostly of UC origin. The functional enrichment analysis showed that cancer cells demonstrate the hyperactivation of energetics and the suppression of multicellular genes involved in communication with the extracellular environment (especially immune surveillance). Collectively, these events can unleash selfish cell behavior aimed at survival at all means. All these changes are boosted by polyploidization. The UCA model may facilitate an understanding of oncogenesis and promote the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

DNA replication during cell proliferation is 'vertical' copying, which reproduces an initial amount of genetic information. Polyploidy, which results from whole-genome duplication, is a fundamental complement to vertical copying. Both organismal and cell polyploidy can emerge via premature cell cycle exit or via cell-cell fusion, the latter giving rise to polyploid hybrid organisms and epigenetic hybrids of somatic cells. Polyploidy-related increase in biological plasticity, adaptation, and stress resistance manifests in evolution, development, regeneration, aging, oncogenesis, and cardiovascular diseases. Despite the prevalence in nature and importance for medicine, agri- and aquaculture, biological processes and epigenetic mechanisms underlying these fundamental features largely remain unknown. The evolutionarily conserved features of polyploidy include activation of transcription, response to stress, DNA damage and hypoxia, and induction of programs of morphogenesis, unicellularity, and longevity, suggesting that these common features confer adaptive plasticity, viability, and stress resistance to polyploid cells and organisms. By increasing cell viability, polyploidization can provide survival under stressful conditions where diploid cells cannot survive. However, in somatic cells it occurs at the expense of specific function, thus promoting developmental programming of adult cardiovascular diseases and increasing the risk of cancer. Notably, genes arising via evolutionary polyploidization are heavily involved in cancer and other diseases. Ploidy-related changes of gene expression presumably originate from chromatin modifications and the derepression of bivalent genes. The provided evidence elucidates the role of polyploidy in evolution, development, aging, and carcinogenesis, and may contribute to the development of new strategies for promoting regeneration and preventing cardiovascular diseases and cancer. [ABSTRACT FROM AUTHOR]

The transcriptome consists of various gene modules that can be mutually dependent, and ignoring these dependencies may lead to misinterpretation. The most important problem is module dependence on cell‐cycle activity. Using meta‐analysis of over 30 000 single‐cell transcriptomes, we show gene module dependencies on cell‐cycle signature, which can be consistently observed in various normal and cancer cells. Transcript levels of receptors, plasma membrane, and differentiation‐related genes are negatively regressed on cell‐cycle signature. Pluripotency, stress response, DNA repair, chromatin remodeling, proteasomal protein degradation, protein network connectivity, and unicellular evolutionary origin are regressed positively. These effects cannot be explained by partial overlap of corresponding gene sets because they remain if the overlapped genes were removed. We propose a visual analysis of gene module‐specific regression lines as complement to an uncurated enrichment analysis. The different lines for a same gene module indicate different cell conditions. The approach is tested on several problems (polyploidy, pluripotency, cancer, phylostratigraphy). Intriguingly, we found variation in cell‐cycle activity, which is independent of cell progression through the cycle. The upregulation of G2/M checkpoint genes with downregulation of G2/M transition and cytokinesis is revealed in polyploid cells. A temporal increase in cell‐cycle activity at transition from pluripotent to more differentiated state is found in human embryonic stem cells. The upregulation of unicellular interactome cluster in human cancers is shown in single cells with control for cell‐cycle activity. The greater scatter around regression line in cancer cells suggests greater heterogeneity caused by deviation from a line of normal cells. [ABSTRACT FROM AUTHOR]

It is shown here that in the yeast protein interaction network the global centrality measure (betweenness) depends on the protein evolutionary age (i.e., on historic contingency) more weakly than the local centrality measure (degree). This phenomenon is not observed in mutational duplication-and-divergence models. The network domains responsible for this difference deal with DNA/RNA information processing, regulation, and cell cycle. A selection vector can operate in these domains, which integrates the network activity and thus compensates for the process of mutational divergence. [ABSTRACT FROM AUTHOR]