Polyploidy and stress

Genome doubling, or polyploidy, the possession of three or more complete sets of chromosomes, characterizes the genomes of many eukaryotes and many Archaea and Bacteria. It exists at the level of cells, tissues, and whole organisms. As both a speciation mechanism and the source of raw material for genomic and phenotypic evolution, polyploidy is central to the study of genetics, evolution, and ecology. Many agricultural crops are polyploid, as are many human organs, and the development of some cancers transitions through polyploidy. Polyploidy impacts all scales of biological function, from molecular, cellular, and developmental biology to organismal and evolutionary biology and ecology, but it remains perhaps the least understood and underappreciated driver of biological function and biodiversity.

Longstanding questions have focused on the relative benefits and costs of polyploidy. An emerging observation is the common association of polyploidy with stress. Environmental stress has long been known to lead to the formation of unreduced gametes and thus the formation of polyploid organisms, but more recent studies have shown that various stresses may also lead to the formation of polyploid cells and tissues, including many cancers. At the same time, polyploidy may function as a response to stress, conferring properties to polyploid cells, tissues, or organisms that differ from those of their diploid equivalents. For example, polyploid organisms are often more resilient to harsh environmental conditions than their diploid relatives. At deep geological time scales, waves of whole-genome duplications seem to correlate with periods of mass extinction, either because environmental upheaval induced polyploid formation or because the polyploids were more resilient to the stresses that led to extinction of lower-ploidy lineages or both. Polyploids may have competitive advantages over their diploid relatives, particularly under stress, and appear to respond differently to pathogens than diploids. If polyploid cells, tissues, and organisms indeed show greater stress tolerance than their diploid counterparts, perhaps this benefit can counteract the many challenges associated with successful function and establishment of polyploid cells or organisms.

The study of polyploidy has long been hindered by a lack of synthesis and pursuit of common goals, and this shortcoming is particularly evident when considering the association of polyploidy with stress. The goal of this Special Feature is to explore the commonalities and distinct roles of polyploidy—as a stress inducer, a stress response, or an adaptation to stress—across disciplines, levels of biological organization, and organismal systems. The nine papers in this collection address various facets of polyploidy and stress, with important implications for basic biology, medicine, agriculture, and the bioeconomy. By highlighting this diverse array of topics involved in the study of genome doubling, we hope to foster more integration across long-siloed disciplines. Collectively, these articles, summarized below, are intended to be a stimulus not only for further research in each area, but more importantly, for greater integration and linkage across fields in the study of polyploidy.

Cellular Level

In a Perspective, Oliver et al. (1) highlight how a variety of stresses—including temperature, chemicals, infection, irradiation, and more—induce polyploidy at the cellular and tissue levels. The resulting polyploid cells often improve tolerance to stressful conditions, frequently by altering the physical properties of cells, enabling the cells to withstand stressful stimuli such as high osmotic pressure. This stress tolerance may be good for polyploid cell survival, and therefore polyploid cells can be agents of evolution. However, the polyploid stress response is not always positive. For example, if the polyploid cells in question are in a tumor, genotoxic stress tolerance could lead to evasion of genotoxic cancer therapies. A major take-home message of this Perspective is that numerous stressors may induce cellular polyploidy in all lineages of eukaryotes, with wide-ranging consequences that extend beyond the cell.

WGD occurs in 30 to 40% of all human cancers and may be involved in both tumorigenesis and cancer progression. Focusing on cancer models in humans and mice, Sweet et al. (2) explore the role of the tumor microenvironment to explain differences in proliferation of 4N (tetraploid) cells and in the number of centrosomes—the microtubule-organizing centers of animal cells—between 4N tumor cells grown in vitro and those from in vivo experiments. In particular, they closely examined how polyploidy synergizes with two common stresses of the tumor microenvironment: oxidative and starvation stress. Starvation stress led to a proliferative disadvantage of 4N cells, yet even a small number of 4N tumor cells was sufficient for tumor progression, while oxidative stress led to centrosome accumulation, which is associated with tumor development. When 4N and 2N tumor cells were injected into mice, the tumors grew at the same rate, despite the proliferative disadvantage of the 4N cells, perhaps due to enhanced recruiting of stromal cells by 4N vs. 2N cells. The results resolve the apparent inconsistency between in vitro and in vivo observations and demonstrate an important role for the stresses of the tumor microenvironment in potentially contributing to tumor progression.

