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The Impact of History on Our Perception of Evolutionary Events: Endosymbiosis and the Origin of Eukaryotic Complexity

Patrick J. Keeling

Canadian Institute for Advanced Research, Botany Department, University of British Columbia, Vancouver BC V6T 1Z4, Canada Correspondence: [email protected]

Evolutionary hypotheses are correctly interpreted as products of the data they set out to explain, but they are less often recognized as being heavily influenced by other factors. One of these is the historyof preceding thought, and here I look back on historically important changes in our thinking about the role of endosymbiosis in the origin of eukaryotic cells. Specifically, the modern emphasis on endosymbiotic explanations for numerous eukaryotic features, including the cell itself (the so-called chimeric hypotheses), can be seen not only as resulting from the advent of molecular and genomic data, but also from the intellectual acceptance of the endosymbiotic origin of mitochondria and plastids. This transformative idea may have undulyaffected how otheraspects of the eukaryotic cell are explained, in effect priming us to accept endosymbiotic explanations for endogenous processes. Molecular and genomic data, which were originally harnessed to answer questions about cell evolution, now so dominate our thinking that they largely define the question, and the original questions about how eukaryotic cellular architecture evolved have been neglected. This is unfortunate because, as Roger Stanier pointed out, these cellular changes represent life’s “greatest single evolutionary discontinuity,” and on this basis I advocate a return to emphasizing evolutionary cell biology when thinking about the origin of eukaryotes, and suggest that endogenous explanations will prevail when we refocus on the evolution of the cell.

he origin and early diversification of eukary- cellular level in possessing a nucleus and en- Totes are topics that invite big stories because domembrane system, cytoskeleton, and semi- the changes that took place were big ones. The autonomous membrane-bounded organelles origin of eukaryotes was the biggest change in (mitochondria and sometimes plastids), for ex- cell biology since the Last Universal Common ample, but they also possess different means Ancestor (LUCA) of all known life—nearly ev- of replicating and expressing genetic informa- ery major aspect of eukaryotic cells is different tion. Moreover, the differences between eukary- in some way from the corresponding characters otes and other cellular life only increase as you found in bacteria and archaeans, some pro- look more closely. At the gross level, eukaryotic foundly so. Not only are they different at the genes are organized differently than prokaryotic

Editors: Patrick J. Keeling and Eugene V. Koonin Additional Perspectives on The Origin and Evolution of Eukaryotes available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016196 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016196

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P.J. Keeling

ones, but the initiation, elongation, and termi- ideas plays an important role in how we con- nation of transcription and translation are also struct and evaluate these hypotheses. In all hy- different, and even the factors involved in core potheses for the origin of eukaryotes, the order components of these events are often different. of events matters; this is true both in the hypoth- Of course, many aspects of archaeal molecular eses about evolutionary history, but also in how biology have been found to be shared with eu- the history of science influences hypotheses karyotes (Ouzonis and Sander 1992; Creti et al. themselves. This effect is not limited to the or- 1993; Langer and Zillig 1993; Zillig et al. 1993; igin of eukaryotes by any means. Philosophers Keeling and Doolittle 1995a,b). Notwithstand- have discussed in detail how history distorts our ing these similarities, much about eukaryotes thinking in many fields, just as psychologists are remains unique, and in need of explanation. well aware of cognitive processes that affect how Unfortunately for evolutionary biologists, this we interpret information. However, most scien- transition has left behind few intermediates tists working in any particular field (including (other than possibly Archaea, depending on myself ) have little awareness of these ideas, and your point of view), and thus we have a quan- they are seldom foremost in our minds when we tum leap in cellular and molecular change to interpret our data, almost as though we are our- explain, and only a few restraints imposed by selves experimental subjects but never get the direct evidence, which Martin (1999) has nicely diagnosis needed to be more self-aware of the described as “...a laborious exercise in deduc- reflexive nature of scientific theories. tion and inference.” Two main ways to look at how such a funda- HISTORICAL VIEWS OF THE ORIGIN mental transition in evolution took place have OF EUKARYOTES emerged. The first of these can be generalized as endogenous or autogenous thinking, in which a Although the basic concepts are older (Chatton large number of small sequential changes took 1925, 1938; Sapp 2005), our modern ideas of the place, generally driven by selection for some differences between prokaryotic and eukaryotic ability or property. This is essentially descent cells are relatively new, primarily informed as with modification. In this case, we have some they were by the technical inventions of electron idea what these changes were, and the challenge microscopy (Robinow 1956, 1962; Stanier and is to work out the order of events and come up Van Niel 1962), and more recently molecular with explanations as to why one change preced- biology (Woese 1987, 1994; Woese et al. 1990; ed anotheror, more powerfully, to suggest where Olsen et al. 1994). The first attempts to compre- a change could have precipitated other changes. hensively explain these differences were synthet- The second view can be generalized as exoge- ic, and primarily endogenous. That is to say, nous, or changes driven by endosymbiosis. these explanations generally arose from a desire Here, one looks for a single sweeping cause of to explain the whole process of how eukaryotic many changes that was precipitated by the fu- cells evolved from prokaryotic cells, and pri- sion or merger of different cells (or a cell and a marily relied on the dominant mode of evolu- virus, in some cases), producing a cell with new tion accepted at the time, gradual and incre- properties. The problem here is to identify the mental accumulation of mutational changes, fusion partners and explain what need or benefit each mostly imparting a small effect (e.g., drove the partnership and eventual merger, and Dodge 1965; Stanier 1970; Cavalier-Smith which extant properties trace back to which 1978, 1987a,b; Stewart and Mattox 1980). A partner. few lines of reasoning dominated this debate; In all likelihood, neither of these two ways of one was to simply identify a plausible series of looking at eukaryotic origins is entirely correct; eventsthat couldlead from a generic prokaryotic the truth probably lies between the two ex- form to a generic eukaryotic one (more on this tremes. But here I wish to review not so much below), but others attempted to identify some what is right or wrong, but how the history of link between a “special” group of prokaryotes

