Reflections from a Workshop by Nivedita Mukherjee1 and Mateus de Oliveira Lisboa2
1National Centre for Biological Sciences, Tata Institute of Fundamental Research, 560065, India (NCBS-TIFR)
2Core for Cell Technology, School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná (PUCPR)
Last November, a unique gathering took place at Fanhams Hall in Hertfordshire, UK, for The Company of Biologists’ workshop titled “Decoding Whole Genome Doubling: Insights from Evolution, Development, and Disease.” Organised by Renata Basto and Zuzana Storchova, the workshop brought together a highly interdisciplinary cohort of scientists studying whole-genome doubling (WGD) across organisms, from flies and frogs to plants and humans.
As two of ten early-career researchers selected to participate, we had the rare opportunity to engage in close discussions with leaders in the field, present our own work, and explore the diverse biological contexts in which the entire chromosomal complement of a cell is doubled, changing its ploidy – the number of copies of the genome. Across three intense days, we uncovered how such changes can drive cellular adaptations, precipitate disease, and drive evolutionary innovation.
A Biological Balancing Act
Ploidy variation is ubiquitous in biology. Even within a single organism, cells often carry different numbers of genome copies depending on the tissue type and developmental stage. For example, while humans are diploid as a species, polyploid cells are routine in organs such as the liver, heart and pancreas. These can arise from either programmed or accidental WGD, resulting from the skipping of one or more cell-cycle steps or through cell fusion. Once polyploidy arises, the cell is thrust into a new regime, one that demands extensive adaptation if it is to continue functioning or proliferating without compromising genome integrity.
Initial responses to genome doubling can be defensive. DNA damage and stress-response pathways are activated, and cell death is a common outcome unless these surveillance mechanisms are suppressed. Survival alone, however, is not enough. To continue to divide successfully, polyploid cells must carefully segregate their excess chromosomes. This often involves re-establishing functional mitotic spindles despite the presence of supernumerary centrosomes. Several talks highlighted molecular strategies that allow polyploid cells to survive and divide by rewiring apoptotic signalling and stabilising centrosome numbers.
Bigger Cells, Bigger Questions
Polyploid cells aren’t just more complex; they’re physically larger. This increase in volume comes with consequences: intracellular transport must traverse greater distances, metaphase spindles must span wider plates, and increased metabolic demands must be sustained. Several speakers described how these physicochemical constraints can be systematically probed using in silico models alongside in vitro perturbations.
Beyond these geometric and energetic challenges, it is tempting to assume that increased DNA content translates to increased gene expression. However, multiple presentations demonstrated that gene expression scales unevenly and nonlinearly with ploidy, with pronounced disparities between transcript abundance and protein yield. In some contexts, specific genes are selectively up- or down-regulated, rewiring the cell’s regulatory network in unexpected ways. This decoupling of genome content from functional output overturns the view of polyploid cells as merely “amplified” versions of their diploid counterparts.
Genomic Instability and Interventions
For a cell, doubling its genome is not always a deliberate developmental strategy or a trivial bookkeeping error; it is often a high-risk gamble. Cardiomyocytes, for instance, become increasingly polyploid with age or heart disease, accompanied by a substantial accumulation of mutations. Whether polyploidy in such settings is adaptive, maladaptive, or merely tolerated remains an open question—one that echoes broader uncertainties about where normal physiology ends, and pathology begins.
Polyploidy-related genomic instability is also characteristic of cancer, with genome-doubled tumours showing many more chromosomal aberrations than diploid tumours. While high levels of such aberrations can be lethal, genome doubling also casts a paradoxical safety net by creating “genomic backups” that restore essential functions. At its extremes, WGD-induced genomic instability can be spectacular. One striking example is chromothripsis, where mis-segregated chromosomes trapped within micronuclei shatter and reassemble in chaotic ways, creating the genomic equivalent of a misassembled jigsaw puzzle.
A silver lining is that, while such drastic mutational events can accelerate cancer cell evolution, their dependence on these aberrant states may also be their undoing. Because WGD imposes unique cellular stresses, polyploid cancer cells acquire distinct vulnerabilities that may be therapeutically exploitable. The workshop highlighted several efforts to leverage these weaknesses, offering hope for selective treatments that preferentially target cancer cells while sparing normal tissue.
Innovation Across Evolutionary Time
At the macro scale, genome doubling acts as a powerful driver of evolutionary change. Ancient WGDs have profoundly shaped the genomes of present-day microorganisms, plants, and vertebrates, with recent events producing drought-resistant plants, pest-resistant crops, and amphibians adapted to arid environments. Polyploid lineages often adapt rapidly, restructuring physiological and metabolic pathways, and frequently adopting self-pollination or asexual reproductive strategies to overcome early barriers to evolutionary establishment.
Across the tree of life, WGD is frequently followed by episodes of rapid diversification, though these bursts typically occur only after a delay. This “radiation lag” is thought to reflect the time required for re-diploidisation, during which redundant genomic content is reduced, and ohnologues or duplicated genes diverge in function. As gene dosage is re-balanced and new regulatory networks emerge, WGD becomes a springboard for long-term evolutionary innovation.
Such innovations may confer resilience during periods of ecological upheaval. Compelling evidence for this comes from the observation that WGD events in the evolutionary history of species are disproportionately clustered around major extinction events, such as the Cretaceous–Palaeogene boundary. Interestingly, environmental stressors, such as extreme heat or cold, can induce the formation of unreduced gametes, providing a direct link between ecological pressures and the origin of polyploid species.
A Shared Language for Polyploidy
Amid the breadth of scientific discussions at the workshop, one unifying theme stood out: WGD is neither an anomaly nor a biological accident. From plants surviving climate shifts to tumours evading physiological checks, genome doubling repeatedly emerges as a powerful strategy in life’s toolkit. Yet it remains a double-edged sword, capable of driving adaptation or unleashing instability.
This raises big questions. In healthy tissues, polyploidy seems to balance on a knife-edge between careful regulation and stochasticity. Understanding this balance could reveal why certain cells become polyploid, how tissues keep their abundance in check, and what stops them from turning cancerous. In cancer cells, it’s still unclear if WGD is a driving force or a downstream manifestation of genomic instability. Moreover, scientists are still figuring out how evolutionary pressures shape newly formed and established polyploid lineages, and how the opportunities for adaptation and diversification play out across different tissues and species.
What the field now needs is a shared language across disciplines. Polyploidy in microbes, plants, animals, cancer, and development has too often been studied in silos. By integrating these perspectives, we may finally decipher how a single genomic event reverberates from the scale of individual cells all the way to the evolution of multicellular species.
This workshop marked a step in that direction, and for us, a turning point in our understanding of what it means to live with, adapt to, and evolve through an extra genome.
Mateus de Oliveira Lisboa is a PhD student at the Core for Cell Technology, PUCPR (Brazil), studying how whole-genome doubling shapes cell fate, evolution, and disease. With a background in chromosome biology, stem cells, and the cancer microenvironment, he integrates molecular biology and bioinformatics to explore the causes and consequences of large-scale genomic alterations, always through an evolutionary lens. Outside the lab, he explores mountains, photography, astronomy, and birds.
Nivedita Mukherjee is a PhD student at the National Centre for Biological Sciences (NCBS–TIFR), Bengaluru, India, where she studies cancer evolution through the computational analysis of large-scale genomics datasets. Her research integrates statistical genomics and evolutionary theory to examine how whole-genome doubling reshapes selective pressures in cancer. Beyond research, Nivedita writes popular science articles and enjoys singing, travelling, photography, and reading.
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