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Origins of Eukaryotic

Ursula Goodenough1 and Joseph Heitman2

1Department of Biology, Washington University, St. Louis, Missouri 63130 2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 Correspondence: [email protected]; [email protected]

Sexual reproduction is a nearly universal feature of eukaryotic organisms. Given its ubiquity and shared core features, is thought to have arisen once in the last common ancestor to all eukaryotes. Using the perspectives of molecular genetics and cell biology, we con- sider documented and hypothetical scenarios for the instantiation and evolution of meio- sis, fertilization, sex determination, uniparental inheritance of organelle genomes, and speciation.

he transition from prokaryote to protoeu- tion of ploidy via cell–cell fusion and ; Tkaryote to the last eukaryotic common an- (2) mating-type regulation of cell–cell fusion cestor (LECA) entailed conservation, modifica- via differentiation of complementary haploid tion, and reconfiguration of preexisting genetic (isogametic and then anisogametic), circuits via mutation, horizontal gene transfer a prelude to species-isolation mechanisms; (3) (HGT), endosymbiosis, and selection, as de- mating-type-regulated coupling of the dip- tailed in previous articles of this collection. Dur- loid/meiotic state to the formation of adap- ing the course of this evolutionary trajectory, the tive diploid resting spores; and (4) mating- LECAbecame sexual, reassorting and recombin- type-regulated transmission of organelle ge- ing in a process that entails regu- nomes. Our working assumption is that lated fusions of haploid gametes and diploid ! the protoeukaryote ! LECA era featured nu- haploid reductions via meiosis. That the LECA merous sexual experiments, most of which was sexual is no longer a matter of speculation/ failed but some of which were incorporat- debateasevidenceofsex,andofgenesexclusively ed, integrated, and modified. Therefore, this involved in meiosis, has been found in all of the list is not intended to suggest a sequence of major eukaryotic radiations (Brawley and John- events; rather, the four innovations most like- son 1992; Ramesh et al. 2005; Kobiyama et al. ly coevolved in a parallel and disjointed fash- 2007; Malik et al. 2008; Phadke and Zufall ion. 2009; Fritz-Laylin et al. 2010; Lahr et al. 2011; Once these core sexual-cycle themes were in Peacock et al. 2011; Vanstechelman et al. 2013). place, the evolution of eukaryotic sex has fea- We propose that the transition to a sexual tured countless prezygotic and postzygotic var- LECA entailed four innovations: (1) alterna- iations, the outcome being the segregation of

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.a016154 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016154

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U. Goodenough and J. Heitman

panmictic populations into distinct species cell–cell fusion entailed the engulfment of one with distinctive adaptations. protoeukaryote by another, with the internal- For additional reviews on the evolution of ized cell membrane then either digested or fused sex, the interested reader is referred to Goode- with the host cell membrane from within. nough (1985), Dacks andRoger (1999), Schurko Increases in ploidy confer indubitable ben- et al. (2009), Wilkins and Holliday (2009), Gross efits: The resultant redundancy allows novel se- and Bhattacharya (2010), Lee et al. (2010), quences/functions to arise in duplicate genes Perrin (2012), and Calo et al. (2013). without compromising existing pathways, and recessive nonadaptive alleles, masked but car- ried through time, may prove to be adaptive ALTERNATION OF PLOIDY VIA CELL–CELL in future contexts. Another potential benefit FUSION AND MEIOSIS of cell–cell fusion is hybrid fitness: If, as seems likely, there existed a variety of fledgling proto- The Benefits and Challenges of Increased eukaryotes in the population that eventually Genome Size and Ploidy gave rise to the LECA, then their fusion would Modern bacteria, and presumably their fore- be expected to have yielded more gene-rich and bears, are adept at taking up DNA from outside occasionally more successful lineages. sources (Narra and Ochman 2006). The proto- Increases in genome size/ploidy are expect- eukaryote, probably at some early stage in its ed to eventually become deleterious, however, evolution, was also phagocytic, at least occasion- one challenge being to organize a successful mi- ally, salient evidence being its engulfment of a tosis, another to regulate appropriate levels of proteobacterium that was then domesticated as gene expression. Hence, there would presum- the mitochondrion. Phagocytosis in modern ably have been positive selection for the acqui- cells is a complex process involving hundreds sition of mechanisms to maintain copy number of proteins (Boulais et al. 2010), but early ver- at a manageable size. sions can be assumed to have been less sophisti- In recent studies, a broad panel of Saccha- cated, and cell membranes capable of engaging romyces cerevisiae and Saccharomyces paradoxus in phagocytosis would presumably also have strains were tested as haploids and diploids un- been capable of engaging in cell–cell fusions, der diverse conditions (Zorgo et al. 2013). For as is the case for wall-less mutants of modern about half of the conditions tested in which bacteria (Errington 2013). It has been suggested there was a difference (such as growth with ra- (Rose 1983; Hickey 1982, 1993) that early cell– pamycin or phleomycin), haploids were more cell fusions might have been promoted by “self- fit, whereas for the other half (such as exposure ish” transposons and plasmids that incur repli- to heat or ethanol), diploids had increased fit- cative advantage in novel genomiccontexts; pos- ness. Which ploidy state was less fit was highly sible evidence for this hypothesis (Keeling and correlated between the two species that are di- Roger 1995) is the use of the HO endonuclease verged over several million years. These findings or a transposase (Barsoum et al. 2010; Rusche suggest that the ability to interconvert from and Rine 2010), conscripted from ancestral haploid to diploid and back again might be transposable elements, to effect mating-type beneficial when conditions shift from those fa- switching in several yeasts. voring the haploid state to those favoring the Cell–cell fusion generates an increase in diploid state (or vice versa). Thus, sexual repro- number, and although the large duction might confer benefits for organisms size of modern eukaryotic genomes could also just by enabling these rapid ploidy transitions, have been the consequence of endomitosis, it independent of any role in shuffling genetic seems likely that cell–cell fusions contributed composition by recombination, with endorepli- to genome expansion during protoeukaryote cation being another avenue. That said, the abil- evolution. An alternative possibility, leading to ity to toggle from haploid to diploid and back the same outcome, is that the earliest versions of again is dependent on a mechanism for ploidy