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History and Perception of Evolutionary Events

and eukaryotes or, similarly, to identify a par- somes are now interpreted as being highly de- ticular group or groups of eukaryotes as being rived (Gornik et al. 2012; Talbert and Henikoff primitive and therefore closer to prokaryotes as 2012). The Mesokaryote hypothesis has had lit- a whole. tle impact since it was overturned, but the im- An example of a special relationship is the pact of the Archezoa hypothesis has been more hypothesis that red algal eukaryotes arose from significant, surviving well beyond the hypothe- cyanobacteria and were thus the first lineage sis itself. The Archezoa hypothesis was based of eukaryote (Dougherty and Allen 1960). on the idea that several lineages were premito- This was based on an observed connection be- chondrial (Cavalier-Smith 1983, 1993). One tween the two groups’ photosynthetic pigments reason why this hypothesis had such impact associated with phycobilisomes, as well as the was that the initial phylogenetic data appeared lack of flagella in red algae. This was, of course, to support it because representatives of Arche- misleading, because at the time the idea of an zoa tended to branch deeply in SSU rRNA and endosymbiotic origin of plastids from cyano- early protein trees (Vossbrincket al. 1987; Sogin bacteria was not widely accepted, and the hy- et al. 1989; Sogin 1991; Hinkle and Sogin 1993; pothesis died with the recognition that the plas- Hashimoto et al. 1994, 1995; Hashimoto and tid was a cyanobacterium (Bonen and Doolittle Hasegawa 1996; Kamaishi et al. 1996). However, 1975, 1976). this hypothesis also died with the discovery of Identification of putatively “primitive” eu- mitochondrion-derived genes and eventually karyotes has led to several ideas. Two recent mitochondrion-related organelles (MROs, e.g., examples are Cavalier-Smith’s proposal that eu- mitosomes and hydrogenosomes) in all arche- glenids are the deepest-branching lineage, pri- zoan lineages (for review, see Roger 1999; Wil- marily because of the absence of proteins asso- liams and Keeling 2003) and concurrent revi- ciated with mitochondrial import (Cavalier- sions to our understanding of the tree of Smith 2010), or Martin’s proposal that fungi eukaryotes, which showed no specifically deep represent the earliest lineage because of their position for these lineages, and that some were metabolic properties (Martin et al. 2003). It obviously related to mitochondrion-bearing is too soon to say what kind of impact these sisters (Hampl et al. 2009). Interestingly, how- ideas will have in the long term, but looking at ever, even though the idea that the four lineages two older ideas shows the range of possibilities: originally proposed to be Archezoa is scientifi- the Mesokaryotes and Archezoa. Mesokaryotes cally dead, it does continue to have a notable were dinoflagellates, and they were proposed to effect on our thinking about those lineages. represent the most ancient lineage of eukaryotes They have, in general, and the diplomonad that arose from some unidentified bacterial lin- Giardia, in particular, maintained a stubborn eage because of their unusual nuclei (Dodge reputation as being ancient or primitive eukary- 1965). Dinoflagellates lack histones and conven- otes (Morrison et al. 2007; Gourguechon et al. tional chromatin, and instead have permanently 2013). This is no longer specifically tied to their condensed DNA bound to nonhistone proteins lack of mitochondria, but it is doubtful that this (Dodge 1965; Leadbeater and Dodge 1967; Li perception would have gained such popularity 1983; Rizzo and Morris 1983; Rizzo 1991). without the Archezoa hypothesis. This therefore Based on this, they were proposed to be primi- represents an interesting case in which an im- tively prehistone and prenucleosome (Dodge plication of a hypothesis outlives the hypothesis 1965; Rizzo and Nooden 1972; Hamkalo and itself, a topic that is discussed in detail below. Rattner 1977; Rizzo and Morris 1983). This the- ory died with the recognition that dinoflagel- COGNITIVE INERTIA AND THE TRIUMPH lates are not an ancient lineage. They branch OF MODERN ENDOSYMBIOTIC THEORIES within the alveolates, whose other members have normal nuclei, and thus these characters Although there were, of course, alternative views are reinterpreted as derived, and their chromo- on eukaryotic origins (Goksoyr 1966), they did

