Polyploidy: a biological force from cells to ecosystems

Abstract

Polyploidy, resulting from the duplication of an organism’s or a cell’s entire genome, greatly affects genes and genomes, cells and tissues, organisms and even entire ecosystems. Despite the wide-reaching importance of polyploidy, communication across disciplinary boundaries to identify common themes at different scales has been almost non-existent. However, a critical need remains to understand commonalities that derive from shared polyploid cellular processes across organismal diversity, levels of biological organization, and fields of inquiry – from biodiversity and biocomplexity to medicine and agriculture. Here, we review the current understanding of polyploidy at the organismal and sub-organismal levels, identify shared research themes and elements, and propose new directions to integrate research on polyploidy toward confronting interdisciplinary grand challenges of the 21^st century.

Polyploidy: a common biological phenomenon lacking cross-disciplinarystudy

Polyploidy (whole-genome duplication; WGD, see glossary), defined as having three or more sets of chromosomes, influences organisms in all clades of eukaryotic life and all levels of biological organization, from genes to cells to entire ecosystems (Fig. 1). The intersection of these axes of biodiversity and biological scale offers new opportunity for insight and research innovation. Yet, polyploidy remains underexplored in many contexts, and its roles and impact in biological processes and across phylogeny are unclear. This lack of clarity derives, in part, from very limited communication across disciplinary boundaries to identify common themes at different scales. The genomics era has accelerated research on polyploidy and provided a shared platform for dialogue and potential interdisciplinary synergy. We argue that cross-disciplinary approaches are crucial to identify common functions and regulation of polyploidy.

Fig. 1.

The central role of polyploidy (whole-genome duplication; WGD). Polyploidy, explained in the center of the diagram, is a driving force in organismal evolution. Elucidating the consequences of WGD at multiple levels (cellular to organismal) is key to understanding global patterns of biodiversity and ecology, as well as cellular fates, physiology, and metabolism. The implications of polyploidy range from cells to ecosystems and from agriculture to medicine and more.

Polyploidy can arise at both the organismal and sub-organismal level. At the organismal level, unreduced gametes (e.g., diploid instead of haploid) formed during meiosis can fuse to generate whole-organism polyploidy. Organismal polyploidy is a major driver of biodiversity that extends across all life, from deep history to the recent past[1,2]. Most, if not all, extant species (including our own) carry a signature of at least one ancient WGD[2]. Within tissues, programmed or aberrant events also increase the ploidy of specific somatic cells and cell lineages, often playing an important role in tissue differention in animals and organ development in plants (Fig. 1)[3,4]. New examples of polyploid tissues continue to emerge, such as in mammary tissue growth during mammalian lactation[5], or in repairing mammalian kidney and bladder tissue[6,7]. Events leading to sub-organismal increases in ploidy include variant cell cycles such as endoreplication or cell-cell fusion and are reviewed elsewhere[8,9].

At both the whole-organism and sub-organismal levels and across diverse areas of life, polyploidy increases cell size[4,10]. This essentially universal property of the polyploid cell results in a decreased cell surface/volume ratio. The full impact of these polyploidy-driven cell changes remains uncertain, but emerging data from across all life suggest profound shifts in numerous cellular processes following polyploidization. Moreover, as we highlight here, cellular and organismal polyploidy may be manifested as both an effect of environmental stress (i.e., increased rates of polyploidization) and an adaptation to it. This intimate relationship to stress makes the study of polyploidy increasingly important as cells, tissues, and whole organisms must respond to rapid changes in their biotic and abiotic environments.

Glossary

• adaptation– genetic changes that lead to higher fitness (e.g., performance or population growth) in a certain environment; the result of natural selection.

• biotrophic– plant pathogens or mutualists that form long-term obligate feeding relationships with host cells, e.g. powdery mildew, mycorrhizae.

• diploidization– the generation of a diploid genome from a polyploid genome [11–15].

• eco-evolutionary dynamics– the result of reciprocal influences between ecological and evolutionary processes, i.e., evolution and ecology occur on the same time scale such that evolution affects ecological interactions and vice versa.

• epigenetic remodeling– DNA sequence-independent alterations in chromatin, such as changes in the condensation state or of active/repressive histone chemical modifications, that lead to alterations in gene expression.

• epigenome– the chemical state of chromatin, such as histone chemical modifications, which can influence gene expression independently of DNA sequence.

• endoreplication– a general term for truncated cell cycles that duplicate the genome without completing cell division, leading to a polyploid cell.

• evolvability– the capacity of a population to evolve through natural selection, depends on the amount of, and ability to generate, genetic diversity.

