arXiv:2105.11784v1 [q-bio.PE] 25 May 2021 in.Temn aeso xrsinfo eoyeto genotype possi- of from ensemble the expression increasing towards of act muta- layers [19] function quasi-neutral many The and neutral tions. beyond ways different few a just 18]. awaiting [17, be apart en- may mutations further functions [16] different that conditions high of sures general space The very the the under that it. percolate sequences fact phenotypes know the abundant we and of as networks spaces life genotype sustain of enough to dimensionality efficient as and suffices so different however, of functions fraction, spectrum a This of guarantee fraction to small phenotypes. a large into mapped very 13–15], are [8, sequences space phe- rep- most sequence of since in to homogeneous abundance metaphor not The updated is notypes an [12]. of landscapes need adaptive resent the to non-trivial that points [11] a consequences also dynamic 11], or- important with are [10, topology genotypes networks-of-networks Such as [7–9]. ganized sequences short genome for complete of spaces by revealed studies empirical as and genotypes, different computational astronom- of an number from large obtained ically be can phenotype molecular achieve. to straight com- relatively molecular Actually, be might [6]. all plexity better at is functionality functionality partial no that than fact the and muta- [3–5] quasi-neutral tions and neutral the of obviating number was overwhelming assumptions [2], arguments whose design functional paradox, intelligent echoed apparent tiniest The the random [1]. where produce molecule appeared ours, to generated, as insufficient systematically large absolutely as be and would myriad old a sequences that as given which universes sequences, on random of material were se- raw act Natural to the had genes. if it ineffective functional be of would being lection into regard- concerns come raised the sequence ing protein unique a on rely h eoyet-ucinmpi eudn nseveral in redundant is map genotype-to-function The same The redundant. highly is function Molecular could specificity gene that idea the ago, century a Half eainhpbtenfntoa eune,nwfunctions new sequences, functional between relationship oeua ains aua eeto osterest. the does combinator selection through Natural attained variants. be molecular proposals. could functional th complexity potentially is molecular new It phe filters structures, sequences. that into ecology genomic between sequences mechani of associations several operative mapping by redundant facilitated as is such function of harb emergence environment cellular The h the could while activity, polymers chemical random ent evolution, molecular of times early tod ihataiinlve fmlclreouinta s that evolution molecular of view traditional a with odds At .INTRODUCTION I. h ipeeegneo ope oeua function molecular complex of emergence simple The nedsilnr ru fCmlxSses(IC,Madrid (GISC), Systems Complex of Group Interdisciplinary ainlCnr o itcnlg (CSIC). Biotechnology for Centre National /Dri ,209Mdi,Spain Madrid, 28049 3, Darwin c/ eateto ytm Biology, Systems of Department Dtd a 6 2021) 26, May (Dated: uan Manrubia Susanna eirlvn o h ucinlt faphenotype. a of functionality the might for composition irrelevant or genotypes, be structure ex- Be- in molecular in their variations changes 23]. also so inconsequential [22, environments multiple plastic, different yond are to phenotypes adapts pression and range a variation, admit phenotypes of so 21]. flexible, [20, is phenotypes function Further, comparable for coding genotypes ble icmtne,as aiiaeteapaac fsimple of certain appearance under may, the but facilitate [32] also evolution to circumstances, visible is what needed. se- if natural optimization, place, towards in act once can But, lection into [31]. engage function functional to secondary of adjustments a initial sort need any not Phe- general, may in molecule and, function. variation genes exogenous different that and implies a endogenous to perform molecule tolerance same to notype the recruited perform hand, be might other can origins the on different the functions; of on similar molecules evolution: hand, in com- relevance one illustrate of mechanisms properties different former plementary The are but structure, [30]. sequence, secondary considered given minimum-free-energy a the from struc- with when catalyze compatible appears to naturally se- tures enzyme principle promiscuity in an RNA was it of which lected. for ability no- those the than related other to reactions conceptually refers a molecules that is RNA tion promiscuity for Enzyme reported also [29]. been has property functions; this same context-dependent the multiple, have moonlighting, may protein protein where In resemble to instances [28]. disguise structure many however,others’ composition the dissimilar concept, embrace of mistaken to The molecules extended be be [24]. to can response as trigger autoimmune consequently, so an and, the peptides sequence are pathogen-derived in in by self-peptides defined similar occasionally, originally sufficiently immunology: was of mimicry flexibil- context functional Molecular and redundancy ity. expres- phenotypic widespread three of are sions [27] promiscuity enzyme or h kwddsrbto fpeoyeszsconditions sizes phenotype of distribution skewed The 26] [25, moonlighting protein [24], mimicry Molecular r yido rt-ucinlmolecules. proto-functional of myriad a ors a emerge can e hntpsadsbeun eesof levels subsequent and phenotypes New viaiiyo ihsi h molecular the in niches of availability e m nrni omlclrorganization, molecular to intrinsic sms v ucdfrteapaac fincipi- of appearance the for sufficed ave a xlrtoso urnl available currently of explorations ial oyi lsiiy ouaiy rco- or modularity, plasticity, notypic esadescent-with-modification a eeks enovo de Spain , ihrltv ae At ease. relative with 2 molecular functions de novo. The emergence of func- quantifying the bias in phenotype (structure) abundance. tion has in all likelihood been relevant in the origin of Accordingly, common phenotypes are orders of magni- an RNA world [33, 34] and in the genesis of simple repli- tude more frequent than average-sized or small pheno- cators [35]. Still, single gene or single molecule redun- types (which are, by any reasonable measure, invisible to dancy, and the selective improvement of their function evolution). RNA structure is tightly related to molecular through point mutations, only represents the fine-tuning function and, as such, it may have played a main role at of molecular evolution. Once originated and optimized, the early stages of chemical evolution and, especially, in small functional sequences might act as the basic