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not really take hold of mainstream scientific lum, glycosomes, peroxisomes, cytoskeleton, thinking until the now-famous and sometimes and even the nucleus itself (Cavalier-Smith bitter struggle over the endogenous-versus-en- 1987b, 1997; Gupta and Golding 1993; Gupta dosymbiotic origin of mitochondria and plas- and Singh 1994; Lake and Rivera 1994; Gold- tids, which primarily took place through the ing and Gupta 1995; Gupta 1999; Li and Wu 1960s and 1970s (Gibor and Granick 1964; 2005). In his trenchant review of these theories, Klein and Cronquist 1967; Sagan 1967; Mar- and the nucleus in particular, Martin (1999) gulis 1970, 1981; Raff and Mahler 1972, 1975; points out that these hypotheses share a funda- Uzzell and Spolsky 1974; Mahler and Raff mental characteristic that distinguishes them 1975; Taylor 1979; Cavalier-Smith 1987b). Ideas from the hypotheses for an endosymbiotic ori- about the endosymbiotic origin of plastids, in gin of mitochondria and plastids, whereas the particular, date back considerably further (for latter were proposed to explain specific similar- review, see Sapp 1994), but at this point in time, ities between the organelles and particular free- they were not widely accepted among cell biol- living cells, the former were put forward to ex- ogists, even when a good deal of data on their plain traits that were complex, but either lacked semi-autonomous nature had accumulated. Ul- such a connection to specific free-living cells or timately, however, the data in favor of the endo- were based on superficial similarities that did symbiotic theory were simply overwhelming, so not stand up to more detailed comparison. that, in 1982, Gray and Doolittle were able to This is an interesting observation; if these ask, “Has the endosymbiosis hypothesis been hypotheses did not take their cues from specific proven?” (Gray and Doolittle 1982). details of free-living cells, then it is worth asking This marked a sea change in thinking, and why were they proposed? The process of pro- not just related to the acceptance of the endo- posing a scientific hypothesis and testing it with symbiotic origin of mitochondria and plastids, data is well known to everyone practicing re- but also relating to how we think about cellular search, even if they are not the only ways to do evolution in general. To some, this was simply so, but the mechanism by which we accomplish an awakening to the truth, for example, Margu- this is itself an imperfect product of evolution lis’s new field of endocytobiology (Margulis and doubtless arose for some entirely different 1990). However, another perspective is that we cognitive purpose. How we as individuals as- have taken a principle that aptly applied to mi- semble data into a hypothesis, or more impor- tochondria and plastids and pushed it beyond tantly how we interpret data in the context of its useful limits. The case for an endosymbiotic existing hypotheses, are things about which we origin of eukaryotic flagella (or undulopodia) is are not generally self-aware, so it might be fun to a good illustration. This hypothesis was first consider how some of the hypotheses for how proposed by Margulis based on the fundamen- we think impact what we think. tal differences between bacterial and eukaryotic At the risk of treading way beyond my ex- flagella and on perceived similarities between pertise, it is worth introducing a few relevant eukaryotic flagella and spirochete bacteria that concepts from Piaget’s schema theory, which adhere to the surface of certain protists (Sagan is a general model for how humans interpret 1967; Margulis 1970, 1981), and it sought to new information in the context of preexisting follow in the footsteps of plastids and mitochon- frameworks that have been built around existing dria but failed simply because it was wrong. Un- ideas (Piaget 1953). It is important to stress that like plastids and mitochondria, the more we a schemata will not reflect all available informa- learned about spirochetes and flagella, the less tion, but just those pieces that easily fit into the they had in common; no direct link has ever framework that is already in place (i.e., things been established, in particular, at the molecular that agree with what we already believe). People level (e.g., Johnson and Dutcher 1991). Similar are remarkably good at ignoring or even altering stories were told and eventually disproven or information that does not fit with preconceived largely forgotten for the endoplasmic reticu- structures, and we are more likely to remember