Shen et al. (3) also examined polyploid cells and response to stress at the cellular level, specifically, polyploidy and resistance to genotoxic stress in fruit flies. Diverse sources of genotoxic stress (radiation, chemicals) impact diverse types of cells. Studying fruit fly abdominal epithelial cells, Shen et al. (3) found that exposure to ultraviolet light (UV-A irradiation) resulted in DNA damage and cell death. UV-A irradiation also promotes cell fusion in the abdominal cells that survive, resulting in the production of giant multinucleated (polyploid) cells. These multinucleate structures (often referred to as syncytia) ultimately occupy most of the epithelium following repair of the UV-induced tissue injury. This fusion of cells was shown to be the major response to UV stress and appears to play a major role in tissue repair. In addition, the activation of the cell death caspase machinery was associated with polyploidization in this fruit fly system, raising an important question: is caspase activation also an important mechanism involved in fusion-based polyploidization at the cellular level in other systems?

Organ Level

In addition to their discussion of stress-induced polyploidy at the cellular level, Oliver et al. (1) also overview connections at the organ level between polyploidy and stress. Cellular loss and mechanical stress necessitate organ remodeling and regeneration, and some organs in both plants and animals rely on polyploidy to restore damaged tissue.

While many organs highlighted by Oliver et al. (1) use polyploidy as an adaptation to mechanical stress, one organ that does not respond well to extreme polyploidy is the heart. Although the mature heart in mammals consists largely of polyploid cardiomyocytes, providing structural integrity to the organ, Purdy et al. (4) highlight a role in rodents for the Shroom3 protein in keeping polyploidy levels in heart muscle low. In mice and rat models, they show that compromising the function of Shroom3, which controls the actin cytoskeleton, leads to hyperpolyploidy and diminished heart function. So, while polyploidy may help cells manage mechanical load in many contexts, too much polyploidy may come at a cost, especially in the heart, where polyploidy is linked to an inability for cells, and thus the organ, to regenerate.

Organismal Level

Fully polyploid organisms that retain their polyploid nature in all component cells (other than gametes) and organs across generations occur in all crown eukaryotes. The impacts of polyploidy may thus be complex, with consequences manifested through integration of smaller effects at the levels of cells and organs and governed by genetic, epigenetic, and regulatory processes. Five papers in this Special Feature focus on the relationship between stress and polyploidy in polyploid organisms; although we group these papers together here, note that the actual consequences of polyploidy at this level may perhaps derive from impacts at lower, or multiple, levels of biological organization, such as the cell, tissue, or organ. Moreover, polyploid organisms do not exist in a vacuum but form natural populations that interact with nonpolyploid individuals and populations. Thus, consideration of organismal polyploidy here ranges from what is typically a unicellular fungus (Cryptococcus neoformans) to establishment of polyploid organisms amid diploid progenitors in nature to the impacts of polyploidy that are relevant to agriculture and the bioeconomy.

Infection.

The fungal pathogen C. neoformans causes meningoencephalitis, a life-threatening disease involving inflammation of the brain and surrounding tissue. Fungal infection is particularly problematic in individuals who are immunocompromised (e.g., individuals with HIV/AIDS or who have recently had chemotherapy or organ transplants). During the infection process, C. neoformans produces enlarged polyploid cells called titan cells. The large size and cell surface changes characteristic of titan cells inhibit phagocytosis of the invading cells by the host individual. Thus, polyploid titan cells can facilitate virulence and promote the persistence of C. neoformans in host individuals. As a response to stress (e.g., exposure to an antifungal drug), titan cells can produce aneuploid or diploid daughter cells that are drug resistant.

Bian et al. (5) explored the process of ploidy reduction in C. neoformans, suggesting that the depolyploidization of titan cells may resemble ploidy reduction in Meiosis I. They show that in C. neoformans, the meiotic protein regulators Dmc1 and Spo11 cause polyploid titan cells to produce stable, viable daughter cells. This process ensures genome stability without introducing detectable meiotic recombination. Loss of either Dmc1 or Spo11 would negatively impact the production of daughter cells, resulting in genome instability (characterized by aneuploidy and/or loss of heterozygosity) as well as phenotypic changes. They conclude that their findings “reveal a ‘para-meiosis’ safeguard that preserves genomic configurations during titan cell depolyploidization in C. neoformans.” This study highlights the ability of polyploidy to facilitate genomic innovation.

Establishment.

Considerable speculation and research have addressed the factors that promote the persistence of new polyploid lineages that are formed in close proximity to their diploid parent(s). The origin of one or a few polyploid individuals within a sea of diploids poses a huge demographic barrier to establishment of the polyploid, known as Minority Cytotype Exclusion. To overcome this barrier, it has been suggested that polyploids must become geographically isolated, outcompete their diploid parents, or evolve novel niche specificity. Although both simulations and empirical evidence point to the possibility of coexistence of diploids and polyploids at a given site, the relative roles of these possible outcomes have not been examined extensively. Here, Kauai et al. (6) reevaluate the purported need for the evolution of a novel niche using a mathematical model of polyploid establishment and then provide an empirical case study. Significantly, Kauai et al. (6) found that simple eco-evolutionary processes such as drift and dispersal limitations occurring at the margins of diploid range expansion can actually facilitate polyploid population persistence and success. Significantly, this study shows that a new polyploid can establish, survive, and thrive, occupying new areas beyond those of the diploid progenitor, without any a priori adaptive advantage (e.g., increased resistance to stress) compared to its diploid ancestor.