bricks an RNA world predating modern cells [51]. The reper- of multi-purpose molecules [36] through a modular con- toire of secondary structures in large populations of short structive principle that applies from proteins [37] to or- RNA polymers is limited [52]: topologically simple RNA ganisms [38, 39]. modules are abundant. In open RNA chains, there is Ensembles of agents that replicate independently — a predominance of stem–loops (composed of a stem and which, in a certain sense, may act as competitors— can a hairpin loop) and hairpin structures [53], while closed integrate to form a new, more complex entity [40] through RNA chains preferentially fold into rod-like structures (a what is known as a major evolutionary transition [41]. stem closed by two hairpin loops) [54]. This fact is solely Many of these transitions are cooperative [42], a paradig- based on thermodynamic principles [55] and implies that, matic example at the molecular level being the emergence by default, short RNA sequences will predominantly yield of chromosomes. However, there are multiple examples, a handful of structures. especially in the viral world, where flexible cooperation, The relevant implication of this high redundancy is that is, without irreversible fusion of the parts, appears as that some of those abundant structures might be the a successful adaptive strategy. In viral quasispecies, eco- end result of random RNA polymerization (as it could logical roles can be allocated in different mutant classes have been the case in prebiotic environments [56]). With [43], and collective cooperation may be needed to main- no previous selection, random polymers might have thus tain pathogenesis [44]. In viruses, horizontal gene trans- covered an array of incipient functions. Such is the case fer (HGT) is not only a common mechanism for adap- of a variety of hairpin-like structures able to promote tation, but probably also a way to generate new viral ligation reactions [57, 58], or of hammerhead structures species [45]. A remarkable form of distributed coop- involved in cleavage [59]. RNA self-ligation might in- eration is that of multipartite viruses, whose genes are deed be instrumental in the modular construction of more propagated in independent capsids [46, 47]. Viruses are complex ribozymes, as theoretically proposed [33] and a powerful system of generation of new molecular func- empirically shown [60, 61]. tion. Together with other mobile elements, they func- There are reasons to believe that the severe pheno- tion as transporters of genomic sequences and may assist typic bias of the sequence-to-structure RNA map, as their integration in higher organisms. In the coevolu- quantified through the log-normal distribution of pheno- tion of viruses with hosts, the former may even promote type sizes, is a general property of genotype-to-phenotype increases in host complexity [48] and spur major evolu- maps [9, 15, 19, 21]. If this is the case, the scenario de- tionary transitions [49]. scribed for RNA should hold broadly, and apply to other In the forthcoming sections, we will focus on specific polynucleotides, to peptides, and to polymers at large. examples that illustrate how some of the mechanistic The next step in the construction of chemical complexity principles outlined in this introduction can be used to regards the emergence of cooperative behaviour of some devise scenarios where complex molecular function could kind [62], such that the proto-functionalities provided parsimoniously emerge. The conceptual framework in- by such molecules do not get lost. Eigen’s hypercycles tegrates low-cost pieces with incipient functionality, dif- [63] were an early proposal in this respect that has been ferent cooperative schemes and an ecological context (or deeply explored [64]. Indeed, some experiments indicate an organized molecular environment) responsible for the that networks of interacting molecules may have formed selective pressures that act on such incipiently functional early in chemical evolution, pointing also at an intrinsic systems. Our aim is to link robust features of the molecu- ability of RNA to evolve complexity through cooperation lar genotype-to-structure map, contingency, and selective [65]. evolution, and to discuss how, at the next level, innova- tion can emerge through distributed cooperation. III. EMERGENCE OF VIROID-LIKE REPLICATORS II. PHENOTYPIC BIAS: THE FREE LUNCH OF MOLECULAR FUNCTION Genotype-to-phenotype redundancy is an intrinsic property of natural systems [66, 67]. This redundancy RNA has been studied in depth as a paradigmatic should have been important in the prebiotic origin of example of the sequence-to-structure map [50]. It has chemical function, but also all along evolution: as first been shown that the frequency distribution of secondary enunciated in geology [68], chemical processes should structures follows a log-normal distribution [14, 15], thus have acted in the same manner and with essentially the 3 same intensity in the past as they do in the present. step in their emergence, as described in the previous We must add that the effect of such processes is dif- paragraph, could have been relatively straightforward, ferent because it is the molecular ecosystem that has as that of other potentially useful functions in the same changed. For instance, it seems reasonable to assume or nearby environments. Once kick-started, their mod- that hairpin-like RNAs with potential ligase activity are ularity strongly supports the possibility that different continuously produced in the RNA-rich cellular envi- functional features of viroids could have been acquired ronment [69], where multiple RNA sequences of various through recombination with RNAs of different origins origins might be present: fragments of RNA transcrip- transiently present in the molecular ecology where they tion [70], transient products of RNA degradation [71], evolved. This is more than a conjecture, since some vi- pieces of viral genomes [72] or rod-shaped microRNAs roids are known to arise from other viroids through re- [73, 74]. Natural processes should be inadvertently and combination [93, 94]. A highly plausible case of modular steadily generating raw proto-functional sequences. How- recombination is provided by hepatitis δ virus [95], which ever, such proposals will be filtered by purifying selection, has a viroid-like non-coding domain [83] linked to a cod- by competition with (probably fitter) existing functions ing domain of independent evolutionary origin [96]. or simply by degradation so, at odds with what happens Despite justified criticism of proposals that assume in geological systems, they mostly disappear without