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those facts that fit these structures than we are to the very origin of eukaryotic cells in an endo- remember other facts that are inconsistent with symbiotic framework. One important distinc- them. Twospecific and related behaviors that we tion to make clear is that, for the most part, I am can likely all recognize (at least in others if not not referring here to theories that expand on ourselves) relate to our reliance on these con- the contribution of the mitochondrion at the structs. One is known as disconfirmation bias, origin of eukaryotes (this distinction is dis- which is our propensity to require a higher stan- cussed in Koonin 2010 and Katz 2012) but, rath- dard of evidence to disprove an accepted struc- er, theories that propose a novel fusion between ture than was required to form the structure in two cells giving rise to the nucleocytoplasmic the first place. The second is cognitive inertia, component of eukaryotes. The demonstration which relates to the general tendency for our that no known extant eukaryotic lineage prim- beliefs to survive longer than the evidence that itively lacks mitochondria has led to sugges- supported them (the latter is more often ap- tions that mitochondrial origins might coincide plied to the world of business, but applies equal- with the origin of eukaryotes as awhole. Koonin ly well to science, e.g., the vague notion that (2010) has usefully defined theories on mito- Giardia is ancient). chondrial origins as archezoan, which are those With these tendencies in mind, it is tempt- that propose that some protoeukaryote evolved, ing to speculate that the timing of this rush of then took up mitochondria, and symbiogenic, sometimes ill-founded endosymbiotic explana- which are those that propose that mitochondria tions for various components of the eukaryotic were taken up by a cell we would not recognize cells was not a coincidence but, rather, was a as a eukaryote and that this symbiotic merger predictable outcome of the intellectual victory was the trigger for the evolution of eukaryotes. of the endosymbiotic origin of mitochondria The bases for these symbiogenic hypotheses and plastids over the endogenous explanation (some of which are listed in Table 1) have been that had previously dominated our thinking. reviewed in detail elsewhere (e.g., Katz 1998, The endosymbiotic theory created a new frame- 2002, 2012; Martin 1999; Koonin 2010) and work for interpreting information, which is ad- are not reviewed here. vantageous if the information really fits into this The majority of chimeric theories are fun- framework (e.g., much of the data relating to the damentally different from both the endogenous origin of mitochondria and plastids), but mis- theories for the origin of eukaryotes and the leading when information is forced into the endosymbiotic theories for individual organ- framework artificially, or ignored when it dis- elles. One important difference is that they agrees with the framework (e.g., proposals sug- mostly seek to explain conflicting molecular gesting an endosymbiotic origin of the nucleus data and typically use cells as vehicles to explain that ignored the fact that the nucleus is not phylogenetic patterns. Because of this, they are bounded by a double membrane as are mito- not synthetic in the sense that they do not seek chondria and plastids). to comprehensively explain the many differenc- es between eukaryotic and prokaryotic cells, but mostly seek to explain some general observa- ARE CHIMERAS REAL, OR MONSTERS tions about the genes encoded in their genomes. FROM A MYTHICAL ENDOSYMBIOTIC Sometimes they delve into differences at the cel- PANTHEON? lular level (at times perilously; several suggest an These theories for endosymbiotic origins of sin- endosymbiotic origin of the nucleus, as dis- gular structures like flagella, peroxisomes, and cussed above and in Martin 1999), but typically the nucleus grew out of a desire to explain a they are driven by molecular observations, and specific, complex feature of eukaryotic cells. the cellular implications of the explanations are But a second, overlapping class of new theories less well explored. The dominance of molecular that we might loosely define as chimeric theo- data in these theories is also important in their ries also followed, and these sought to explain history because, unlike our knowledge of cyto-

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Table 1. Summary of chimeric theories for the origin of eukaryotes Hypothesis Partners (and what it aims to explain) References Hartman (1984) Archaean and bacterium and RNA Hartman 1984 organism (RNA metabolism) Zillig (1989–1991) Ancestral bacterium and ancestral archaean Zillig et al. 1989; Zillig 1991 (conflicting characters) Sogin (1991) Protoeukaryote and archaean (conflicting Sogin 1991a roots of protein and rRNA trees) Gupta and Golding (1993–1996) Gram-negative bacterium and archaean Gupta and Golding 1993; (conflicting phylogenies) Gupta 1995, 1999; Golding and Gupta 1995 Lake and Rivera (1994) Nuclear endosymbiosis Lake and Rivera 1994 Hydrogen hypothesis (Martin Methanogenic archaean and Martin and Muller 1998 and Muller 1998) a-protebacterium (metabolism) Syntropy hypothesis (Moreira Methanogenic archaean and Moreira and Lopez-Garcia and Lopez-Garcia 1998–2006) d-protebacterium (metabolism) 1998 Clostridium–Sulfolobus nexus Sulfolobus-like archaean and Clostridium- Karlin et al. 1999 (Karlin 1999) like bacterium (dinucleotide signatures and metabolism) Karyomastigont hypothesis Thermoplasma-like archaean and Margulis et al. 2000 (Margulis 2000) spirochete bacterium (cellular traits) Takemura (2001) Archaean and orthopoxvirus (a DNA Takemura 2001 polymerase) Ring of life (Rivera and Lake Eocyte and proteobacterium (conflicting Rivera and Lake 2004 2004) phylogenies) Viral eukaryogensis hypothesis Archaean and virus (meiosis and mitosis) Bell 2006 (Bell 2006) Forterre (2006–2011) Thaumarchaeon and Planctomycetes- Forterre 2006, 2011 Verrucomicrobia-Chlamydiae-like bacterium (DNA)

logical differences between prokaryotes and potheses, which focus on biological reasons eukaryotes, which is changing rather slowly, for the partnership rather than seeking to ex- our access to molecular data has increased dra- plain a specific incongruence in molecular data matically since the 1980s and is changing com- (Martin and Muller 1998; Moreira and Lopez- paratively quickly. As a result, early theories Garcia 1998), and are included in Table 1 de- emerged from the analysis of a single gene, or spite this critical difference because they are the- conflict between a gene and the then established ories that have had impacts on our thinking and SSU rRNA phylogeny (e.g., Zillig and RNA po- should not be ignored. lymerase, Sogin and the root, or Gupta and At the same time as molecular databases HSP70) (Table 1). Sometimes these were ex- grew, the chimeric theories also became more panded to take in other characteristics or genes specific. Early versions tended to suggest vague (Golding and Gupta 1995; Gupta 1995), and partnerships between archaea and bacteria or sometimes they were not. Eventually these eventually Gram-positive bacteria because the grew into analyses of many genes (for review, diversity of available data was so poor (Sogin see Brown and Doolittle 1997), and ultimately 1991; Zillig 1991; Gupta and Golding 1993). whole genomes (Table 1) (e.g., Rivera et al. Subsequent versions tended to be more precise 1998; Rivera and Lake 2004), but they tend to (e.g., proteobacteria or Thermoplasma-like or- stick to genes. Obvious exceptions to these gen- ganism) (Moreira and Lopez-Garcia 1998; Ri- eralities are the syntrophy and hydrogen hy- vera and Lake 2004), but even now genome-

