Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

Abstract

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.

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

“…However, LOH at a few specific loci is different from generalized LOH produced by mitotic recombination, which entails a loss of complementation for thousands of genes distal to the site of crossing over, including numerous non-driver genes that are essential for the cell [ 62 , 63 , 64 ], and is more likely to be overall deleterious for cells. In tumors, gene expression is higher for genes conserved with unicellular organisms, which have generally systemic effects (such as housekeeping genes) than for genes of metazoan origin [ 65 , 66 ], especially in polyploid cancer cells [ 67 ]; therefore, the coordinated expression of interacting multicellularity and unicellularity processes is lost in cancer progression, and LOH may enhance this mismatch. It has been suggested [ 68 ] that the unmasking of recessive deleterious alleles may not be critical because the compensatory growth of the remaining viable cells allows that clonal lineage to thrive anyway.…”

Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue

“…Then, through depolyploidization, Hayflick’s limit is renewed, cells regain synchronization between CC, and the cell cycle and mitotic cell cycle are activated [ 6 ]. Other studies also indicate the importance of polyploidy during cancer development [ 7 , 8 ]. To answer to the question, “what is the reason for cancer, and what is the mechanism of its development”, it is necessary to combine existing theories into one unified theory on the basis of which it will be possible to interpret all phenomena (including that the occurrence of which is considered paradoxical) observed during cancer transformation and development.…”

Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers

“…Microarray and RNA sequencing analyses of sorted diploid and polyploid mouse hepatocytes did not identify clear transcriptional differences between diploid and polyploid hepatocytes [ 31 , 32 ]. On the other hand, some studies have suggested that polyploidy in hepatocytes affects cellular biological processes, such as lipid and carbohydrate metabolism; however, no consensus has been established with respect to the results [ 33 , 34 , 35 ]. A recent study in which mouse liver cells were analyzed by single-nucleus RNA sequencing after ploidy-based sorting provided many important insights into the expression patterns of polyploid hepatocytes [ 36 ].…”