a an unbroken phylogenetic connection between extant vi- trace. With an exception: when an ecological niche is roids and their potential ancestors in an RNA world, available. there is reason to believe that the molecular niche oc- Viroids are small, non-coding, circular RNA cupied by viroid-like molecules may have been contin- molecules [75]. Despite having a small genome of uously available (and likely occupied) given a minimal a few hundred nucleotides, they behave as competent chemical complexity. It will be extremely difficult, if not and persistent replicators in higher plants, apparently impossible, to solve this question empirically. However, their only natural hosts. The evolutionary origin of it comes to reason that any self-replicating system, how- viroids has been a matter of discussion, and various ever rudimentary, is subject to the emergence of parasites hypotheses have been put forward [76, 77]. It has [97, 98], of non-cooperative defectors that use system’s been suggested that viroids may be related to other resources for their sole benefit. The cellular environ- extant cellular RNAs [78], could have originated from ment is an extremely rich and varied ecology [99] where retroelements or retroviruses [79], or be ancient relics of multiple control mechanisms, up to cell death [100] are a precellular RNA World [80, 81]. All these possibilities acting and, indirectly, thus limiting the selfish escape of seek the origin of viroids in a previously functional sys- functional molecules. Another mechanism contributing tem, assuming shared ancestry and a broad phylogeny to the preservation of system’s integrity might be the linking viroids to other extant functional RNAs [82, 83]. difficulty of newcomers to invade a functional ecology This assumption has been criticized on the basis that [101]. Molecules that may potentially occupy a given the observed sequence similarity might be spurious [84] niche may find it difficult to succeed if the system al- (see also referee reports in [85]), attending as well to the ready has an optimized solution for that function. This high mutation rates of viroids [86], the diversity of their sort of non-invasibility principle implies a degree of phy- populations [87] and their low sequence conservation logenetic continuity, and endows first-comers with an im- [88]. plicit advantage. Extant viroids, as a possible example Actually, it cannot be discarded that modern viroids of such process at a molecular level, might be a combi- emerged once eukaryotic cells had evolved [35, 89]. In- nation of contingency (a frozen accident) and continuity spection of the two families of viroids reveals important as a side-effect of non-invasibility. In a viroid-free situa- differences in their structure and replication cycle, as well tion, it is highly likely that similar viroid-like replicators as in the interactions with host proteins [90, 91]. The would emerge in short evolutionary time, occupying the two families are so different that a polyphyletic origin vacant niche in the same way that radiating species do cannot be ruled out [84]. In a context of a de novo emer- [102]. Macroecological niches enjoy long periods of func- gence of rudimentary replicons, phenotypic bias may have tional stasis, even in the face of taxonomic variability played a role: for example, all circular RNAs of length 20 [103]. At odds with macroevolution and macroecology and lower fold into rod-like structures [35, 54]. Remark- [104], an integration of molecular ecology and evolution ably, the rod-like structure of viroids could be a case (and phylogeny) is yet to be worked out. of molecular mimicry, since that structure resembles ds- DNA and facilitates the recognition by RNA polymerases [81]. Hence, a small rod could be ”recognized” by the IV. VIRAL GENE SHARING replicating machinery of the cell, triggering its replica- tion and therefore its differential selection. Viruses are extremely abundant, diverse, strict molec- Viroids exhibit a modular structure that has prompted ular parasites that, perhaps with rare exceptions, infect their description as a “collection of structural motifs all cellular organisms on Earth. It is difficult to overstate which play specific functional roles in viroid replication, the role that viruses may have played in the construction processing, transport, and pathogenesis” [92]. The first of our complex biosphere [105, 106]. They are motors 4 of biodiversity [107], regulate ecosystems and global bio- genomes where they are found. From an evolutionary geochemical cycles [108], and constitute a huge reservoir perspective, genes can be in principle classified into dif- of genetic diversity [109]. Metagenomic techniques are ferent groups, as signature genes (characteristic of one enormously enlarging the quantity and quality of previ- particular group of viruses), hallmark genes (encoding ously described viral species, and strongly suggest that key proteins and shared by overlapping sets of diverse we have only grasped the surface of viral gene diversity viruses), or orphan genes (found in a single genome) [45]. [110, 111]. However, the bipartite network representation or viral Viruses mutate much faster than cellular genes [112]: genes and genomes allows the use of multiple quantita- a viral gene explores in a few thousand years a sequence tive measures that, in the framework of complex networks space comparable to that explored by a typical nuclear [125], might both reveal the intimate architecture of gene gene since the Cambrian explosion [113]. Single viral sharing and point at dominant evolutionary mechanisms. populations are organized in viral quasispecies, swarms For example, the observed scale-free distribution of the of mutants where each sequence may differ from each number of genomes that contain a given gene suggests other in at least one mutation [114], allowing a much a unique underlying generating mechanism. Community more efficient exploration of sequence spaces [115]. Not analyses [126] of the bipartite network corresponding to surprisingly, viral sequences found in metagenomic stud- the double-stranded DNA viruses reveal, however, the ies are dominated by rare genes, with up to 90% of DNA existence of non-trivial correlations among genomes that reads encoding proteins not found in other cellular organ- translate into the consistent identification of major viral isms, or in other viruses [116]. The evolutionary freedom groups [45]. enjoyed by viruses may turn them into cradles of func- Our current knowledge of the virosphere is, as of yet, tional diversity. A substantial part of organismal evolu- poor and biased [127], a fact that certainly limits our tion