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wide analyses are not leading to a great deal of ing ideas that are new. Especially when higher- specificity, and theories with the most exactly profile papers tend to make more radical claims specified partners tend to do so based on mod- (that are on average more likely to be wrong), it ern analogs rather than an overwhelming signal is impossible to tally up the data in favor of one from genomic data (e.g., Martin and Muller or the other kind of hypothesis by what is being 1998; Moreira and Lopez-Garcia 1998). This is published. Indeed, it is possible that the vast excellent in terms of testability but problematic majority of specialists in a field believe a set of in the sense that we must assume that the met- ideas that has not been explicitly detailed in a abolic properties of modern bacteria reflect well publication for many years (because it is widely those of their ancient relatives, which maybe held and unchanging), but it is conversely pos- untrue given the timescales involved. sible that the repeated statement that an idea is As can be seen from Table 1, these theories widely held because of the number of papers on came to several different conclusions based on this topic can actually lend credibility to the different observed conflicts between different idea, deserved or not. kinds of data; thus, it is not really possible to summarize this as a polemic like the endosym- DOES THE ORDER OF DISCOVERIES AFFECT biotic origin of mitochondria and plastids, with OUR INTERPRETATION OF THEM? chimeric theories versus endogenous theories, because neither is a homogeneous collection Looking back at the history of ideas for the or- of consistent proposals. Instead, both kinds of igin of eukaryotes, there are a couple of poten- theories are collections of independent and gen- tially interesting correlations, but distinguish- erally incompatible proposals, in the case of ing between correlation and cause is not chimeric theories most often based on nonover- straightforward. The rise in popularity of chi- lapping data that led to speculation for chime- meric theories did correlate with the acceptance rism between different partners. The fact that of the endosymbiotic origin of mitochondria many people have proposed chimeric theories and plastids, but also correlates with the rise of does not lend support to the notion as a whole; molecular biology, and these are the data from because the theories tend to propose different which they were predominantly derived. Thus, chimeric events, each should be weighed on its it maybe more complicated than stating that one merits individually. In addition to this issue of gave rise to the other directly, because on one consistency (who ate whom), there is also the hand is a new source of information, while on issue of rationale (why). The theories were the other is a new way to interpret information. mostly proposed to explain different inconsis- Both are extremely influential, but for the most tencies in the data (e.g., phylogenies of different part we are only conscious of the former, and it genes), many of which have either disappeared is very difficult to untangle their relative contri- with addition of more data (e.g., Sogin 1991; butions to the way information is organized and Zillig 1991) or have not been revisited since perceived. additional data on the issue became available, Some insights might come from looking at or since our understanding of horizontal gene the consistency of interpretation of similar transfer has matured somewhat. kinds of data. For the sake of a thought exper- Despite the inconsistencies between differ- iment (and because these were dominant struc- ent chimeric theories, it is easy to fall into the tures in our thinking when the conclusions I am trap of summarizing them on aggregate because about to review were drawn), accept for a min- we often think about the progress of scientific ute that the tree of life consists of three domains ideas according to changing trends in what gets and that the root lies in the branch leading published. It is difficult to publish papers stat- to Bacteria (Gogarten et al. 1989; Iwabe et al. ing the continued persistence of a decades-old 1989; Brown and Doolittle 1995). If we plot idea, even if the idea remains widely accepted, biological characteristics that are common to but remarkably easy to publish papers propos- two of the three domains on that tree, there

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are three possible patterns (Fig. 1). We use par- and eukaryotes are the same and Archaea differs simony to interpret how each of these three pat- (type A in Fig. 1, e.g., Embden-Meyerhof vs. terns evolved, but our logic is not applied con- Entner-Doudoroff glycolysis, or ester-linked sistently, in a fascinating way. fatty acid lipids vs. ether-linked isoprenyl lip- In the case in which Bacteria and Archaea ids), applying the same logic would lead to the are the same and eukaryotes are different, we conclusion that the bacterial/eukaryotic state is historically tend to conclude that the bacte- ancestral and Archaea changed. But when faced rial/archaeal state is ancestral and eukaryotes with these characters (at a time when the tree simply evolved a different state (type E in Fig. structure described above was still widely ac- 1, e.g., having a cytoskeleton vs. not, or having a cepted), we seemed to think they were somehow rotary motor driving flagella vs. dynein motors harder to explain. It is as though the question of driving flagellar motion). In cases in which Ar- how the Archaea can be more closely related to chaea and eukaryotes are the same and Bacteria eukaryotes but differ in character states is are different (type B in Fig. 1, e.g., TATA-bind- uniquely problematic; but, in fact, the logic is ing protein vs. s factor, or Shine-Delgarno vs. no different from eukaryotes having a unique ternary complex-based translation initiation), character state that they do not share with Ar- we tend to conclude that the eukaryotic/archae- chaea, which we readily fit into existing struc- al state was ancestral to these two groups (and tures of thought. whether Bacteria, the archaeal/eukaryotic an- This inconsistency is particularly interesting cestor, or neither is ancestral is ambiguous). because the unique characters of Archaea have Both of these conclusions are based on the been featured (often post hoc) in several chime- same logic and are consistent with one another. ric hypotheses, even if the root evidence of the It is therefore interesting that the third pattern is theory is generally molecular trees. For example, handled differently. In cases in which Bacteria eukaryotes are sometimes said to have informa- tion systems from Archaea and metabolism from Bacteria, which is derived from molecular