Agriculture.

The important role of polyploidy in agriculture and horticulture has long been recognized. Most crops are of polyploid origin, having formed thousands to perhaps a few million years ago. These plants were often selected by early humans for their robust stature, increased yield, and/or resilience.

The immediate effects of allopolyploidy due to the combination of divergent genomes may be extensive and span processes involving gene expression and the resulting proteome, metabolome, and phenotype, but the long-term success of polyploids depends on a multitude of factors, including the complex reprogramming of regulatory networks. Using cotton (Gossypium) as a model system, Wang et al. (7), in their Perspective, demonstrate the intricacies of this reprogramming: it involves changes in genome structure, functional diversification of the duplicated genes, and profound epigenetic changes. These multifaceted changes lead to expression biases and novelty. The two parental subgenomes in an allotetraploid (as in cotton) may result in different contributions of the parental genomes (genome dominance) to development and response to biotic and abiotic stress. Given the high incidence of polyploidy among crops, these processes merit ongoing study to enhance agricultural production.

As presented in the Perspective by Edger et al. (8), polyploid crops often exhibit greater resilience and response to various sources of biotic and abiotic stress. This response can vary greatly from one system to another, with no single universal rule. In some crops, polyploids are more drought-resistant, and in other cases more resistant to higher or lower temperatures. Response to pathogens can also be modified following genome doubling, with polyploids more resistant to biotic stress. Edger et al. (8) reinforce and expand on themes noted in cotton by Wang et al. (7). The enhanced stress resilience observed in crops appears to result from dynamic epigenetic and genetic changes. Some of these changes involve variation in gene content and cis-regulatory elements that appear after genome doubling. New insights into stress adaptations and resilience in polyploid crops will likely come from additional research in areas such as the regulatory role of transposable elements and using pangenomes to predict phenotypes.

The genetic variability and redundancy of polyploids have long made it problematic to use molecular breeding approaches in polyploid crops. As a result, some breeding efforts have focused on research on diploid progenitors. However, major advances in sequencing and informatic tools now make genotype work with polyploids more practical; particularly important has been the ready availability of new haplotype-phased genomes and the incorporation of multiple genomes for assembly and use of pangenomes. These DNA breeding tools have revolutionized (again) plant breeding, increasingly expanding these applications to an ever-wider range of polyploid crops. The Perspective of Edger et al. (8) emphasizes the importance now placed on stress resistance and polyploidy in the rapidly changing and challenging world of crop breeding.

Bioeconomy.

Increasingly, the important properties of polyploidy are being explored and employed in a growing bioeconomy. Several of the papers reviewed above highlight the impact of polyploidy on the bioeconomy, in agriculture (7, 8), as well as medicine (2, 5). In their Perspective, Peeters and Van de Peer (9) note that the bioeconomy is huge, encompassing agriculture, medicine, biofuels, and emerging new technologies. Translation of knowledge about genome doubling obtained through studies of natural systems, extensive lab experiments, and computer simulations has many diverse applications for a rapidly growing and sustainable bioeconomy. The long-recognized advantages of polyploidy such as increased genetic diversity, novelty, and stress resilience can all be co-opted, but most of these advantages remain to be tapped. The authors provide timely examples such as improvements in plant breeding, development of new medicines from plants, better biofuel production, implementation of bioremediation, and the discovery of new bioactive compounds (9). We add that there are likely many additional potential applications, such as crop production in space, given that polyploids are better able than diploids to cope with diverse sources of stress, perhaps including the stressors of space flight.

The early history of polyploidy research was dominated by studies of plants, leading to the long misconception that “polyploidy is just a plant thing.” We now know that polyploidy is everywhere: it is not only found commonly across the tree of life but is also a major force from cells to tissues to organisms to ecosystems. As the interest in polyploidy has grown, spanning medicine to agriculture, ecology, and evolutionary biology, it has often been studied in a discrete or siloed manner. But over the past decade, it has become clear that polyploidy researchers have much in common and that major advances will often come with communication across disciplines. The papers in this collection highlight diverse areas of research, all under the umbrella of genome doubling and stress, and point to the need for integrated study of this topic across all scales and lineages of life.