could be virus driven, since viruses contribute essen- understanding of its role as source of functional diver- tial (functional) pieces that promote complexity increases sity. The apparent phylogenetic discontinuity between in organisms [62]. Viruses harbor protein domains with viral groups that we observe may also result from that folds unknown in cellular organisms, and some of these poor sampling: a more comprehensive knowledge of vi- domains have been transferred to the host [113]. Massive ral diversity could bring about a more parsimonious un- transfers of genes from virus to host are not uncommon derstanding of how viral evolution has unfolded [128]. [117, 118]. With obvious differences, this suggestion recalls the in- Viruses are extreme examples of mosaicism. They are terpretative difficulties (and even the disdain) that sur- truly chimeric in their composition, most often the emer- rounded paleontology, due to the incompleteness of the gent result of broad and wide viral gene sharing [45] and fossil record, until well into the 20th century. A history occasionally puzzles of pieces assembled from the most of the world imperfectly kept, in Darwin’s words [129], distant origins [119]. The identification of common ele- severely delayed the incorporation of paleontology as a ments with a shared phylogenetic history in large viral discipline proper of evolutionary biology [130]. This is groups is relatively limited, with exceptions [120]. Recent certainly not the case of virology, but suggests that evolu- studies suggest that a hierarchical taxonomy of large viral tionary principles inferred from too sparse data might re- groups is possible [121] though, more often, viral phylo- quire substantial revision when data becomes more abun- genies are limited to viral cohorts [122]. The recognition dant and complete. Evolutionary theory is on the move. of a phylogenetic signal speaks for the evolutionary con- tinuity of the shared element, but does not inform on the actual composition of viral genomes or on the vi- V. FLEXIBLE COOPERATION AND ral phenotype: the former are dominated by extensive MULTIPARTITE VIRUS HGT and divergent evolution, the latter by the viral eco- logical niche, both being interdependent. Actually, it is The viral world harbors amazing examples of competi- important to distinguish between bona fide phylogenetic tion and cooperation, both among kin and non-kin. Qua- elements and genes that have been recently acquired by sispecies are ensembles of genetically related genomes HGT from contemporary bacteria or from the viral host where multiple associations and interactions are possi- [119] which, instead of revealing common origin, might ble, and whose composition depends on the joint action represent examples of recent, likely fast, viral adaptation of endogenous antagonistic interactions [131, 132]. Repli- to new niches. cation at high mutation rates favors the generation of di- Modularity is a driving force of viral genome evolution versity, thus facilitating, in principle, adaptation [133]. [123] and, probably, also a mechanism for the generation However, too high a mutation rate might hinder the fix- of new viral species. Actually, the proneness of viruses ation of beneficial mutations [134] and produce an excess to loss, gain, and exchange genes has prompted the rep- of defective genomes. Defective interfering particles were resentation of large viral groups as bipartite networks originally considered as artifacts of in vitro evolution with with viral genomes and viral genes as the two classes a detrimental effect on viral fitness [135]. But these par- of nodes [45, 124]. Each genome has as many links as ticles are produced in vivo and play a role, among others, genes it contains, while genes are linked to all of the in viral adaptation and in disease progression [136]. High 5 mutation rates also permit the coincident appearance of novo associations, gene duplication or genome fragmen- mutations with similar beneficial effect in independent tation may also promote the emergence of multipartite genomes, causing clonal interference and potentially de- viral species [47]. Multipartitism has appeared multiple laying adaptation [137]. The previous effects notwith- times in evolution and, as such, it has to be understood standing, the mutation rate is itself subject to selection as a successful evolutionary strategy [151]. along evolutionary time, so it is sensible to assume that it has been tuned to favor viral survivability [138]. Quasispecies diversity is actually needed to maintain VI. CONCLUSION specific viral phenotypes which, in agreement with con- ceptual hypotheses [139], are a collective property of the ensemble. A decrease in quasispecies diversity limits The genotype-to-function map is many-to-many. its adaptive ability and attenuates its pathogenic poten- Many genotypes can code for similar phenotypes and tial [44], and hinders the production of new phenotypes each genotype has the potential to express a variety through cooperative interactions [140]. Even within a of phenotypes. As a consequence, the map is proto- population, therefore, different genotypes interact non- functional and highly adaptable. The exploration of evo- linearly: the whole is more than the sum of its parts. lutionary innovations, further, is a process that runs in A quasispecies bears an enormous innovative potential parallel under many different selective conditions. Also, that can be explored through genotype combinatorics. what is not useful in a certain context may provide an Population bottlenecks, which are common in viral prop- advantage and thrive in another. HGT in its many agation and facilitate the fixation of mutants [141], could expressions promotes this distributed assay-select-share- act as filters to explore many random combinations of combine process. Once a variety of pieces is in place, few genotypes simultaneously, thus benefiting viral phe- spontaneous cooperative associations can give rise to new notypic innovation and, eventually, viral persistence. levels of complexity. Multipartite viruses take flexible cooperation to the Evolution operates at such long time scales that even extreme. These viruses have their genomes fragmented detailed observations of the here and now turn out to in a variable number of pieces, from two to eleven, that be insufficient to educate our intuition on the diversity are encapsidated and propagated in independent parti- of complex molecular organizations possible, and on the cles [46, 47]. This lifestyle faces the risk of loosing ge- underlying mechanisms. It happens often that certain nomic information due to the seemingly small number evolutionary