E, Eukaryotes B, Bacteria A, Archaea phylogenies but linked to the unusual metabo- unique unique unique lism of Archaea (Rivera et al. 1998). This is a result of looking at the shared similarities of BA E BA E BA E eukaryotic and bacteria metabolism as indicat- ing direct transmission (via chimerism, HGT, EGT, etc.); but another way to look at it is that archaeal metabolism has simply changed a great deal and thus no longer shares many genes with eukaryotes, and some of those that they do share are very divergent. Moreover, this pattern of Figure 1. Distribution of character states between character-state changes observed for the three three domains on the tree of life and how we interpret domains is not unique—if you select any three them. When Bacteria and Archaea share a state and eukaryotes are different (type E), we typically con- lineages within the tree, you can likely assemble clude that the shared state is ancestral to the LUCA sets of characters representing all three possible and eukaryotes changed. When eukaryotes and Ar- patterns, and likely they would all be explained chaea share a state and Bacteria are unique (type B), by differential descent with modification (i.e., we similarly conclude that the shared state was ances- one lineage simply changed). Which raises the tral to the LECA, and either Bacteria or the lineage question, why are character-state patterns that leading to the LECA changed. But when Bacteria and distinguish the Archaea not interpreted as sim- eukaryotes share a state and Archaea are unique (type A), we seem to have trouble applying the same logic, ply reflecting change in that lineage? One pos- which would at face value simply be to conclude that sible factor that may influence our thinking is the shared state was ancestral to the LUCA and that the way in which Archaea were perceived at the Archaea had changed. time their significance was discovered. Many of

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the unique features of eukaryotes are cytological neous origin of mitochondria and eukaryotes. and relatively obvious, and these were accord- These arose from our recognition that mito- ingly recognized very early, and form the foun- chondria did not demonstrably postdate other dations of the “prokaryotic–eukaryotic di- eukaryotic features (like the nucleus, endo- chotomy” that so profoundly influenced our membrane, and cytoskeleton), but all this really thinking historically (Stanier and Van Niel says is that mitochondria may be as old or older 1962; Stanier 1970). Only subsequently did than these features, but it does not suggest that the distinctions between Archaea and Bacteria mitochondria must be older, because the ab- become clear, and only when molecular phylog- sence of evidence for an archezoan intermediate enies showed that they were a distinct domain is not evidence for its absence, any more than and then suggested a close relationship between that logic can be applied to any other feature Archaea and eukaryotes did the importance of (e.g., we cannot say the absence of a cytoskele- archaeal characteristics begin to have an impact ton-lacking eukaryote means that its evolu- on larger evolutionary schemes. Our concept of tion must have coincided with the origin of prokaryote was based primarily on Bacteria, and mitochondria). Indeed, the idea that mito- because many of the characteristics of Archaea chondria arose after the diversification of extant that differ from Bacteria are at the molecular eukaryotes is itself a relatively recent idea (Stew- level and were discovered concurrently with art and Mattox 1980; Cavalier-Smith 1983). If the discovery that they are distinct and closer our understanding of mitochondrial diversity to eukaryotes, they became the exceptions. At had been established 10 years earlier, the Arche- the same time, the powerful notion that Archaea zoa hypothesis would never have been pro- were an ancient lineage took hold (Balch et al. posed, and would never have been disproven. 1977; Woese and Fox 1977a,b). Although there Without all this context, the simultaneous sym- is no evidence to support this idea, it neverthe- biogenic hypotheses might never have been pro- less strongly affected how Archaea were and still posed. are interpreted. Indeed, it is entirely plausible that the notion that Archaea are ancient or BIASED BY DATA: WHAT COULD primitive continues to undermine the interpre- COUNTERFACTUAL HISTORIES TELL US? tation of unique features of the group as being due to relatively recent modifications. In his seminal review on the origin of eukary- Ideally, how we evaluate evidence to arrive at otes, Roger Stanier (1970) made his now- a likelihood through logical thinking like parsi- famous remark that evolutionary speculation mony should be a commutative process (which was “...a relatively harmless habit, like eating is to say, the order of operations will not affect peanuts, unless it assumes the form of an obses- the outcome, e.g., 1 þ 2 ¼ 2 þ 1), but it is not. sion; then it becomes a vice.” If excessive evolu- The order in which we discover or learn things tionary speculation can be a vice, then exces- contributes to how we interpret their meaning sively speculating about how we think about because we do not interpret information in a evolutionary speculation surely is much worse. vacuum but, rather, in the context of established Indeed, taking into account how we might think structures. It is interesting to consider how our about new information can only really tell us thinking might have differed had Archaea been how the history of ideas might affect what we the mainstream microbes of study that formed think, but does it contribute anything to suggest our beliefs about prokaryotes. Bacteria are both what version of the evolutionary origin of eu- more distantly related to eukaryotes and more karyotes might actually reflect what really hap- different in their molecular character states; pened? The answer is, maybe, but in any event it thus, it is not unreasonable to think that they is worthwhile to return to the question really might now be considered the more strange and being asked, and the data itself. unusual prokaryotes. A similar case may be seen The question of how eukaryotes originated in the symbiogenic hypotheses for the simulta- was initially a cytological one. Early theories fo-