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Origins of Eukaryotic Sexual Reproduction

reduction, which, in modern eukaryotes, entails Parasexuality in meiotic or parasexual processes. Wealso know about an unusual parasexual cycle that is extant in the most common human fun- PARASEXUALITY gal pathogen, Candida albicans (Bennett et al. In the following sections, in which we consider 2005; Sherwood and Bennett 2009; Berman the origins and evolution of parasexual and 2012). In this species, mating occurs between meiosis-based sexual cycles, we use as examples diploids when the mating-type locus is homo- modern organisms whose mating-type-based zygous (a/a and a/a) and the cells switch to a is already established. In specialized mating cell type called opaque (Mil- subsequent sections we will consider how sexual ler and Johnson 2002). Cell–cell fusion then differentiation itself might have originated and generates tetraploid cells, and adverse media evolved. conditions stimulate random chromosome loss to return to a diploid, or near diploid, state via a parasexual process (Bennett and Johnson Parasexuality in 2003; Forche et al. 2008). Given that Candida is As one must walk before one can run, the fusion embedded among sexual fungi (Butler et al. of cells may have led to early parasexual cycles 2009), this is presumably an example of a de- from which true meiotic sexual cycles evolved at rived parasexual state, but one can envision a later time. We know a great deal about extant analogous earlier versions of genetic exchange parasexual cycles from the classic work of Pon- involving cell–cell fusion followed by parasexu- tecorvo on the filamentous Aspergillus al ploidy change from which true sexual cycles nidulans in the 1950s, and these can provide evolved viathe invention of meiosis. In this view, insight into both possible ancestral states as the evolution of meiosis would have been a late well as more recent derived states given that step in the evolution of sexual cycles. parasexuality, like asexuality, is likely both an In the C. albicans parasexual cycle, a low level ancestral and a derived state (Pontecorvo 1956). of chromosomal recombination is detected in Aspergillus has a bona fide homothallic (self- addition to chromosome loss and assortment, ing) sexual cycle, but also undergoes a parasex- and these recombination events require the ual cycle under laboratory conditions: Diploids function of the C. albicans Spo11 ortholog are generated from haploid progenitors by hy- (Forche et al. 2008), a central player in meiosis. phal fusion and the resulting diploid then loses One interpretation isthat the functions of Spo11 chromosomes randomly to return to the hap- have been reconfigured to play a mitotic, para- loid state. Recent studies have shown that this sexual role. Alternatively, the parasexual cycle of parasexual cycle provides access to a sheltered C. albicans could involve some aspects of meio- diploid state that can serve as a capacitor for sis (such as Spo11-dependent chiasmata), but evolution (Schoustra et al. 2007): More rapidly given the high rate of (e.g., 2N þ growing variants readily arise from homozygous 1, 2N þ 2) that is generated, it does not produce diploids, but not from the corresponding hap- accurate outcomes, and might be considered loid “parent,” and they are then reduced to a something akin to a “parameiosis” (Becker and haploid state. The faster growing variants prove De Castro-Prado 2004; Wilkins and Holliday to harbor multiple recessive alleles, reciprocally 2009; Heitman 2010). Studies on whether other epistatic, that together are beneficial but indi- meiotic orthologs are involved may further illu- vidually are deleterious, and thus they can only minate this interesting example of what could accumulate in the diploid and then be released represent a derived state similar to an ancestral during parasexual genome reduction. These parasexual-sexual transitional intermediate. studies illustrate the capacity of haploid-dip- Numerous studies have identified genes ex- loid-haploid parasexual cycles to generate geno- pressed exclusively in cells undergoing meiosis, typic and phenotypic diversity de novo. generating an inventory of “meiosis-specific

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U. Goodenough and J. Heitman

genes” (Schurko and Logsdon 2008). The C. genome and also reveals recessive alleles in hap- albicans genome was reported to be missing loid progeny of a heterozygous diploid progen- members of this list, which would be consistent itor. The return to the diploid state may have with its parasexual cycle (Tzung et al. 2001). To initially entailed endoreplication, with cell– explore what might be required in related spe- cell fusion mechanisms evolving later. Advan- cies, a series of Candida species that are para- tages of meiosis compared with parasexual sexual, asexual, and fully sexual was sequenced mechanisms are fidelity and more extensive in- (Butler et al. 2009). Quite remarkably, two sex- trachromosomal recombination, at least for the ual species were found to be missing key mat- forms of meiosis that are extant today. ing-type locus genes and yet remain sexually In either view, the enzymes and machinery fertile. Moreover, the sexual species were miss- for meiosis presumably evolved from a core set ing the same key meiotic genes as C. albicans,as of DNA-manipulating enzymes brought in and well as two dozen others! That the unusual sex- modified as needed from prokaryotic forebears, ual species Candida lusitaniae truly undergoes including both bacterial and archaeal lineages meiosis was documented experimentally, and (Marcon and Moens 2005). We see this evolu- thus the gene repertoire to complete meiosis is tionary history quite clearly in the case of apparently more plastic than thought (Reedy Spo11 (Klapholz et al. 1985; Wagstaff et al. et al. 2009). Quite interestingly, this sexual spe- 1985), which introduces the DNA double- cies produces about two-thirds euploid proge- strand breaks (DSBs) that provoke meiotic re- ny, whereas one-third is either aneuploid or combination (Cao et al. 1990; Keeneyet al. 1997; diploid, possibly because they fail to execute Schurko and Logsdon 2008). Spo11 is derived meiosis properly in the absence of important from an ancestral archaeal topoisomerase VI ho- components. Thus, like a V8 engine missing molog that became included in the protoeukar- one spark plug, or a dog with three legs, the yote genome and was then adapted for meiosis engine or animal can run but it is not pretty. (Bergerat et al. 1997). In essence, Spo11 is a Sex in nature may be messier than when studied topoisomerase that lost the ability to re-ligate in the laboratory with optimized S. cerevisiae DNA. That Spo11 was present in the LECA can strains, such as SK1 (which sporulates and ger- be inferred by its presence in all of the major minates at higher frequency than many other eukaryotic lineages studied thus far, with the isolates) (Ben-Ari et al. 2006), and meiotic in- notable exception of Dictyostelium discoidium fidelity may in fact function as a further source and closely related slime molds that have appar- of diversity generated by sexual reproduction. ently lost Spo11 but undergo complete meiotic Alternatively, meiotic infidelity may simply be sexual cycles (discussed further below). tolerated in scenarios wherein a sufficient num- We regard meiosis as accomplishing four ber of viable, fit progeny are generated and/or functions: (1) reducing ploidy (parasexuality the consequences of aneuploidy are small also accomplishes this, albeit less efficiently); enough to be tolerated by the population. (2) purging deleterious alleles (Kondrashov 1988) and unmasking advantageous recessives when meiotic products are haploid (parasexu- MEIOSIS ality also does this); (3) reducing ploidy while An alternative view is that meiosis arose early, also generating complete chromosome sets rath- without prior parasexual experimentation, as a er than incomplete or chaotic sets (the elegance means to generate haploid progeny from a dip- of meiosis I); and (4) generating recombinant loid progenitor. Early meiosis was likely messy offspring via independent assortment and and inaccurate—perhaps only somewhat better crossing over in heterozygotes. We focus here than parasexual changes in ploidy—with more on meiosis, and later consider mating type and accurate mechanisms evolving subsequently. its imposition of heterozygosity on the system. Like parasexuality, meiosis also serves as a mech- Meiosis entails chromosome segregation, anism to purge deleterious mutations from the and thus it is important to consider the nature