pathways are disregarded only because we of viral particles that are transmitted from host to host. never considered them as a possibility or never looked Until now, the advantages of such genomic organization for their products. An example is the idea of a de novo remain unclear [142, 143], though there are two impor- generation of function: only in the last decade have we tant factors that may have contributed to the repeated uncovered how genes can be generated from non-genic emergence of multipartite viruses in evolution: the pos- sequences [152, 153], how transposable elements can be sibility to adapt to new hosts through gene copy number ”domesticated” to perform specific functions in their host variation [144] and the advantage conferred by fast adap- [154], how promoters emerge from random sequences tation through rapid associations with non-kin when new [155] and how this can happen even in the absence of niches become available [47]. The scenario where multi- sequence diversity, simply through successive cycles of partitism emerges as a successful adaptive strategy of mutation, enrichment and selection [34]. the type first-come first-served is supported by a num- Evolution is a powerful tinkerer. It will use any mech- ber of empirical observations. First, there was a fast ra- anism that is available, low-cost, and constructive in a diation of multipartite viruses when agriculture became very generic way. It uses from phenotypic redundancy to common practice [145]; second, the genome of some mul- gene combinatorics. When all these elements are taken tipartite viruses has genes originated in different viral into consideration, what comes as a difficulty is to imag- families [146]; third, many viruses undergo transient as- ine a world devoid of molecular complexity. sociations with subviral particles, such as virus satellites, that change the viral phenotype [147]. This flexible coop- eration might be a first step to permanent associations in the form of a bipartite virus: there are examples of Acknowledgments viral families with virus-satellite associations and bipar- tite species, as Geminiviruses [148]. Fourth, multipartite The author is grateful to Jos´eA. Cuesta, Ester L´azaro, viruses rapidly modify the copy number of each genomic and Luis F. Seoane for their insightful comments. This fragment from one host species to another [149]. work has been funded by the Spanish Ministerio de Cien- Multipartite viruses infect mostly plants, which are of- cia, Innovaci´on y Universidades-FEDER funds of the Eu- ten simultaneously infected by viruses of different families ropean Union support, under project MiMevo (FIS2017- [150]. This permissiveness may underlie the exploration 89773-P). The Spanish MICINN has also funded the of new associations among viral genes. The route to mul- “Severo Ochoa” Centers of Excellence to CNB, SEV tipartitism, however, should not be unique as, beyond de 2017-0712. 6

[1] F. B. Salisbury, Natural selection and the complexity of the multi-level organisation of the genotype-phenotype the gene, Nature 224, 342 (1969). map, Sci. Rep. 4, 7549 (2014). [2] C. B. Ogbunugafor, A reflection on 50 years of john may- [21] P. Catal´an, A. Wagner, S. Manrubia, and J. A. Cuesta, nard smith’s “protein space”, Genetics 214, 749 (2020). Adding levels of complexity enhances robustness and [3] M. Kimura and T. Ohta, On the rate of molecular evo- evolvability in a multi-level genotype-phenotype map, lution, J. Mol. Evol. 1, 1 (1971). J. R. Soc. Interface 15, 20170516 (2018). [4] T. Ohta, Slightly deleterious mutant substitutions in [22] S. A. Kelly, T. M. Panhuis, and A. M. Stoehr, Phe- evolution, Nature 246, 96 (1973). notypic plasticity: Molecular mechanisms and adap- [5] J. Maynard Smith, Natural selection and the concept of tive significance, in Comprehensive Physiology (Ameri- a protein space, Nature 225, 563 (1970). can Cancer Society, 2012) pp. 1417–1439. [6] R. Dawkins, Climbing Mount Improbable. (Viking, [23] R. J. Sommer, Phenotypic plasticity: From theory and 1996). genetics to current and future challenges, Genetics 215, [7] A. A. Louis, Contingency, convergence and hyper- 1 (2020). astronomical numbers in biological evolution, Stud. [24] K. W. Wucherpfennig, Structural basis of molecular Hist. Philos. Sci. C 58, 107 (2016). mimicry, Journal of Autoimmunity 16, 293 (2001). [8] S. E. Ahnert, Structural properties of genotype- [25] J. Piatigorsky, Gene sharing and evolution: the diversity phenotype maps, J. R. Soc. Interface 14, 20170275 of protein functions (Harvard University Press Cam- (2017). bridge MA:, 2007). [9] J. A. Garcia-Martin, P. Catal´an, J. A. Cuesta, and [26] N. Singh and N. Bhalla, Moonlighting proteins, Annual S. Manrubia, Phenotype size distributions in exact enu- Review of Genetics 54, 265 (2020). merations of genotype spaces, Europhys. Lett. 123, [27] O. Khersonsky and D. S. Tawfik, Enzyme promiscuity: 28001 (2018). a mechanistic and evolutionary perspective, Annu. Rev. [10] P. Yubero, S. Manrubia, and J. Aguirre, The space Biochem. 79, 471 (2010). of genotypes is a network of networks: implications [28] P. A. Tsonis and B. Dwivedi, Molecular mimicry: Struc- for evolutionary and extinction dynamics, Sci. Rep. 7, tural camouflage of proteins and nucleic acids, Biochim- 13813 (2017). ica et Biophysica Acta (BBA) - Molecular Cell Research [11] J. Aguirre, P. Catal´an, J. A. Cuesta, and S. Manrubia, 1783, 177 (2008). On the networked architecture of genotype spaces and [29] N. Vaidya and N. Lehman, One RNA plays three roles its critical effects on molecular evolution, Open Biol. 8, to provide catalytic activity to a group I intron lacking 180069 (2018). an endogenous internal guide sequence, Nucleic Acids [12] P. Catal´an, C. F. Arias, J. A. Cuesta, and S. Manrubia, Res. 37, 3981 (2009). Adaptive multiscapes: An up-to-date metaphor to vi- [30] A. Wagner, Mutational robustness accelerates the origin sualize molecular adaptation, Biol. Direct 12, 7 (2017). of novel RNA phenotypes through phenotypic plasticity, [13] A. Wagner, The origins of evolutionary innovations Biophys. J. 106, 955 (2014). (Oxford University Press, 2011). [31] G. C. Conant and K. H. Wolfe, Turning a hobby into [14] K. Dingle, S. Schaper, and A. A. Louis, The struc- a job: How duplicated genes find new functions, Nat. ture of the genotype-phenotype map strongly constrains Rev. Genet. 