• genetic buffering– gene interactions wherein variation in one gene can be compensated for by variation in other genes, e.g., genes that function in the same biochemical process, leading to a stable phenotype.

• inbreeding depression– the reduction in fitness or a trait due to mating with close relatives (e.g. selfing) that results from expression of deleterious alleles or loss of heterozygosity.

• karyotypic– referring to the state and/or number of chromosomes in a given nucleus.

• neopolyploid– a newly formed polyploid via synthetic manipulation or natural processes.

• unreduced gamete– a gamete produced from an aberrant meiosis I, in which homolog disjunction fails and ploidy is not reduced.

• whole-genome duplication– a general term for any process leading to a doubling of cellular or organismal DNA content.

Emerging commonalities

Greater insight into the distinctive functions and regulation of polyploid cells and organisms can unravel strategies to fight some of the world’s most pressing social crises. These efforts include sustaining biodiversity and ecosystem services, increasing and diversifying agricultural yield in rapidly changing environments, and advancing biotechnology and medical interventions. This is particularly true with respect to diseases such as cancer, where polyploidy is now appreciated to be a major player in both promoting and suppressing tumor progression [16–20]. Yet, polyploidy research has long been compartmentalized, with investigators in evolution, ecology, genomics, agriculture, cancer, and other branches of biology having few, if any, interactions, despite often asking very similar questions about the drivers and consequences of polyploidy at cellular, tissue, organ, and organismal levels (Fig. 1). WGD events likely result in a plethora of recurring downstream effects that are common across biological settings, including changes in gene expression and cell size, epigenetic remodeling, modifications to subcellular networks of gene interaction, and altered responses to environmental stress[4]. Thus, a WGD can alter the phenotype, not only at the level of the cell and cellular organization, but also at the organismal level. Going forward, we argue that interdisciplinary collaboration aimed at identifying common themes of genome doubling/polyploidy will unify currently disparate fields, unearth novel insight, and generate paradigm shifts.

Here, we present two major research themes that clearly illustrate common responses to polyploidy in plants and animals. These commonalities argue for increased interaction among scientists studying polyploidy at multiple organizational levels and across large phylogenetic distances.

Polyploidy as a response to acute stress

At the organismal level, environmental stress (e.g., high or low temperature, water availability, or salinity) may induce meiotic events leading to unreduced gamete production[21–24] and organismal genome doubling, resulting immediately in a polyploid line. This stress-induced WGD plays a major role in agriculture and horticulture in generating new synthetic polyploids in a manner similar to the processes that lead to new polyploid species and ultimately polyploid lineages in nature.

Comparably, at the sub-organismal level, tissue stresses such as acute wounding or viral infection can induce polyploidy at the cellular level[6,7,25–28], which can result in an increase in tissue mass via enlarged cells. This WGD response represents an alternative to generating new cells through cell division. In animals, several recent examples of WGD after injury have been described in vertebrate tissues such as the kidney, bladder, and epicardium, as well as multiple insect tissues[25,29,30]. Such injury-triggered WGD may enable rapid tissue re-growth without compromising the integrity of a tissue barrier during cell division[31] or provide necessary mechanical force[32]. Similarly, in plants, endoreplication responses (cell cycle activation without mitosis) can be stimulated by both major pathogens of agricultural crops (e.g., powdery mildew, root knot nematodes[33]) as well as ancient mutualistic associations (e.g., mycorrhizal fungi and nitrogen-fixing rhizobia) in which most plants engage[34,35]. While endoreplication can arise via various shortcuts in the cell cycle, endoreplication in response to biotrophic interactions that involve penetration of the plant tissue results in upregulation of the same genes, suggesting that the effectors involved are generic reactions to cell stress[34]. Furthermore, recent work in root nodules that house nitrogen-fixing rhizobia demonstrated that changes in transcription are related to increasing ploidy and dynamic changes in the epigenome[36]. Interestingly, it has been proposed that cellular-level plasticity for ploidy (endoreplication) may trade-off with whole-organism ploidy[30,37], as both are different routes to mitigate stress.

In both organismal and tissue-level examples of environmental stress leading to WGD, molecular connections between stress-sensing and ploidy increases remain unknown. The above-mentioned examples suggest that a common response or set of responses linking stress to WGD may be awaiting discovery. For example, similar epigenetic processes could be involved in other endoreplication-mediated differentiation programs associated with injury and other stresses, a hypothesis that could be tested across human and plant systems, as it is now clear that WGD is a common response to tissue injury. The researcher investigating injury-induced polyploidy in tissues such as the heart, where polyploidy has recently been shown to block therapeutic regeneration[38–41], has much in common with plant researchers similarly investigating stress-induced endopolyploidy in plant leaves or other tissues. Collaborative study in this area could potentially lead, for example, to new strategies to repair injured tissue in diverse organs and organisms or arrest growth of cancer cells with WGD.