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P.J. Keeling

cused on explaining the significant differences tion, and now we are like children mesmerized between prokaryotic and eukaryotic cells and by a new toy. how the many unique characteristics of eukary- It is interesting, therefore, to consider what otes arose. Currently, however, we are obsessed kinds of conclusions we might draw if we as a field with genomic data. Evolutionary biol- learned what we know today in a different order, ogy and molecular biology have rapidly ad- or learned it all at once. Counterfactual histories vanced together, as have cell biology and molec- refer to the intellectual exercise of “what if,” ular biology. In contrast, however, a strongly where some historical facts are altered, and integrated evolutionary cell biology has lagged then we consider what effects those changes behind; thus, molecular and genomic data have would have on other facts. This kind of thinking come to dominate recent thinking about the is mostly applied to political histories (e.g., what origin of eukaryotes. This is also aided by the if Hitler was born a woman), where there is no relative ease of molecular methods and, in par- set outcome and an infinite number of possibil- ticular, their scalability (-omics), and perhaps ities that might play out. These ideas have been a certain degree of genomic arrogance that applied to several fields of science (Pessoa 2000, arose from the transformational changes that 2010; Radick 2008), but there are two ways to do molecular biology genomics have legitimately this. Science, as opposed to the history of sci- wrought on other biological disciplines, giving ence, is typically seeking to discover something this kind of data an air of objectivity and supe- that exists whether we discover it or not. Chang- riority. Consequently, modern chimeric theo- ing some of these facts would be implausible, ries that arose from molecular and genomic even silly, and do not really tell us much about data were typically not formulated to explain reality (like, what if ice was heavier than water). the characteristics of eukaryotic cells but, rather, But, in other cases, reality is sufficiently re- to explain inconsistencies in the molecular and moved from our direct knowledge and involves genomic data itself. In Doolittle’s prescient and a sufficient degree of chance to allow informa- referential review at the 25th anniversary of Sta- tive changes to be imposed, like replaying evo- nier’s (Doolittle 1996), he concluded, “Peanuts lutionary history to see if humans are likely are often just snacks before supper. Such specu- (Gould 1990; Dawkins 2005). Thus, counterfac- lations based on limited quantifiable data whet tual histories of science are constrained by the our appetites for the multi-course meal of ge- facts that exist to be discovered, but if we focus nome sequences about to be served, but by the on alternative histories of the human activity of time we get to the dessert of comparative ge- science, then these constraints limit the universe nome analysis, we will have forgotten many of of possible histories in away that may allow us to them.”This has certainly proved true, and, going consider whether our interpretation of the facts further, it seems that we have forgotten why we stands up to scrutiny. If, for example, we were to applied genomics to this question in the first develop a series of counterfactual histories in place. Even if the genome of the nucleocytoplas- which a certain set of now-accepted scientific mic lineage is ultimately proven to be derived observations was made in different chronolog- from a fusion of two cells to produce a genomic ical order, would we always interpret them in chimera, this only adds one step in the origin of the same way? The answer is probably no. eukaryotes, but by itself does not explain the If we go back to the original question we set cellular innovations like the cytoskeleton, endo- out to address, the list of eukaryotic innovations membrane system, or potentially even the dif- that need explanation has not changed much. ferences in information storage and process- The similarities in information systems of Ar- ing systems, which represent the hallmark chaea and Eukarya push back some character- eukaryotic features initially in need of explain- istics to before the origin of eukaryotes (Ouzo- ing. We have called upon genomic data to help nis and Sander 1992; Creti et al. 1993; Langer explain these changes, but having generated the and Zillig 1993; Zillig et al. 1993; Kaine et al. data, it is proving in some ways to be a distrac- 1994; Marsh et al. 1994; Keeling and Doolittle

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History and Perception of Evolutionary Events