9, 938 (2008). the evolution of non-coding RNA, Interface Focus 5, [32] S. Schaper and A. A. Louis, The arrival of the frequent: 20150053 (2015). How bias in genotype-phenotype maps can steer popu- [15] S. Manrubia and J. A. Cuesta, Distribution of geno- lations to local optima, PLoS ONE 9, e86635 (2014). type network sizes in sequence-to-structure genotype- [33] C. Briones, M. Stich, and S. C. Manrubia, The dawn of phenotype maps, J. R. Soc. Interface 14, 20160976 the rna world: Toward functional complexity through (2017). ligation of random rna oligomers, RNA 15, 743 (2009). [16] S. Gavrilets and J. Gravner, Percolation on the fitness [34] F. Wachowius, B. T. Porebski, C. M. Johnson, hypercube and the evolution of reproductive isolation, and P. Holliger, Emergence of function from sin- Journal of Theoretical Biology 184, 51 (1997). gle rna sequences by darwinian evolution, bioRxiv [17] W. Fontana, Modelling ‘evo-devo’ with RNA, BioEssays 10.1101/2021.03.03.433769 (2021). 24, 1164 (2002). [35] P. Catal´an, S. F. Elena, J. A. Cuesta, and S. Manrubia, [18] E. A. Schultes and D. P. Bartel, One sequence, two Parsimonious scenario for the emergence of viroid-like ribozymes: implications for the emergence of new ri- replicons de novo, Viruses 11, 425 (2019). bozyme folds, Science 289, 448 (2000). [36] S. C. Manrubia and C. Briones, Modular evolution [19] S. Manrubia, J. A. Cuesta, J. Aguirre, S. E. Ahnert, and increase of functional complexity in replicating rna L. Altenberg, A. V. Cano, P. Catal´an, R. Diaz-Uriarte, molecules, RNA 13, 97 (2007). S. F. Elena, J. A. Garc´ıa-Mart´ın, P. Hogeweg, B. S. [37] E. N. Trifonov and Z. M. Frenkel, Evolution of protein Khatri, J. Krug, A. A. Louis, N. S. Martin, J. L. Payne, modularity, Current Opinion in Structural Biology 19, M. J. Tarnowski, and M. Weiß, From genotypes to or- 335 (2009). ganisms: State-of-the-art and perspectives of a corner- [38] F. P. Ryan, Genomic creativity and natural selection: stone in evolutionary dynamics, Physics of Life Reviews, a modern synthesis, Biological Journal of the Linnean to appear (2021), https://arxiv.org/abs/2002.00363. Society 88, 655 (2006). [20] C. F. Arias, P. Catal´an, S. Manrubia, and J. A. [39] G. P. Wagner, M. Pavlicev, and J. M. Cheverud, The Cuesta, toyLIFE: a computational framework to study road to modularity, Nature Reviews Genetics 8, 921 7

(2007). hammerhead ribozyme: A long history for a short rna, [40] S. A. West, R. M. Fisher, A. Gardner, and E. T. Molecules 22, 78 (2017). Kiers, Major evolutionary transitions in individuality, [60] S. Gwiazda, K. Salomon, B. Appel, and S. M¨uller, Rna Proceedings of the National Academy of Sciences 112, self-ligation: From oligonucleotides to full length ri- 10112 (2015). bozymes, Biochimie 94, 1457 (2012). [41] J. Maynard Smith and E. Szathmary, The Major Tran- [61] Y. Staroseletz, S. Nechaev, E. Bichenkova, R. A. Bryce, sitions in Evolution (Freeman, Oxford, 1995). C. Watson, V. Vlassov, and M. Zenkova, Non-enzymatic [42] J. E. Stewart, Towards a general theory of the major recombination of rna: Ligation in loops, Biochimica et cooperative evolutionary transitions, Biosystems 198, Biophysica Acta 1862, 705 (2018). 104237 (2020). [62] L. Villarreal and G. Witzany, Social networking of [43] E. S. Colizzi and P. Hogeweg, Evolution of functional quasi-species consortia drive virolution via persistence, diversification within quasispecies, Genome Biol. Evol. Viruses (2021). 6, 1990 (2014). [63] M. Eigen and P. Schuster, The hypercycle, Naturwis- [44] M. Vignuzzi, J. K. Stone, J. J. Arnold, C. E. senschaften 65, 7 (1978). Cameron, and R. Andino, Quasispecies diversity deter- [64] N. Szostak, S. Wasik, and J. Blazewicz, Hypercycle, mines pathogenesis through cooperative interactions in PLoS Comput. Biol. 12, e004853 (2016). a viral population, Nature 439, 344 (2006). [65] N. Vaidya, I. A. Chen, R. Xulvi-Brunet, and N. Hay- [45] J. Iranzo, M. Krupovic, and E. V. Koonin, The double- den, Eric J.and Lehman, Spontaneous network forma- stranded DNA virosphere as a modular hierarchical net- tion among cooperative rna replicators, Nature 491, 72 work of gene sharing, mBio 7, e00978 (2016). (2012). [46] A. Sicard, Y. Michalakis, S. Guti´errez, and S. Blanc, [66] J. I. Jim´enez, R. Xulvi-Brunet, G. W. Campbell, The strange lifestyle of multipartite viruses, PLoS R. Turk-MacLeod, and I. A. Chen, Comprehensive ex- Pathog. 12, e1005819 (2016). perimental fitness landscape and evolutionary network [47] A. Luc´ıa-Sanz and S. Manrubia, Multipartite viruses: for small RNA, Proc. Natl. Acad. Sci. USA 110, 14984 Adaptive trick or evolutionary treat?, npj Sys. Biol. (2013). App. 3, 34 (2017). [67] J. L. Payne and A. Wagner, The robustness and evolv- [48] L. F. Seoane and R. Sol´e, How turing para- ability of transcription factor binding sites, Science 343, sites expand the computational landscape of 875 (2014). digital life, arXiv:1910.14339 [q-bio.PE] (2020), [68] M. D. J. Hutton, Theory of the earth, Transactions arxiv.org/abs/1910.14339. of the Royal Society of Edinburgh 1, 209 (1785), read [49] E. V. Koonin, Viruses and mobile elements as drivers of March 7. and April 4. evolutionary transitions, Interface Focus 371, 20150442 [69] M.-C. Maurel, F. Leclerc, J. Vergne, and G. Zaccai, (2016). RNA back and forth: Looking through ribozyme and [50] P. Schuster, W. Fontana, P. F. Stadler, and I. L. Ho- viroid motifs, Viruses 11, 283 (2019). facker, From sequences to shapes and back: A case [70] A. C. Tuck and D. Tollervey, Rna in pieces, Trends in study in RNA secondary structures, Proc. Roy. Soc. Genetics 27, 422 (2011). London B 255, 279 (1994). [71] J. Houseley and D. Tollervey, The many pathways of [51] W. Gilbert, The RNA world, Nature 319, 618 (1986). rna degradation, Cell 136, 763 (2009). [52] W. Gr¨uner, R. Giegerich, D. Strothmann, C. Reidys, [72] M. Combe, R. Garijo, R. Geller, J. M. Cuevas, and J. Weber, I. L. Hofacker, P. F. Stadler, and P. Schuster, R. Sanju´an, Single-cell analysis of rna virus infection Analysis of RNA sequence structure maps by exhaustive identifies multiple genetically diverse viral genomes enumeration. I. Neutral networks, Monatsh. Chem. 127, within single infectious units, Cell Host Microbe 18, 424 355 (1996). (2015). [53] M. Stich, C. Briones, and S. C. Manrubia, On the [73] D. P. Bartel, Micrornas: genomics, biogenesis, mecha- structural repertoire of pools of short, random RNA se- nism, and function, Cell 116, 281 (2004). quences, J. Theor. Biol. 252, 750 (2008). [74] L. He and G. J. Hannon, Micrornas: small rnas with a [54] J. A. Cuesta and S. Manrubia, Enumerating secondary big role in gene regulation, Nature Reviews Genetics 5, structures and structural moieties for circular RNAs, J. 522 (2004). Theor. Biol. 419, 375 (2017). [75] T. O. Diener, Potato spindle tuber “virus”: IV. A [55] R. Lorenz, S. H. Bernhart, C. H¨oner zu Siederdissen, replicating, low molecular weight rna, Virology 45, 411 H. Tafer, C. Flamm, P. F. Stadler, and I. L. Hofacker, (1971). ViennaRNA