Adaptation via ploidy-induced genomic change

Genome doubling in both whole organisms and individual cells ultimately results in numerous downstream effects, regardless of the context. First, the increased copies of each chromosome greatly enhance genetic diversity. This diversity can then seed additional modifications to gene expression, epigenetics, gene networks, the proteome, cell size, as well as altered responses to stress. This overall increased genetic diversity/versatility in the new polyploid cell line or organism represents the fuel that, once filtered by selection, ultimately leads to adaptation. Stress may not only induce polyploidy, but substantial data reveal that WGD also provides an adaptive advantageto both cells and organisms, particularly under unstable, stressful environments. As one example, polyploidy promotes increased salinity tolerance in both animals[42] and plants[43–45]. In sweet potato, polyploids better maintain K+/Na+ homeostasis under saline conditions than diploids, begging the question of whether a similar mechanism may operate more broadly.

At the organismal level, in a stable environment, gradual processes can successfully explain many aspects of evolution. However, despite the buffering imposed by duplicate gene copies and the consequent delay in fixation of beneficial as well as deleterious alleles, the dynamic nature of polyploid genomes may drive organismal change. This increased evolvability provides a mechanism of rapid adaptation to a quickly changing environment whether it be in response to local/regional stresses on populations or the massive environmental changes that accompanied meteor impact at the K-Pg boundary[46]. Moreover, polyploids may be better able to respond rapidly to projected rapid climate change scenarios in the remainder of this century.

At the cellular level, the adaptability of polyploid cell lines has numerous implications. The adaptive advantage of polyploidy may have deleterious consequences when genome doubling occurs in tissues that are normally diploid. In many cancers, the occurrence of polyploidy is now appreciated to significantly shape the evolution and prognosis of tumors[16–18], perhaps by increasing rates of genomic instability[4,47,48] and therefore cancer-driving mutations or drug resistance[4,17,49]. In support of this idea, polyploidy was recently found not only to be present in roughly one third of solid tumors[16,17], but also to be even more prevalent (>50%) in advanced metastatic disease[50].

Likewise, increases in ploidy (followed by mis-segregation of chromosomes) in Candida albicans, a prevalent human pathogenic fungus, occur in response to the antifungal drug fluconazole (FLC)[51], creating FLC-resistant aneuploid progeny. In contrast to the oft-described negative attributes of aneuploidy[52,53], many FLC-resistant aneuploids that were derived from WGD show little fitness cost. Aneuploidy may also provide occasional opportunities for adaptation to stress and cancer[54,55]. Experimental evolution systems can offer additional insight into mechanisms. In yeast (single cells), for example, polyploid cells adapt faster than haploids or diploids, especially in stressful environments, as a result of more frequent beneficial mutations and stronger fitness effects[56]. In plants, researchers are just beginning to understand how polyploidy in some tissues leads to increased adaptation and evolutionary and agronomic success; for example, polyploid cells are important in the development of structures such as trichomes, fruits, and root nodules[3,57].

While the above discussion centers on polyploidy fueling increased adaptability, the converse can also occur. The duplicated gene copies in a polyploid cell or organism can minimize deleterious phenotypic variation, because the additional genomic copies provide a buffer against the impact of deleterious mutations[58,59]. In a newly formed polyploid organism, this buffering can be advantageous, but negative mutations may accumulate over time, eventually reaching a high frequency that could be disadvantageous for a population[60,61]. However, these copies are rarely exposed because of duplicate gene copies, leading to reduced inbreeding depression in most polyploids[61–64]. At the sub-organismal level, a recent example of genetic buffering by polyploidy is the demonstration that polyploidy prevents tumor growth that is driven by homozygous recessive tumor suppressor mutations[65]. Overall, the above examples highlight similarities in the adaptive responses conferred by polyploidy from plant genomes to tumors and show that commonalities are beginning to be revealed across systems, emphasizing the need for much more coordinated, cross-disciplinary research.

Integrating disciplines to identify common rules to polyploidy

Greater integration of research on WGD promises to identify further commonalities across biological scales and phylogenetic distances while also clarifying which responses might be unique to a specific organ, biological process, or species. Such interdisciplinary collaborations could potentially reveal underlying ‘rules’ to polyploidy that cut across organisms and disciplines (from agriculture to medicine). We suggest that knowing such ‘rules’ can help address a host of outstanding “moonshot” questions that are important in diverse WGD settings, as outlined in the Outsanding Questions Box.