1995a,b; Langer et al. 1995; Ouzonis et al. 1995), to prevailing ideas, the problem can sometimes and we have identified distant relatives of many be simplified or at least seen more clearly. The other uniquely eukaryotic proteins (Sanchez origin of eukaryotes began as a cytological prob- et al. 1994; Erickson 1995; Erickson et al. lem, and if we return to thinking about the cells 1996), but cytologically much of what Roger as a whole, I suspect it will lead us back to au- Stanier suggested in 1970 still makes sense, re- togenous mechanisms to explain the most im- gardless of whether some chimerical hypotheses portant transitions. Molecular biology and ge- are correct or not. Stanier’s intuition was to nomics are powerful tools to test hypotheses propose characteristics that most likely preced- that explain cytological changes, but it is a mis- ed other characteristics because they made sub- take to let these kinds of data dominate the sequent changes more plausible. For example, formulation of hypotheses with no reference he identified the cytoskeleton as a key innova- to their cytological implications. This leads us tion because it would logically precede the en- away from the transformation of cellular archi- domembrane system, which itself had to be in tecture, which, as Stanier also pointed out (Sta- place to make the nucleus (which is a part of the nier et al. 1957), remains “...the greatest single endomembrane system) and for endocytosis to evolutionary discontinuity to be found in the take place, which is itself a logical predecessor of present day world.” endosymbiosis, which gave rise to mitochon- dria. Stanier was wrong on some details because our understanding of the endosymbiotic origin ACKNOWLEDGMENTS of mitochondria and plastids was in its infancy, Nearly all of the reading and thinking behind and he did not elaborate on the details of why this work was done during the tenure of a fel- some of these events could happen. Now, how- lowship from the John Simon Guggenheim Me- ever, many molecular-based hypotheses fail not morial Foundation, from 2012 to 2013. I also only to explain why these changes took place, thank the Canadian Institute for Advanced Re- but do not even explain how they might have search for long-term support. This review is the anymore. The noteworthy exceptions serve to direct result of a rash letter sent to my co-editor, prove the rule. Martin has approached the prob- Eugene Koonin, and I thank him for his, prob- lem from an energetics point of view that also ably misguided, encouragement. I also thank takes into account the actual cellular transition Ford Doolittle, Michael Gray, Fabien Burki, from prokaryote to eukaryote (Martin and Todd Handy, and Maureen O’Malley for valu- Muller 1998; Sousa et al. 2013), whereas Cava- able discussions on this topic and extremely lier-Smith has for many years been developing helpful guidance and criticism. variations of the neomuran hypothesis that, while based on cytological principles, incorpo- rate molecular data (phylogenies in particular) REFERENCES and are about as close in form to the original Reference is also in this collection. cytological explanations as we now have (e.g., Balch WE, Magrum LJ, Fox GE, Wolfe RS, Woese CR. 1977. see Cavalier-Smith 1987a, 2014). An ancient divergence among the bacteria. J Mol Evol 9: This can all be summed up rather simply. 305–311. Scientific hypotheses are the products of several Bell PJ. 2006. Sex and the eukaryotic cell cycle is consistent factors, the data being only one of them. As with a viral ancestry for the eukaryotic nucleus. J Theor Biol 243: 54–63. scientists, we focus on the data and are largely Bonen L, Doolittle WF. 1975. On the prokaryotic nature of unconscious of the many other factors influenc- red algal chloroplasts. Proc Natl Acad Sci 72: 2310–2314. ing how we interpret it, but the influence of Bonen L, Doolittle WF.1976. Partial sequences of 16S RRNA history should not be underestimated. If we and the phylogeny of blue-green algae and chloroplasts. can occasionally slough off history and rethink Nature 261: 669–673. Brown JR, Doolittle WF. 1995. Root of the universal tree of the problem and what information we have that life based on ancient aminoacyl-tRNA synthetase gene might address it, without being quite so bound duplications. Proc Natl Acad Sci 92: 2441–2445.

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The Impact of History on Our Perception of Evolutionary Events: Endosymbiosis and the Origin of Eukaryotic Complexity

Patrick J. Keeling

Cold Spring Harb Perspect Biol 2014; doi: 10.1101/cshperspect.a016196

Subject Collection The Origin and Evolution of Eukaryotes

The Persistent Contributions of RNA to Eukaryotic Origins: How and When Was the Eukaryotic Gen(om)e Architecture and Cellular Mitochondrion Acquired? Function Anthony M. Poole and Simonetta Gribaldo Jürgen Brosius Green Algae and the Origins of Multicellularity in Bacterial Influences on Animal Origins the Plant Kingdom Rosanna A. Alegado and Nicole King James G. Umen The Archaeal Legacy of Eukaryotes: A Missing Pieces of an Ancient Puzzle: Evolution of Phylogenomic Perspective the Eukaryotic Membrane-Trafficking System Lionel Guy, Jimmy H. Saw and Thijs J.G. Ettema Alexander Schlacht, Emily K. Herman, Mary J. Klute, et al. Origin and Evolution of the Self-Organizing The Neomuran Revolution and Phagotrophic Cytoskeleton in the Network of Eukaryotic Origin of Eukaryotes and Cilia in the Light of Organelles Intracellular Coevolution and a Revised Tree of Gáspár Jékely Life Thomas Cavalier-Smith On the Age of Eukaryotes: Evaluating Evidence Protein Targeting and Transport as a Necessary from Fossils and Molecular Clocks Consequence of Increased Cellular Complexity Laura Eme, Susan C. Sharpe, Matthew W. Brown, Maik S. Sommer and Enrico Schleiff et al. Origin of Spliceosomal Introns and Alternative How Natural a Kind Is ''Eukaryote?'' Splicing W. Ford Doolittle Manuel Irimia and Scott William Roy

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Protein and DNA Modifications: Evolutionary What Was the Real Contribution of Imprints of Bacterial Biochemical Diversification Endosymbionts to the Eukaryotic Nucleus? and Geochemistry on the Provenance of Insights from Photosynthetic Eukaryotes Eukaryotic Epigenetics David Moreira and Philippe Deschamps L. Aravind, A. Maxwell Burroughs, Dapeng Zhang, et al. The Eukaryotic Tree of Life from a Global Bioenergetic Constraints on the Evolution of Phylogenomic Perspective Complex Life Fabien Burki Nick Lane

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Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved