Clonality and Intracellular Polyploidy in Virus Evolution and Pathogenesis

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Clonality and Intracellular Polyploidy in Virus Evolution and Pathogenesis PAPER Clonality and intracellular polyploidy in virus evolution COLLOQUIUM and pathogenesis Celia Peralesa,b,c, Elena Morenoa, and Esteban Domingoa,b,1 aCentro de Biologia Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28049 Madrid, Spain; bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and cLiver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d’Hebron Institut de Recerca-Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain Edited by Francisco J. Ayala, University of California, Irvine, CA, and approved March 24, 2015 (received for review February 11, 2015) In the present article we examine clonality in virus evolution. Most genome replication and gene expression. Retroviruses permitted viruses retain an active recombination machinery as a potential the discovery of a reverse-transcriptase activity, an enzyme that means to initiate new levels of genetic exploration that go beyond forced the modification of an established dogma of molecular those attainable solely by point mutations. However, despite biology in that the flow of genetic information can also go from abundant recombination that may be linked to molecular events RNA to DNA (many implications are discussed in ref. 7). essential for genome replication, herein we provide evidence that Viruses also provided the first evidence of the presence of generation of recombinants with altered biological properties is interrupted genes (introns, exons, and the process of splicing), not essential for the completion of the replication cycles of viruses, and they have been instrumental in the establishment of key and that viral lineages (near-clades) can be defined. We distinguish immunological concepts, such as MHC restriction associated mechanistically active but inconsequential recombination from with cytotoxic CD8 cells, among other mechanisms of cellular evolutionarily relevant recombination, illustrated by episodes in immunology (see refs. 8–10 for overviews). The presence of the field and during experimental evolution. In the field, recombi- endogenous viruses and other virus-like elements in the DNA of nation has been at the origin of new viral pathogens, and has differentiated organisms has provided evidence of the long-term conferred fitness advantages to some viruses once the parental relationships between viral elements and the cellular world (11, viruses have attained a sufficient degree of diversification by point among many other studies). More recently, viruses are emerging EVOLUTION mutations. In the laboratory, recombination mediated a salient ge- as suitable experimental systems to address problems of bi- nome segmentation of foot-and-mouth disease virus, an important ological complexity, a concept that, having its origin in physics, animal pathogen whose genome in nature has always been charac- pervades the biological world (12). Thus, viruses are studied terized as unsegmented. We propose a model of continuous muta- because they are disease agents and because they provide genetic tion and recombination, with punctuated, biologically relevant entities for basic research. recombination events for the survival of viruses, both as disease In the ongoing debate about clonal versus nonclonal evolution agents and as promoters of cellular evolution. Thus, clonality is the in biological systems, particularly cellular parasites (compare, for standard evolutionary mode for viruses because recombination is example, refs. 13–17), it is of obvious interest to examine the largely inconsequential, since the decisive events for virus repli- extent of clonality of viruses, the most abundant and prolific ge- cation and survival are not dependent on the exchange of genetic netic entities amenable to field analyses and to controlled labora- material and formation of recombinant (mosaic) genomes. tory experimentation. The debate bears directly on the advantage (historical or present) of sex as a reproductive strategy (18, 19). evolutionary dynamics | mutation | quasispecies | recombination | In the present study, we first define some terms for clarity genome segmentation regarding how we deal with virus genetics, and we review evi- dence that suggests a predominantly clonal evolution as the iruses are the most abundant and ubiquitous genetic ele- standard “way of life” for viruses, despite most viruses keeping Vments in our biosphere, with an estimated total number of the molecular machinery for active recombination. The general 1031 to 1032, which means that they outnumber the total cells by a availability of recombination leads to the distinction between factor of 10. Viruses infect all host phyla in the most diverse unproductive or inconsequential recombination and evolutionary environments, with an estimated number of new infections of meaningful recombination. That is, recombination is occasion- 1023 per second, according to metagenomic surveys (1–5). The ally exploited for relevant transitions that we term “discontinuity fact that viruses can infect all types of unicellular and multicel- points.” A similar duality exists for mutation at shorter time lular organisms suggests that viruses have been (and probably scales. We illustrate recombination-driven transitions with some are) key players in the evolution of life. Uniquely, viruses exploit field observations, and also with an example of recombination- a variety of replication strategies of their genetic material that, based segmentation recently described for the important animal unlike cells, can be either RNA or DNA, and either single- pathogen foot-and-mouth disease virus (FMDV). We propose stranded, double-stranded, linear, circular, a single molecule, or that, despite sex having the potential to counteract detrimental multiple molecules (segmented genomes, termed multipartite effects of high mutation rates, high mutability and virus fecundity when the segments are encapsidated in different viral particles; may have maintained sufficient adaptive potential to allow a see ref. 6 for an overview). Despite often being called autono- mous genetic elements, viruses need a cell to express their ge- netic program and to produce progeny. They are endowed with This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “ ” – two of the features that characterize life: the capacity to replicate In the Light of Evolution IX: Clonal Reproduction: Alternatives to Sex, held January 9 10, 2015, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering and to evolve. Outside a cell, viruses behave as inert macromo- in Irvine, CA. The complete program and video recordings of most presentations are available on lecular aggregates. the NAS website at www.nasonline.org/ILE_IX_Clonal_Reproduction. By virtue of their limited amount of genetic material com- Author contributions: C.P., E.M., and E.D. designed research; C.P. and E.M. performed pared with cells, viruses have been instrumental in the de- research; and C.P. and E.D. wrote the paper. velopment of many fundamental concepts in biology. Viruses The authors declare no conflict of interest. have contributed to the understanding of genome organization, This article is a PNAS Direct Submission. as well the programs and regulatory mechanisms that guide 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1501715112 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 predominantly clonal evolution of viruses without continued mutation rates is that these error-prone replicating viruses form evolutionary meaningful recombination. complex and highly dynamic distributions of related but non- identical genomes, termed “viral quasispecies.” In several viral Clarifications of Terminology: Recombination Mechanisms systems, the complexity of viral quasispecies and the total We follow Tibayrenc and Ayala (14), and we use the term amount of viral particles (viral load) in an infected organism are “clonality” to refer to absence or limited recombination as a parameters that have been correlated with pathogenic potential requirement for viruses to survive as genetic elements. We use (i.e., invasion of specific organs by subsets of viral variants) and recombination in its broader sense to mean any type of exchange disease progression (27). The mathematical description of qua- of genetic material between two parental viruses or viruses and sispecies (30) is one of several interconnected treatments of cells, and even viral genome alterations that result in the oc- population dynamics that include the Lotka-Volterra, game dy- currence of insertions or deletions. With our terminology, for- namical, Price, replicator-mutator, and replicator-mutator-Price mation of defective interfering particles (20) is a consequence of equations (31). Mutation is the most prominent feature of the recombination events. Two general types of recombination have quasispecies description of evolutionary dynamics and, therefore, been described for RNA and DNA viruses: replicative homolo- quasispecies is a suitable theoretical framework for highly variable gous and nonhomologous recombination (depending on the se- viruses. Despite the simplification to represent an RNA viral ge- quence identity at the recombination sites or cross-over points), nome as a defined sequence, in reality we are representing a
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