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Origins of Eukaryotic Sexual Reproduction

of the chromosomes involved given that most sis and the persistence of sister-chromatid co- modern prokaryotes have circular genomes. hesion through meiosis I into meiosis II. There are several reasons to suggest that proto- There are at least two models for the promo- eukaryotes had linear chromosomes, or at least tion of recombination between homologs ver- that these arose when meiosis evolved. The ear- sus sister chromatids. In model A, 2N ! 4N liest protoeukaryotes may have had only one or DNA replication (hereafter meiotic replication) a few linear chromosomes encompassing the does not occur. Therefore, pairing can only oc- entire genome (which also necessitated the evo- cur between homologs (because replication is lution of centromeres and telomeres to allow required to produce sister chromatids), and faithful segregation and protect the ends from breaks stimulate a crossover between them, gen- decay). Linear chromosomes are required be- erate tension, and promote segregation (note cause crossing over between two circular chro- that breaks might also stimulate their pairing). mosomes generates a circular dicentric that is This is similar to repair of DNA DSBs that oc- unstable (the chromosome is broken if the two curs in diploid fungal and human cells in the G1 centromeres attach to opposite spindle micro- phase of the cell cycle before DNA replication tubules). Even crossing over between one linear (Takata et al. 1998). and one circular chromosome will yield a linear In model B, if we allow meiotic replication dicentric that would also be unstable. The ad- of the 2N to 4N state, there are now both chro- vent of sexual crosses may well have driven the mosome homologs and sister chromatids. Even advent of the linear chromosome: An ancestral without chromosome alignment and synapsis, protoeukaryote might have had two circular DNA DSBs can still be repaired via either the chromosomes with centromeres; their recombi- homolog chromatid or the sister chromatid. If nation would have yielded a circular dicentric this occurs with the homolog, tension will be that, when subjected to incomplete breakage- generated on the meiotic spindle, whereas if fusion-reunion cycles, could have given rise to recombination occurs with the sister chromatid, linear chromosomes. Alternatively, linear chro- tension will not be generated (tension is gener- mosomes may have arisen in other ways, as has ated when the centromeres of the homologs at- occurred in some bacteria and some organelle tach to microtubules from different spindle pole genomes, and predated sexual crosses. bodies/centrosomes; when this does not occur, The evolution of meiosis resulted in homo- segregation is aborted [Nicklas 1997]). So even log chromosome pairing, independent assort- if there were, for example, 10 breaks per chro- ment, chiasmata-based crossing over, and ploi- mosome, and there were a 10:1 preference for dychanges (2N to 4N to 2N to 1N). Independent repair with the sister chromatid versus the ho- assortment produces diversity in the meiotic molog chromatid, that single crossover per products of heterozygotes regardless of levels chromosome would achieve the required ten- of crossing over, and chiasmata have been shown sion. to play an additional role, aligning homologous Either starting point could evolve into a chromosomes and providing tension on the more efficient system that reduces recombina- spindle for accurate meiosis I segregation (Hi- tion with the sister chromatid and/or promotes rose et al. 2011). recombination with the homolog. Why then At a molecular genetic level, the evolution of even include the meiotic replication step? Be- meiosis would have entailed the following inno- cause the key events in a modern meiosis I, in- vations: (1) mechanisms to promote breaks that cluding breaks and repair, occur in a 4N context, stimulate meiotic recombination frequencies to it is difficult to speculate about original condi- higher levels than mitotic recombination fre- tions, but one certain outcome is that more mei- quencies; (2) crossovers that occur between ho- otic progeny are produced (four instead of two), mologs and not between sister chromatids; (3) and in many biological settings brood size mat- DNA replication stimulated at meiosis I and ters. The chances are also increased that there inhibited at meiosis II; and (4) homolog synap- will be at least one viable spore product given

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U. Goodenough and J. Heitman

that meiosis was doubtless less accurate ab initio mosome arms is released but cohesion near the than it later evolved to be. kinetochores persists to allow homologs to seg- Perhaps the most interesting hypothesis for regate. Each of these steps is mediated by mei- why replication occurs before meiotic recombi- osis-specific elements that evolved from ances- nation in meiosis I is that in the pre-Spo11 era, tral roles: step 1 by Spo11 (a former archael the sister-chromatid copies served as the source topoisomerase); step 2 by Rec8 (S. pombe and of DSBs. DSBs are formed by replication of other organisms) or the monopolin complex nicked DNA, in which the nicks might have (S. cerevisiae) and temporal orchestration of been incurred by UV or gamma rays before microtubule-kinetochore interactions to pro- Spo11, and DSBs (but not nicks) are potent mote monopolar rather than bipolar spindle stimulators of homologous recombination. attachment (Miller et al. 2012); and step 3 by Such a model is supported by the finding that Rec8 again (and other related cohesins in many the meiotic defects of S. cerevisiae spo11 mutants organisms) as the meiosis-specific cohesins that can be in part suppressed by gamma irradiation, replace mitotic cohesins (Parisi et al. 1999) and suggesting that random DSBs can suffice to en- persist at kinetochores through meiosis I. Rec8 hance meiotic crossovers and increase spore vi- and related meiotic cohesins can also serve ad- ability and germination (Thorne and Byers ditional roles, including the enhancement of 1993; Celerin et al. 2000). Notably, other types synapsis and recruitment of recombination fac- of DNA lesions, such as abasic sites or nicks tors (Wilkins and Holliday 2009). generated by DNA deaminase acting to convert That Spo11 and its associated cofactors are cytosine to uracil (a substrate for uracil N-gly- nearly universal throughout eukaryotes sug- cosylase), can restore meiotic recombination in gests that it was already a key element in the mutants of the fission yeast Schizosaccharomyces meiosis of the LECA. The one known exception pombe lacking Spo11 (rec12) without generating is the slime mold D. discoideum and closely re- DSBs (Pauklin et al. 2009). These studies show lated species, which appear to have complete that one can take the activation-induced deam- sexual cycles including meiosis but which lack inase (AID) enzyme that stimulates hy- Spo11 (Eichinger et al. 2005; Sucgang et al. permutation of antibody-encoding genes in im- 2011). This implies that the slime molds are a mune cells, express it heterologously in fission derived rather than ancestral state, but that said, yeast mutants lacking Spo11, and the resultant it seems likely that other types of DNA damag- DNA lesions and their processing promote mei- ing pathways have taken the place of Spo11 in otic recombination, restore fidelity of chromo- slime molds. These novel pathways remain to be some segregation, and enhance spore viability identified, and may also function in aspects of and germination frequency. meiosis in other extant organisms. Elucidating A key innovation—indeed, the hallmark of how Spo11-independent meiotic recombina- meiosis—was synapsis between homologs. For tion can occur should shed further light on pos- this to succeed, mechanisms promoting sister sible early steps in the evolution in meiosis in a chromatid cohesion were required. The unique pre-Spo11 era that presumably existed in the feature of meiosis compared with is posited transition from parasexual to sexual ex- meiosis I in which chromosome homologs rath- perimentation in the extinct protoeukaryote er than sister chromatids segregate in a reduc- lineages that antedate the LECA. tional division (Watanabe 2004; Wood et al. It is worth noting explicitly that original 2010). For this to occur, there are three key steps: versions of meiosis may have taken tetraploids (1) homologs must synapse, and this is typically to diploids rather than diploids to haploids, or driven by Spo11-dependent DSBs that provoke octoploids to tetraploids for that matter be- meiotic recombination; (2) the kinetochores cause the key metric is ploidy transition rather from sister chromatids both attach to microtu- than absolute ploidy level; there is no basis to bules from the same spindle pole body via mo- the claim that the original meiotic products nopolar attachment; and (3) cohesion of chro- were haploid, other than the parsimony argu-