Outstanding Questions.

How does the increased complexity of duplicated gene regulatory networks affect polyploid cells (both normal and diseased), tissues, and organisms?

What advantageous gene expression networks may explain the emergence of polyploidy in specific plant and animal tissues following acute stress?

What are signature characteristics of polyploid cancer cells that can be exploited for preventive and therapeutic purposes?

Why is the polyploid state in ecological niches or tumors often transient, leading to the process of ‘diploidization’ – the return of at least part of a polyploid genome to a diploid state?

We are also reminded that “nothing in biology makes sense except in the light of evolution”[66]. With this in mind, replaying the ‘genome duplication’ tape of life with populations of fast-growing cells or organisms should offer novel insights regarding when and how WGD confers a selective advantage. This can be done through ‘evolve and resequence’ experiments, where genomes of natural and/or artificial polyploid cells or organisms, including experimental tumor models, are (re)sequenced after many generations of selection[67,68]. This approach could provide clues, for example, to how WGD facilitates adaptations to different environmental or stressful conditions. Similarly, mathematical modeling can reveal possible effects of WGD from an evolutionary dynamics perspective in ecological, developmental, and disease settings. Applications of such an approach are broad. Such forward-time simulations that can accommodate eco-evolutionary dynamics of mixed-ploidy populations could, for example, inform us on the fate of polyploid plants during increasing frequency/severity of drought, or of a fungal parasite following exposure to an anti-fungal agent in a human host environment[51]. Importantly, mathematical modeling suggests that tumors derived from WGD may optimally converge on a narrow karyotypic range[18], supporting the validity and importance to human health of such evolutionary/modeling approaches in this field.

Concluding Remarks and Future Perspectives

That many normal and malignant cells, tissues, and even entire organisms often possess, or sometime in their evolutionary history have possessed, multiple copies of their genome, has intrigued scientists across disciplines for over one hundred years. However, research on polyploidy has long been siloed; medical, agricultural, and evolutionary biologists who study genome doubling have much in common, but currently have only limited contact. We argue that an integrative approach is now needed to fully understand the many facets and intricacies of ‘life with multiple genomes’. We propose that joint research ventures across diverse disciplines will promote a better understanding of polyploidy, at both the cellular and organismal levels. Undoubtedly, research that seeks commonalities will have important downstream benefits to our own species through novel discoveries spanning medicine, agriculture and evolution/ecology. Polyploidy’s link to biological novelty and innovation[69] and the success of polyploid cells within organisms, of polyploid organisms in nature, and of polyploid lines in plant domestication and synthetic evolution experiments[56] suggest that polyploidy is an untapped resource for advances in many fields (Fig. 1). Knowledge gained from natural polyploid cells and organisms, coupled with the potential of synthesizing neopolyploids, may lead to new technologies to solve pressing global problems. We anticipate, for example, that it may soon be possible to edit genes in polyploids[70,71] or engineer synthetic polyploid cells or organisms with novel functions, including mitigation of greenhouse gases or plastics pollution or organ repair.

We thus propose that researchers engage in a broad interdisciplinary grand challenge, polyploidy 2030 - within the next decade. This effort would involve researchers studying polyploidy in the entire tree of life, as well as in diverse areas including evolutionary biology, ecology, agriculture and medicine, working collectively to provide a meaningful synthesis of the role of polyploidy in biological systems and subsystems. Polyploidy 2030 should address major questions of central importance to human health and well-being. Additional funding will be needed to accomplish these goals. For example, poyploidy is more common in human tumors than mutations in some of the best funded oncogenes, such as the Ras family genes[16,72]. Central questions to be answered include, but are not limited to, the role of genome doubling in generating biodiversity, and improvements in agriculture and medicine.

Sharing of data, knowledge, and expertise across disciplines should catalyze new research into the roles, rules, and diverse impacts of polyploidy. Such cooperation can lead to breakthroughs in the major interdisciplinary grand challenges of the century, such as maintaining human health, food security, and ecosystem services in the face of rapid population growth and environmental change.

Highlights.

• Communication across disciplinary boundaries to identify common themes of polyploidy has been extremely limited.

• Identifying commonalities that derive from shared polyploid cellular processes across disparate fields of inquiry holds promise to identify breakthroughs in numerous areas – from biodiversity and biocomplexity to medicine and agriculture.

• We propose new directions to integrate research on polyploidy toward confronting interdisciplinary grand challenges of the 21^st century.