Package 2.0, Algorithms for Mol. Biol. 6, [76] T. O. Diener, Origin and evolution of viroids and viroid- 26 (2011). like satellite rnas, Virus Genes 11, 119 (1996). [56] W. Huang and J. Ferris, Synthesis of [77] F. D. Serio, B. Navarro, and R. Flores, Origin and evolu- 35–40 mers of rna oligomers from unblocked tion of viroids, in Viroids and satellites, edited by A. Ha- monomers. a simple approach to the rna world, didi, R. Flores, J. Randles, and P. Palukaitis (Academic Chemical Communications 9, 1458 (2003). Press, 2017) pp. 125–134. [57] J. M. Buzayan, W. L. Gerlach, and G. Bruening, Nonen- [78] T. O. Diener, Are viroids escaped introns?, Proc. Natl. zymatic cleavage and ligation of rnas complementary to Acad. Sci. USA 78, 5014 (1981). a plant virus satellite rna, Nature 323, 349 (1986). [79] M. C. Kiefer, R. A. Owens, and T. O. Diener, Structural [58] M. J. Fedor, Tertiary structure stabilization promotes similarities between viroids and transposable genetic el- hairpin ribozyme ligation, Biochemistry 38, 11040 ements, Proc. Natl. Acad. Sci. USA 80, 6234 (1983). (1999). [80] T. O. Diener, Viroids as prototypes or degeneration [59] M. de la Pe˜na, I. Garc´ıa-Robles, and A. Cervera, The products of viruses, in Viruses, Evolution and Cancer, 8

edited by E. Kurstak and K. Maramorosch (Academic [100] W. G. van Doorn and E. J. Woltering, Many ways to Press, New York, 1974) pp. 757–783. exit? cell death categories in plants, Trends in Plant [81] R. Flores, S. Gago-Zachert, P. Serra, R. Sanju´an, and Science 10, 117 (2005). S. F. Elena, Viroids: Survivors from the RNA world?, [101] M. A. Brockhurst, N. Colegrave, D. J. Hodgson, and Annu. Rev. Microbiol. 68, 395 (2014). A. Buckling, Niche occupation limits adaptive radiation [82] T. O. Diener, Prog. Clin. Biol. Res. 364, 243 (1991). in experimental microcosms, PLoS ONE 2, e193 (2007). [83] S. F. Elena, J. Dopazo, R. Flores, T. O. Diener, and [102] J. Losos, Adaptive radiation, ecological opportunity, A. Moya, Phylogeny of viroids, viroidlike satellite rnas, and evolutionary determinism, The American Natural- and the viroidlike domain of hepatitis δ virus, Proc. ist 175, 623 (2010). Natl. Acad. Sci. USA 88, 5631 (1991). [103] F. Blanco, J. Calatayud, D. M. Mart´ın-Perea, M. S. [84] G. M. Jenkins, C. H. Woelk, A. Rambaut, and E. C. Domingo, I. Men´endez, J. M¨uller, M. H. Fern´andez, and Holmes, Testing the extent of sequence similarity among J. L. Cantalapiedra, Punctuated ecological equilibrium viroids, satellite rnas, and hepatitis delta virus, J. Mol. in mammal communities over evolutionary time scales, Evol. 50, 98 (1983). Science 372, 300 (2021). [85] T. O. Diener, Viroids: “living fossils” or primordial [104] M. G. Weber, C. E. Wagner, R. J. Best, L. J. Harmon, RNAs?, Biol. Direct 11, 15 (2016). and B. Matthews, Evolution in a community context: [86] S. Gago, S. F. Elena, R. Flores, and R. Sanju´an, Ex- On integrating ecological interactions and macroevolu- tremely high mutation tate of a hammerhead viroid, tion, Trends in Ecology & Evolution 32, 291 (2017). Science 323, 1308 (2009). [105] G. Witzany, ed., Viruses: Essential Agents of Life [87] F. M. Codo˜ner, J.-A. Dar´os, R. V. Sol´e, and S. F. Elena, (Springer, 2012). The fittest versus the flattest: experimental confirma- [106] E. Domingo, Introduction to virus origins tion of the quasispecies effect with subviral pathogens, and their role in biological evolution, in PLoS Pathog. 2, e136 (2006). Virus as Populations (Second Edition), edited by [88] J.-P. S. Glouzon, F. Bolduc, S. Wang, R. J. Naj- E. Domingo (Academic Press, 2020) second edition ed., manovich, and J.-P. Perreault, Deep-sequencing of the pp. 1–33. peach latent mosaic viroid reveals new aspects of pop- [107] E. V. Koonin, T. G. Senkevich, and V. Dolja, The an- ulation heterogeneity, PLoS ONE 9, e87297 (2014). cient virus world and evolution of cells, Biol. Direct 1, [89] D. Zimmern, Do viroids and rna viruses derive from 29 (2006). a system that exchanges genetic information between [108] J. Weitz and S. Wilhelm, Ocean viruses and their ef- eukaryotic cells?, Trends in Biochemical Sciences 7, 205 fects on microbial communities and biogeochemical cy- (1982). cles, F1000 biology reports 4, 17 (2012). [90] B. Ding, The biology of viroid-host interactions, Annual [109] C. A. Suttle, Viruses in the sea, Nature 437, 356 (2005). Review of Phytopathology 47, 105 (2009). [110] R. A. Edwards and F. Rohwer, Viral metagenomics, Na- [91] P. Palukaitis, What has been happening with viroids?, ture Reviews Microbiology 3, 504 (2005). Virus Genes 49, 175 (2014). [111] Y.-Z. Zhang, Y.-M. Chen, W. Wang, X.-C. Qin, and [92] G. Steger and J.-P. Perreault, Structure and associated E. C. Holmes, Expanding the rna virosphere by unbi- biological functions of viroids, Advances in Virus Re- ased metagenomics, Annual Review of Virology 6, 119 search 94, 141 (2016). (2019). [93] R. Hammond, D. R. Smith, and T. O. Diener, Nu- [112] R. Sanju´an, M. R. Nebot, N. Chirico, L. M. Mansky, and cleotide sequence and proposed secondary structure of R. Belshaw, Viral mutation rates, Journal of Virology columnea latent viroid: a natural mosaic of viroid se- 84, 9733 (2010). quences, Nucleic Acids Res. 17, 10083 (1989). [113] A. Abroi and J. Gough, Are viruses a source of new pro- [94] M. A. Rezaian, Australian grapevine viroid—evidence tein folds for organisms? – virosphere structure space for extensive recombination between viroids, Nucleic and evolution, Bioessays 33, 626 (2011). Acids Res. 18, 1813 (1990). [114] E. Domingo and C. Perales, Viral quasispecies, PLoS [95] P.-J. Chen, G. Kalpana, J. Goldberg, W. Mason, Genet. 15, e1008271 (2019). B. Werner, J. Gerin, and J. Taylor, Structure and repli- [115] L. Villarreal, Evolution of viruses, in cation of the genome of the hepatitis δ virus, Proc. Natl. Encyclopedia of Virology (Third Edition), edited Acad. Sci. USA 83, 8774 (1986). by B. W. Mahy and M. H. Van Regenmortel (Academic [96] A. J. Weiner, Q. L. Choo, K. S. Wang, S. Govindara- Press, Oxford, 2008) third edition ed., pp. 174–184. jan, A. G. Redeker, J. L. Gerin, and M. Houghton, A [116] D. M. Kristensen, A. R. Mushegian, V. V. Dolja, and single antigenomic open reading frame of the hepatitis E. V. Koonin, New dimensions of the virus world dis- delta virus encodes the epitope(s) of both hepatitis delta covered through metagenomics, Trends in microbiology antigen polypeptides p24 delta and p27 delta, J. Virol. 18, 11 (2010). 62, 594 (1988). [117] H. Liu, Y. Fu, D. Jiang, G. Li, J. Xie, J. Cheng, Y. Peng, [97] J. Iranzo, P. Puigb´o, A. E. Lobkovsky, Y. I. Wolf, and S. A. Ghabrial, and X. Yi, Widespread horizontal gene E. V. Koonin, Inevitability of genetic parasites, Genome transfer from double-stranded rna viruses to eukaryotic Biol. Evol. 8, 2856 (2016). nuclear genomes, Journal of Virology 84, 11876 (2010). [98] E. V. Koonin, Y. I. Wolf, and M. I. Katsnelson, In- [118] C. Gilbert and R. Cordaux, Viruses as vectors of hor- evitability of the emergence and persistence of genetic izontal transfer of genetic material in eukaryotes, Cur- parasites caused by evolutionary instability of parasite- rent Opinion in Virology 25, 16 (2017). free states, Biol. Direct 12, 31 (2017). [119] D. Moreira and C. Brochier-Armanet, Giant viruses, [99] M. J. Nathan, Molecular ecosystems, Biology & Philos- giant chimeras: The multiple evolutionary histories ophy 29, 101 (2014). of mimivirus genes, BMC Evolutionary Biology 8, 12 9

(2008). [137] R. Miralles, P. J. Gerrish, A. Moya, and S. F. Elena, [120] Y. I. Wolf, D. Kazlauskas, J. Iranzo, A. Luc´ıa-Sanz, Clonal interference and the evolution of rna viruses, Sci- J. H. Kuhn, M. Krupovic, V. V. Dolja, and E. V. ence 285, 1745 (1999). Koonin, Origins and evolution of the global rna virome, [138] K. M. Peck and A. S. Lauring, Complexities mBio 9 (2018). of viral mutation rates, Journal of Virology 92, [121] E. V. Koonin, V. V. Dolja, M. Krupovic, A. Varsani, 10.1128/JVI.01031-17 (2018). Y. I. Wolf, N. Yutin, F. M. Zerbini, and J. H. Kuhn, [139] M. Eigen, Viral quasispecies, Global organization and proposed megataxonomy of the Scientific American 269, 42 (1993). virus world, Microbiology and Molecular Biology Re- [140] Y. Shirogane, S. Watanabe, and Y. Yanagi, Cooperation views 84, e00061 (2020). between different variants: A unique potential for virus [122] M. Dion, F. Oechslin, and S. Moineau, Phage diversity, evolution, Virus Research 264, 68 (2019). genomics and phylogeny, Nature Reviews Microbiology [141] C. Escarm´ıs, E. L´azaro, and S. C. Manrubia, Population 18, 125 (2020). bottlenecks in quasi-species dynamics, Curr. Topics Mi- [123] P.-A. Jachiet, P. Colson, P. Lopez, and E. Bapteste, crobiol. Immunol. 299, 141 (2006). Extensive gene remodeling in the viral world: new ev- [142] A. Luc´ıa-Sanz, J. Aguirre, and S. Manrubia, Theoretical idence for nongradual evolution in the mobilome net- approaches to disclosing the emergence and adaptive work, Genome biology and evolution 6, 2195 (2014). advantages of multipartite viruses, Current Opinion in [124] J. Iranzo, E. V. Koonin, D. Prangishvili, and Virology 33, 89 (2018). M. Krupovic, Bipartite network analysis of the archaeal [143] M. P. Zwart, S. Blanc, M. Johnson, S. Manrubia, virosphere: Evolutionary connections between viruses Y. Michalakis, and M. T. Sofonea, Unresolved advan- and capsidless mobile elements, J. Virol. 90, 11043 tages of multipartitism in spatially structured environ- (2016). ments, Virus Evolution 7 (2021), veab004. [125] S. Bocaletti, V. Latora, Y. Moreno, M. Chavez, and [144] A. Sicard, M. Yvon, T. Timchenko, B. Gronenborn, D. U. Hwang, Complex networks: structure and dy- Y. Michalakis, S. Guti´errez, and S. Blanc, Gene copy namics, Phys. Rep. 424, 175 (2006). number is differentially regulated in a multipartite virus, [126] R. Guimer`a, M. Sales-Pardo, and L. A. N. Amaral, Nat. Comm. 4, 2248 (2013). Module identification in bipartite and directed net- [145] A. J. Gibbs, D. Fargette, F. Garc´ıa-Arenal, and M. J. works, Phys. Rev. E 76, 036102 (2007). Gibbs, Time – the emerging dimension of plant virus [127] M. J. Tisza, D. V. Pastrana, N. L. Welch, B. Stewart, studies, J. Gen. Virol. 91, 13 (2010). A. Peretti, G. J. Starrett, Y.-Y. S. Pang, S. R. Krish- [146] E. V. Koonin, V. V. Dolja, and M. Krupovic, Origins namurthy, P. A. Pesavento, D. H. McDermott, P. M. and evolution of viruses of eukaryotes: The ultimate Murphy, J. L. Whited, B. Miller, J. Brenchley, S. P. modularity, Virology 479–480, 2 (2015). Rosshart, B. Rehermann, J. Doorbar, B. A. Ta’ala, [147] M. Krupovic, J. H. Kuhn, and M. G. Fischer, A clas- O. Pletnikova, J. C. Troncoso, S. M. Resnick, B. Bolduc, sification system for virophages and satellite viruses, M. B. Sullivan, A. Varsani, A. M. Segall, and C. B. Archives of Virology 161, 233 (2016). Buck, Discovery of several thousand highly diverse cir- [148] M. S. N. ul Rehman and C. M. Fauquet, Evolution of cular dna viruses, eLife 9, e51971 (2020). geminiviruses and their satellites, FEBS Lett. 583, 1825 [128] Y.-Z. Zhang, M. Shi, and E. C. Holmes, Using metage- (2009). nomics to characterize an expanding virosphere, Cell [149] Y. Michalakis and S. Blanc, The curious strategy of 172, 1168 (2018). multipartite viruses, Annual Review of Virology 7, 203 [129] C. Darwin, On the Origin of Species by Means of Nat- (2020). ural Selection, or the Preservation of Favoured Races [150] S. F. Elena, G. P. Bernet, and J. L. Carrasco, The games in the Struggle for Life, 1st ed. (John Murray, London, plant viruses play, Curr. Opin. Virol. 8, 62 (2014). 1859). [151] J. Maynard Smith, Evolution and the Theory of Games [130] D. Sepkoski, Rereading the Fossil Record: The Growth (Cambridge University Press, Cambridge, 1982). of Paleobiology as an Evolutionary Discipline (The Uni- [152] A.-R. Carvunis, T. Rolland, I. Wapinski, M. A. Calder- versity of Chicago Press, 2012). wood, M. A. Yildirim, N. Simonis, B. Charloteaux, [131] J. Arbiza, S. Mirazo, and H. Fort, Viral quasispecies C. A. Hidalgo, J. Barbette, B. Santhanam, G. A. Brar, profiles as the result of the interplay of competition and J. S. Weissman, A. Regev, N. Thierry-Mieg, M. E. Cu- cooperation, BMC Evolutionary Biology 10, 137 (2010). sick, and M. Vidal, Proto-genes and de novo gene birth, [132] R. Andino and E. Domingo, Viral quasispecies, Nature 487, 370 (2012). Virology 479-480, 46 (2015), 60th Anniversary Issue. [153] N. Vakirlis, A.-R. Carvunis, and A. McLysaght, [133] R. Sanju´an and P. Domingo-Calap, Genetic diversity Synteny-based analyses indicate that sequence di- and evolution of viral populations, Encyclopedia of Vi- vergence is not the main source of orphan genes, rology , 53 (2021). eLife 9, e53500 (2020). [134] M. Stich, C. Briones, and S. C. Manrubia, Collec- [154] L. Sinzelle, Z. Izsv´ak, and Z. Ivics, Molec- tive properties of evolving molecular quasispecies, BMC ular domestication of transposable elements: Evolutionary Biology 7, 110 (2007). From detrimental parasites to useful host genes, [135] A. S. Huang, Annual Reviews in Microbiology 27, 101 Cellular and molecular life sciences : CMLS 66, 1073 (2009). (1973). [155] A. H. Yona, E. J. Alm, and J. Gore, Random sequences [136] V. V. Rezelj, L. I. Levi, and M. Vignuzzi, The defec- rapidly evolve into de novo promoters, Nature Commu- tive component of viral populations, Current Opinion nications 9, 1530 (2018). in Virology 33, 74 (2018).