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Origins of Eukaryotic Sexual Reproduction

ment that because they are so now then they loid cell adherence to trigger intracellular signals may also have been so when they originated. that elicited the conditions for cell–cell fusion. That said, haploid meiotic products have the Modern sexual recognition systems are over- advantage of allowing the “purging” of delete- whelmingly prezygotic—cells recognize “self” rious alleles and the “unmasking” of potentially via pheromones or cell-surface molecules that adaptive recessive alleles, both clear benefits of stimulate zygotic cell fusion—but postzygotic the modern version of meiosis. mechanisms have also evolved that permit cells to monitor how similar their chromosomal se- quences are with respect to their fusion partner. REGULATION OF CELL–CELL FUSION For example, when different yeast species are induced to fuse with each other, their hybrid is Restricting Cell–Cell Fusion to “Self” unable to proceed smoothly through meiosis, Interactions even if all the chromosomes are colinear and Although the initial pressure to develop meiosis syntenic, because a higher level of DNA mis- may have been to effect ploidy reduction, the matches provokes the mismatch repair machin- process evolved into something far more so- ery to abort meiotic recombination events, and phisticated: a mechanism to generate complete spores fail to germinate (Chambers et al. 1996; chromosome sets during meiosis I and then Hunteret al. 1996). That said, there are examples halve their ploidy during meiosis II. In order in which hybrids that have formed from cross- for haploid products to recapitulate these species cell–cell fusions have ultimately given events, and hence again avail themselves of the rise to new species, such as the posited origin advantages of diploidy, they must in turn fuse of S. cerevisiae from an ancestral whole genome together to create diploids that are both capable duplication event following fusion of two relat- of meiosis and precluded from undergoing ad- ed, but different, yeast species (Wolfe and ditional fusion events. Indiscriminate cell–cell Shields 1997; Scannell et al. 2006). Exciting re- fusions, although they may have generated im- cent studies report adaptive changes that occur portant novelties during early protoeukaryotic in the genomes of such cross-species hybrid evolution, generate disparate chromosome yeasts isolated and passaged under laboratory complements that are toxic to a successful mei- conditions; genome rearrangements arise re- osis. Hence the invention of meiosis puts pres- peatedly and independently (Dunn et al. 2013). sure on the development of mechanisms where- in haploid cells first recognize other haploid Limiting Expression of Recognition/Fusion cells with the same chromosome complement, Molecules to Particular Conditions and then fuse with them selectively. Recognition of self is not, of course, a eu- In haploid eukaryotic microorganisms, the dis- karyotic novelty. The widespread occurrence of play of self-recognition/fusion molecules is biofilm formation and quorum sensing in mod- usually not constitutive. Instead, postmeiotic ern bacteria (Vlamakis et al. 2013) and archaea cells first enter a mitotic phase and multiply (Koerdt et al. 2010; Frols 2013) suggests that the until receiving an exogenous signal. In yeasts forebears of protoeukaryotes likely engaged in and Volvox, a pheromone is detected; in most such self-recognition behaviors as well. Modern other microbes some kind of environmental prokaryotic systems feature the secretion of lin- stress, such as the depletion of essential nutri- eage-specific extracellular matrix materials and ents in the environment (often nitrogen), is de- small molecules; their receptor-mediated per- tected (Sager and Granick 1954; Ueno et al. ception then triggers signal-transduction cas- 2001). Detection of such signals then induces cades that modulate growth and metabolism. the expression of genes encoding the necessary Hence self-recognition modules presumably ex- components for adhesion and fusion, where isted in the protoeukaryotic gene pool that, with cells displaying such competence are called evolutionary tinkering, allowed like-like hap- gametes. Again, such a system need not be con-

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U. Goodenough and J. Heitman

sidered a eukaryotic novelty because prokary- tions might have been heterotypic, like pres- otes also limit production of their biofilm and ent-day integrins that adhere to intercellular quorum-sensing components to particular en- adhesion molecules (ICAMs) (Kim et al. 2011). vironmental circumstances (Ng and Bassler Any heterotypic recognition/adhesion pairs 2009). (hereafter H1/H2) in a protoeukaryote would Pheromone-induced control over mating be candidates for the next posited stage in the competence has the advantage of requiring origins of sex, namely, the exclusive expression that a potential mating partner is nearby. A of H1 in gametes that we will generically call stress-imposed elicitation of mating compe- plus mating type and exclusive expression of tence has the effect of enabling the mitotic prog- H2 in gametes that we will call minus mating eny of meiotic products to first test out their type. The regulatory system that limits expres- haploid genomes in the environment into sion of mating-related genes to one or the other which they germinate, with deleterious alleles type of will be called the mating-type- purged and adaptive alleles/genomes spreading determination (MTD) system, with that leading into the population. The survivors can then to plus mating type called MTDP and the other avail themselves of the benefits of entering the leading to minus mating type called MTDM. diploid state when the environment is no longer A simple model for the incarnation of mat- supportive. Life cycles with extended haploid ing type might go as follows. (1) The original phases and occasional diploid phases are often MTD was a transcription factor that, in re- said to engage in facultative sex, as contrasted sponse to the appropriate exogenous signal, ac- with the obligate sex that characterizes most tivated expression of unlinked genes encoding land plants and animals. The conditions that H1 and H2 by binding to common upstream elicit facultative sex may be difficult to identify, sites. (2) A copy of the MTD gene mutated such meaning that sexual interactions may occur in that the DNA-binding motif of its protein prod- the wild that investigators have thus far failed to uct was altered, converting it to MTDP. (3) Mu- recapitulate in the laboratory (Fritz-Laylin et al. tations altered the upstream sequence of the 2010; Grimsley et al. 2010; Halary et al. 2011; gene encoding H1 to match this new MTDP Lahr et al. 2011). configuration so that MTDP now induced Systems that detect an appropriate exoge- only H1 expression. (4) The original version nous signal—hormonal and/or environmen- of MTD continued to activate expression of tal—and elicit downstream gametic differenti- H2; because it is now different from MTDP,it ation are expected to include receptor is designated MTDM. components that are coupled to the regulation The outcome would then be that, with en- of gene expression via signal-transduction cas- vironmental stress, plus gametes displaying H1 cades. Such pathways are well understood in the will only adhere and fuse with minus gametes fungal response to pheromones (Di Segni et al. expressing H2. Because the MTDP and MTDM 2011; Kim et al. 2012), but they have thus far alleles now elicit the formation of two different remained more elusive in microbes that respond kinds of gametes, we can say that they specify to environmental cues because the expression of mating type and that their chromosomal locus many non-sex-related genes is also influenced defines the mating-type (MT) locus, such that by environmental stress. we speak of the MT-plus and MT-minus loci. And because the MT loci are allelic, indepen- dent assortment would generate two plus and THE ORIGINS OF MATING TYPE two minus haploid products at each meiosis. The original self-recognition molecules in pro- That there would be selection for and even- toeukaryotic gametes might have engaged in tual fixation of such a heterozygous system is homotypic interactions, like present-day cad- inherent in the argument most often offered herins that adhere to one another (Hulpiau as the “reason” for eukaryotic sex: its promotion and van Roy 2009). Alternatively, the interac- of outcrossing and hence the generation of nov-

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Origins of Eukaryotic Sexual Reproduction

el genotypes via independent assortment and/ absent from the MT-plus locus. Any organism or crossing over. Although meiosis operates cor- expressing an endogenous or transgenic MID rectly when the chromosomes are fully isogenic, gene differentiates as a minus gamete, switching imposing the requirement that the fusing gam- on minus-specific genes and not expressing etes be heterozygous, at least at the MT-plus/ plus-specific genes, whether or not the MT- MT-minus locus, introduces a whole new role plus locus is also present. When MID is absent for meiosis in the sexual life cycle. or mutant, organisms differentiate as plus (Fer- Outcrossing can carry a proximal cost as ris and Goodenough 1997; Lin and Goode- well, namely, the disruption of adaptive geno- nough 2007). Interestingly, an analogous system types during independent assortment and also operates in mammals. The crossing over (Maynard Smith 1976; Otto and SRY gene, encoding a Sox transcription factor, Gerstein 2006; Goodenough et al. 2007; Escobar dictates male differentiation when present; fe- et al. 2008), a cost that can be overridden by a male differentiation occurs in its absence (Se- shift to asexuality/homothallism/inbreeding kido and Lovell-Badge 2009). or by the occurrence of speciation. Clearly, how- The S. cerevisiae version is similar except ever, this cost has not overridden the benefits of that two tightly linked genes in the MATa locus, genetic shuffling within a population to gener- a1 and a2, collectively perform the same func- ate phenotypes adapted to an ever-changing en- tion as MID: The a1 product (an a-domain vironment, as attested by the retention of the transcription factor) induces a-specific genes meiotic option in most if not all major eukary- and the a2 product (a homeobox transcription otic lineages for more than a billion years. factor) represses a-specific genes (Ni et al. A number of theoretical studies, cited in 2011). The MATa locus lacks the a1 and a2 Hadjivasiliou et al. (2013), have posited that genes; cells inheriting MATa, or cells carrying a the uniparental inheritance of organelles, con- deletion of MAT, differentiate as a gametes. sidered in a later section of this review, preced- Modern microbial gamete-differentiation ed, and led to, the instantiation of mating types. programs have expanded well beyond our min- Hadjivasiliou et al. (2013) present arguments imalist model—many plus/a-specific genes are against this hypothesis, concluding that mat- induced in addition to the H1 equivalent, and ing-type systems would have been buttressed many minus/ a-specific genes are induced in but are not likely to have been initiated by uni- addition to the H2 equivalent (Mata et al. parental systems. 2007; Snell and Goodenough 2008; van Werven et al. 2012)—but the core principle holds. The frequent turnover and convergent evolution of MODERN VERSIONS OF MTD SYSTEMS MT systems indicates the importance and im- AND MT LOCI pact of variations in this system. Two MTD systems are well characterized in The MT loci of yeasts contain only two con- modern eukaryotic microbes, and both prove tiguoustranscription-factor genes; the genes en- to use a variation on our simple model. Instead coding sexual traits are found elsewhere in the of there being two MTD alleles, there exists a genome and regulated in trans. In several other single determinant which, when expressed, dic- organisms, MT loci are more complex (Ferris tates the differentiation of one mating type. et al. 2002, 2010; Metin et al. 2010; Umen When this determinant is absent, the second 2011; De Hoff et al. 2013): As in the yeasts, mating type differentiates “by default.” most genes encoding sexual traits are not linked In the Chlamydomonas reinhardtii version to MTand are regulated in trans, but some sex- of this arrangement (Goodenough et al. 2007), related genes have come to reside in MT along the MID gene encodes a transcription factor in with the mating-type determinant(s). These the RWP-RK family (Lin and Goodenough genes are typically interspersed with non-sex- 2007; Konishi and Yanagisawa 2013). The MT- related genes, and their linkage to MTDs is es- minus locus carries a copy of MID, whereas it is tablished via some form of recombinational re-

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pression. Extreme examples of this phenome- in these cases more encounters are sexually fer- non are the dimorphic (e.g., XY and WZ) sex tile (.98% in some basidiomycetes). But more chromosomes of mammals, birds, and some outcrossing is not always better, and in basidio- land plants, in which recombination is repressed mycete fungi there are multiple independent by reducing the DNA homology needed for syn- transitions from the tetrapolar outcrossing spe- apsis to short pseudoautosomal regions (Waters cies with thousands of back to bipolar et al. 2007; Ellegren 2011). In the fungus Cryp- species with just two mating types, where it tococcus neoformans and the green algae has been suggested that different environments C. reinhardtii and V.carteri, numerous chromo- favor outcrossing versus inbreeding sexual cy- somal rearrangements act to inhibit successful cles (Heitman et al. 2013). synapsis, assuring, for example, cotransmission Yet another way to enhance the efficiency of of the MID gene and the gene encoding the mi- finding a compatible mate is to dispense entirely nus recognition protein in C. reinhardtii (Ferris with the requirement of different mating types et al. 2002, 2004, 2010). Although this feature of for cell–cell fusion. In such unisexual species, complex MT loci and sex chromosomes assures any isolate can fuse with any other (under some that certain sex-related genes are cotransmitted, conditions in the presence of a third partner the fact remains that most sex-related genes are that serves as a pheromone donor to trigger dispersed throughout the genome. Hence the like-with-like cell fusion in me´nage a` trois mat- “purpose” of and the pressures generating such ings). This strategy has been adopted by two of genomic differentiations are not yet clear. the most common systemic human fungal path- In modern multicellular organisms, the ogens, C. neoformans and C. albicans, and also MTD systems are themselves complex (Pomian- several nonfungal eukaryotic microbial patho- kowski et al. 2004; Kimchi et al. 2007; Salz gens (Lin et al. 2005; Heitman 2006, 2010; Pox- 2011), highly diverse (Haag and Doty 2005), leitner et al. 2008; Alby et al. 2009; Wendte et al. and often labile (Charlesworth and Mank 2010; Carpenter et al. 2012). 2010), and the H1/H2 programs they specify Finally, many lineages, including algae and have expanded to include control over tissue fungi, abandon heterothallism for homothal- and organ differentiation and, in animals, brain lism, wherein a single haploid genome contains and behavioral patterning. both MTDP and MTDM equivalents; these are tightly linked in the case of some filamentous ascomycetes, and unlinked in others (Vanwin- Multiple Mating Types and Homothallism kle-Swift and Burrascano 1983; Lee et al. 2010; In addition to the cost of outcrossing noted Ni et al. 2011). One or the other determinant is earlier, the introduction of heterozygous mating expressed in individual gametes during the types restricts fusion partners to half the popu- course of , the result being “self- lation. In most modern eukaryotes, this handi- fertilization.” Heterothallic species often have cap has been assuaged by the evolution of closely related homothallic counterparts (Ny- countless systems for identifying the opposite gren et al. 2011), indicating that this trait is sus- type via pheromones and mating behaviors, en- ceptible to evolutionary pressures. Modern hancing the efficiency of finding a mate, but multicellular parthenogens are also known to options are still limited to half the population. engage in “occasional sex” (Pires-daSilva 2007; In some lineages, the odds have been improved D’Souza and Michiels 2010). by the presence of multiple mating types—three or more in Dictyostelium (Bloomfield et al. 2010, 2011), seven in Tetrahymena (Phadke MATING-TYPE-REGULATED COUPLING OF DIPLOIDY TO THE FORMATION et al. 2012; Cervantes et al. 2013; Umen 2013), OF RESTING SPORES 13 in Physarum polycephalum (Collins and Tang 1977; Clark and Haskins 2010), and often thou- In previous sections we have suggested that the sands in the basidiomycetes (Raper 1966)—and selective advantage of diploidy lies in the pres-

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ence of at least two copies of each gene, allowing as S. pombe that arrest in the G2 phase of the complementation of recessive lethal mutations cell cycle to enable repair from the other sister and the potential generation of novel alleles/ chromatid. genes in the second copy. At some point during In those cases in which the molecular basis the evolution of protoeukaryotes, there evolved for shifting to diploid resting-spore differentia- an additional and far more immediate and tan- tion is understood in eukaryotic microbes, the gible benefit to transitions from the haploid to transition is triggered by the formation of a het- the diploid state, namely, restricting the forma- erodimeric transcription-factor complex, with tion of a resting spore to diploid cells, diploid subunits that we will generically designate P cells, a capability that came to be controlled by and M (for plus and minus). Synthesis of P is mating type. restricted to plus gametes and hence regulated by Haploid resting spores are produced by sev- MTDP; synthesis of M is restricted to minus eral modern bacterial lineages (Henriques and gametes and hence regulated by MTDM. Fusion Moran 2007); they are also found in several of plus and minus gametes permits the forma- amoeba lineages (West 2003; Chatterjee et al. tion of P/M heterodimers, and these are 2009; Fritz-Laylin et al. 2010) and in many fungi uniquely capable of activating expression of dip- (Feofilova et al. 2012) and algae (Hagen et al. loid-specific genes (and repressing haploid-spe- 2002). Hence it is plausible to propose that the cific genes), including genes involved in resting- protoeukaryote possessed a genetic program for spore formation and, at some later stage, genes haploid spore differentiation that was indepen- involved in entering meiosis and spore germi- dent of any sexual process. Sporulation pro- nation. Importantly, it is not necessary to posit grams typically entail the assembly of a novel that the P/M factor orchestrates all spore- and cell wall that preserves viability in the face of meiosis-related genes directly—these programs noxious environmental circumstances such as are presumably coordinated by preexisting cir- high temperature, freezing, desiccation, preda- cuits from haploid sporulation and diploid mei- tion (Coluccio et al. 2008), and exposure to otic programs. Rather, P/M is posited to initiate ionizing radiation. They also impose modula- a cascade that permits the regulated expression tion of gene expression to a minimalist “main- of these genes during diploid-spore maturation tenance” mode and the accumulation of poly- and subsequent germination. saccharide and lipid storage products for use There is, of course, a pleasing symmetry in during germination and the resumption of mi- this arrangement in that the P/M requirement tosis when conditions improve. Hence the pro- for diploid differentiation mirrors the H1/H2 grams that govern haploid spore formation are requirement in the fertilization process, both expected to include “spore-specific” genes that being regulated by mating type. In a recent are not expressed in cycling cells and are acti- review, Perrin (2012) lifts up this feature as vated at the time that the circumstances dictate well, noting that “mating types have evolved to the importance of shifting to a resting state. switch on the right program at the right mo- As noted earlier, such deteriorating con- ment.” ditions commonly also trigger the expression The P/M pairs thus far identified in mi- of the MTD systems that control gametic recog- crobes are usually members of the homeopro- nition/fusion programs. Therefore, the stage tein transcription-factor family: a1/a2in would be set for mating type to acquire control S. cerevisiae (Madhani 2007) (in which a2 per- over diploid resting-spore formation as well, forms “double duty,” functioning as well in the the spore thereby endowed with both long- haploid phase); Sxi1a/Sxi2a in C. neoformans term viability and the advantages, already listed, (Hull et al. 2002, 2005); bW/bE in Ustilago of generating recombinant progeny via an even- maydis (Schulz et al. 1990); and GSP1/GSM1 tual meiosis. An advantage of diploid spores in C. reinhardtii (Lee et al. 2008a). The one could also be to promote repair of DSBs dur- known exception is that HMG-family or a- ing dormancy, similar to haploid yeasts such box transcription factors drive differentiation

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in the zygotes of filamentous ascomycetes and function in photosynthesis, and presequences zygomycetes (Glass et al. 1988; Fraser et al. 2007; that target their import into the cyanelle have Idnurm et al. 2008; Lee et al. 2008b), groups that been identified. Hence the posited gene-transfer lack MT-encoded/regulated homeoproteins. events that accompanied mitochondrial and Whether these factors dimerize or act indepen- chloroplast domestication are apparently being dently on common target promoters is not yet recapitulated in Paulinella. known. Yeast two-hybrid studies failed to detect Importantly, what is already in place in Pau- dimerization between the SexM and SexP pro- linella is a mechanism to coordinate the repli- teins of Phycomyces (A Idnurm, unpubl.), sug- cation of the cyanelle’s DNAwith the replication gesting that novel mechanisms may operate. of the amoeba’s DNA such that, at each mitosis, An explosive expansion of homeoprotein- each daughter cell inherits two cyanelles. Be- encoding genes has accompanied the evolution cause the growth rate of free-living Synechococ- of multicellularity in animals and land plants, cus (6–12 h doubling time) far exceeds the with homeoprotein-based combinatorial con- growth rate of testate amoebas (1–3 d dou- trol exerted over core domains of the body bling time), the imposition of such control is plan: PBC/MEIS þ HOX proteins specify the presumably an early and critical event in estab- anterior–posterior axis of animals (Mann and lishing any endosymbiotic relationship, pre- Morata 2000), and KNOX þ BELL proteins venting the engulfed bacterium from over- specify the initiation of the moss sporophyte whelming the host cell, and it was presumably program (Sakakibara et al. 2013) and regulate quickly established during the protoeukaryote’s the architecture of shoot apical meristems acquisition of protomitochondria and proto- (Hake et al. 2004). As expanded elsewhere (Lee chloroplasts. Eukaryotes vary widely in num- et al. 2008a), it is appealing to posit that the bers of mitochondria and chloroplasts per cell combinatorial-control “idea,” originally gov- and in numbers of genomes per organelle, but erning the differentiation of diploid zygotic in a given microorganism, or cell type in a mul- spores, was co-opted to govern the differentia- ticellular organism, these values are maintained tion of multicellular diploids. at constant levels. The development of a sexual cycle would be expected to place such a control system in jeop- MATING-TYPE-REGULATED ardy. The fusion of gametes would generate dip- TRANSMISSION OF ORGANELLE GENOMES loid zygotes with twice the organelle- genome tally, and without some way to return to the Theoretical Considerations “organelle-haploid” value, meiotic products The stages in the domestication of a proteo- would be “organelle-diploid” and then, in the bacterium into a mitochondrion, a seminal next round, “organelle-tetraploid” and so on. achievement of the protoeukaryote, are not This dilemma suggests a hypothesis regard- known. However, the analysis of an ongoing ing the origin of the near-universal pattern of domestication process—the conversion of a organelle inheritance in modern sexual eukary- Synechococcus cyanobacterium into a “cyanelle” otes—the uniparental (UP) transmission of or- (protochloroplast) in the testate amoeba Pauli- ganelle genomes to meiotic products. In this nella chromatophora (Rhizaria)—is providing scenario, the solution adopted by the LECA fascinating insights into what is entailed (Chan was to (1) tag the organelles residing in plus et al. 2011; Bodyl et al. 2012; Nowack and Gross- gametes differently from the organelles residing man 2012). During the 60 million years since the in minus gametes, and (2) devise a system that estimated onset of this conversion, the genome recognizes these tags in the diploid zygote and of the endosymbiont has undergone an estimat- selectively prevents one set of organelles/organ- ed 75% reduction in size, and roughly 1% of the elle genomes from being transmitted, thereby amoeba’s nuclear genes are of endosymbiont or- reestablishing the “organelle-haploid” number igin. Many of these genes encode proteins that in all four meiotic products. By placing the tag-

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ging system under the purview of the mating- the two genomes might assemble into defective type system, the LECA would have been able complexes. to control organelle ploidy using the same The zygotes of budding and fission yeasts system that it used to regulate nuclear ploidy, receive mitochondrial genomes from both par- albeit the downstream mechanisms are totally ents and do not destroy one set (Solieri 2010); different. however, they carefully segregate mitochondria That modern UP systems are sensitive to during the early diploid mitotic divisions such organelle ploidy has been shown in C. reinhard- that daughter-cell clones become “homoplas- tii. The usual pattern, described in detail below, mic” for one or the other input genome (Basse is that chloroplast genomes from the minus par- 2010). Similarly, C. reinhardtii meiotic products ent are destroyed by nucleases in the early zy- manipulated to be heteroplasmic for chloro- gote, leading to UP inheritance of plus genomes. plast genomes rapidly “sort out” to yield homo- However, if the zygotic input of plus chloroplast plasmic mitotic clones within 10–20 cell gen- genomes is reduced, either by growth in FuDR erations (VanWinkle-Swift 1980; Forster et al. (Wurtz et al. 1977; Matagne and Beckers 1983; 1980). Thus most modern eukaryotic organ- Armbrust et al. 1995) or by the mat3 mutation isms manage to acquire homoplastic organelle (Gillham et al. 1987; Armbrust et al. 1995; profiles by one means or another, suggesting Umen and Goodenough 2001), destruction of that this condition is adaptive. minus genomes is aborted and chloroplast DNA Countering this inference is the demonstra- inheritance is biparental (BP). tion that in Medicago (clover) (Matsushima et al. In most modern egg/sperm systems, the egg 2008), Passiflora (Hansen et al. 2007), and Myti- can have millions of organelle genomes, where- lus (mussel) (Jha et al. 2008), organelle inheri- as sperm are either stripped of organelles or tance is or can be biparental without known their organelle DNA is destroyed by the zygote. adverse consequences. Clearly there are funda- Therefore, if an “organelle ploidy” system mental features of UP that are not yet under- played a role in establishing UP in isogamous stood, leading us to quote a quip from Maynard organisms, this consideration is clearly irrele- Smith (1976) regarding another sex-related vant to modern anisogamous organisms. enigma: “One is left with the feeling that some A second consequence of UP inheritance is essential feature of the situation is being over- that at each sexual generation, a uniform set of looked.” organelle genomes is exposed to natural selec- tion in the “unmasked” haploid state, and a Modern UP Systems uniform set of organelle genomes is eliminated from the gene pool altogether. This may serve to That UP inheritance of organelle genomes is guard against “selfish” genomes (Hurst and controlled by mating type was first discovered Werren 2001) that might otherwise infest and by Sager and Tsubo (1961) in the alga C. rein- destroy the population, or even the species, with hardtii: Traits encoded by chloroplast genomes unregulated organelles. Again we encounter and carried by plus gametes are usually transmit- meiotic symmetry in that such “purging” func- ted to all meiotic progeny, whereas few if any of tions are also a feature of meiosis. the progeny inherit traits encoded bychloroplast A third consequence of a UP system is that it genomes and carried by minus gametes. Subse- guards against “heteroplasmy,” the presence of quent studies showed that the reciprocal is true two or more different organelle genomes in the for mitochondrial genomes: Those contributed same organism. In a recent study, mice were ar- by minus gametes are transmitted, whereasthose tificially manipulated to be heteroplasmic for contributed by plus gametes are not (Aoyama mitochondrial genomes, and they showed a et al. 2006). Both systems entail DNA degrada- number of developmental and cognitive defects tion; shortlyafter gamete fusion, the minus-con- (Sharpley et al. 2012); the investigators suggest tributed chloroplast chromosomes are de- that disparate OXPHOS subunits encoded by stroyed by nucleases (Nishimura et al. 2002;

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Kuroiwa 2010), whereas the plus-contributed crossed, progeny inherit mitochondria from ei- mitochondrial chromosomes are destroyed ther parent and show a higher frequency of mi- 24 h later (Nakamura 2010). The GSP1/ tochondrial recombination (Fedler et al. 2009). GSM1 heterodimer, described above, that trig- Correspondingly, when rga2 is expressed heter- gers spore development, is also required to acti- ologously in a1 cells, the a1 mitochondrial ge- vate these recognition/destruction programs; nome is now protected and again progeny in- when disabled, inheritance of both chloroplast herit mitochondria from either parent. Finally, and mitochondrial genomes is biparental (Nish- deletion of rga2 from a2 cells results in loss of imura et al. 2012). Little is yet known about the the a2 mitochondrial genome and inheritance molecular basis of the tagging systems except of mitochondria from the a1 parent—exactly that the activity that servesto protect chloroplast the opposite of the pattern observed with DNA from being destroyed is evidently encoded wild-type crosses. Thus rga2 protects the host by gene(s) in the MT-plus locus (reviewed in cell mitochondrial genome, whereas lga2 func- Goodenough et al. 1995, 2007). tions in mitochondrial destruction via a dyna- In the basidiomycete C. neoformans, the mi- min-dependent mitophagy pathway (Mahlert tochondrial genome is selectively inherited from et al. 2009; Nieto-Jacobo et al. 2012). the parent of a mating type; a small proportion Although there is as yet no information on of meiotic products inherit the a parent’s mito- the molecules that exert mating-type UP con- chondrial genome or a recombinant mitochon- trol in most systems, the selective destruction drial genome (Xu et al. 2000; Yan and Xu 2003; of one set of organelle genomes has been shown Toffaletti et al. 2004). It is not known whether in several disparate radiations, including the thisprocessinvolvesaselectivedestructionofthe chlorophytes Gonium (Setohigashi et al. 2011) parental a mitochondrial genome (possibly via and Bryopsis (Kuroiwa and Hori 1986), the ul- mitophagy), preferential migration of the a mat- vophyte Ulva (Kagami et al. 2008), brown algae ing-type mitochondria into the zygote, or both (Motomura et al. 2010), the slime mold Physa- (Gyawali and Lin 2011). What is known is that rum (Moriyama and Kawano 2010), Drosophila both the SXI1a and the SXI2a homeodomain (DeLuca and O’Farrell 2012), the fish Orizias proteins that activate the a/a zygotic program (Nishimura et al. 2006), and the mouse (Ka- are required for UP mitochondrial inheritance neda et al. 1995; Kuroiwa 2010; Sato and Sato (Yan et al. 2004; Yan et al. 2007), just as in the 2013). Notably, in the vertebrate examples, the C. reinhardtiisystem. Recentstudies also provide sperm organelles enter the egg but are quickly evidence for both prezygotic and postzygotic and selectively eliminated in the zygote in a spe- levels of control, with the Mat2 pheromone-re- cies-specific fashion (Kaneda et al. 1995). In sponse high-mobility group (HMG) factor play- land plants, plastids are excluded from the ing a role in prezygotic marking of mitochon- sperm cell or are left behind in synergid cells drial genomes (Gyawali and Lin 2013), again during fertilization (Mogensen 1996; Liu et al similar to the system in C. reinhardtii. 2004); mechanisms are again unknown. In the plant pathogenic basidiomycete U. maydis, sexual reproduction results in UP mi- SEX AND SPECIATION tochondrial inheritance that is also controlled by the mating-type locus. The mating-type lo- A signature feature of eukaryotes is that they cus, encoding the pheromones and pheromone speciate, segregating into closely related popu- receptors necessary for mate recognition, oc- lations that fail to respond to each other’s mat- curs as two alleles. One (a1) encodes just the ing cues to form zygotes (prezygotic isolation) pheromone and pheromone receptor genes; and/or form zygotes that fail to produce aviable the other (a2) encodes both of these and also next generation (postzygotic isolation). Postzy- two additional genes (lga2 and rga2) that govern gotic incompatability between nuclear and mi- UP mitochondrial inheritance during sexual re- tochondrial genomes (Chou and Leu 2010) or production. When a2 mutants lacking lga2 are between multiple nuclear loci (Kao et al. 2010)

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have both been shown to play a role in Saccha- the inclusion of premeiotic DNA replication as a romyces species incompatibilities. Hence sex-re- first step of meiosis might have been to replicate lated genes are integral to establishing species across nicks and provide DNA double-strand boundaries. As developed more fully elsewhere breaks to promote meiotic recombination in (Goodenough et al. 2007), it can be argued that the pre-Spo11 era. Wealso warmly acknowledge “speciose” lineages, poised to branch into pop- the experimental and intellectual contributions ulations with separate and distinctive gene of past and present members of our laboratories. pools, are more likely to navigate long-term en- Research on sexual differentiation in the Good- vironmental fluctuations and hence move enough laboratory has been supported by grants through time (i.e., avoid extinction) than “non- from the National Science Foundation and the speciose” lineages confined to more narrow National Institutes of Health, and in the Heit- niche dimensions. man laboratory by NIH/NIAID R01 grant A corollary of this argument is that speciose AI50113-10 and R37 award AI39115-16. lineages are predicted to have “evolvable” pre- zygotic mating systems, capable of generating REFERENCES new dyadic combinations so that isolation bar- riers can be erected. An evolvable H1/H2 rec- Alby K, Schaefer D, Bennett RJ. 2009. Homothallic and ognition system, for example, might consist of a heterothallic mating in the opportunistic pathogen Can- dida albicans. Nature 460: 890–893. polysaccharide that can readily accommodate Aoyama H, Hagiwara Y,Misumi O, Kuroiwa T,Nakamura S. novel glycan subunits and a lectin whose active 2006. Complete elimination of maternal mitochondrial site can incur amino acid changes and still DNA during meiosis resulting in the paternal inheritance adopt a functional, and variant, fold. Examples of the mitochondrial genome in Chlamydomonas species. Protoplasma 228: 231–242. of rapidly evolving mate-recognition systems Armbrust EV,Ibrahim A, Goodenough UW.1995. A mating have in fact been documented in multiple eu- type-linked mutation that disrupts the uniparental inher- karyotic lineages (Palumbi 2009; Jagadeeshan itance of chloroplast DNA also disrupts cell-size control et al. 2011; Nygren et al. 2012; Singh and Jaga- in Chlamydomonas. Mol Biol Cell 6: 1807–1818. Barsoum E, Martinez P,Astrom SU. 2010. a3, a transposable deeshan 2012). Yeast-mating-type switching element that promotes host sexual reproduction. Genes and other selfing mechanisms (Lee et al. 2010) Dev 24: 33–44. could also have promoted speciation: Genome Basse CW. 2010. Mitochondrial inheritance in fungi. Curr rearrangements and chromosomal transloca- Opin Microbiol 13: 712–719. Becker TC, De Castro-Prado MA. 2004. Parameiosis in As- tions lead to postzygotic blocks to sexual repro- pergillus nidulans in response to doxorubicin. Folia Mi- duction, but if an individual with a rearranged crobiol (Praha) 49: 699–704. genome simply switches mating type, it now has Ben-Ari G, Zenvirth D, Sherman A, David L, Klutstein M, a mate with a colinear genome with whom to Lavi U, Hillel J, Simchen G. 2006. Four linked genes par- ticipate in controlling sporulation efficiency in budding found a new species. Although nothing is yeast. PLoS Genet 2: e195. known about the speciosity of the LECA itself, Bennett RJ, Johnson AD. 2003. Completion of a parasexual evolutionary history indicates that the tendency cycle in Candida albicans by induced chromosome loss in to speciate was instantiated early (Parfrey et al. tetraploid strains. EMBO J 22: 2505–2515. Bennett RJ, Miller MG, Chua PR, Maxon ME, Johnson AD. 2011). Hence the “Why sex?” question has yet 2005. Nuclear fusion occurs during mating in Candida another answer: It offers the means to diversify albicans and is dependent on the KAR3 gene. Mol Micro- in a eukaryote-specific fashion, one that has had biol 55: 1046–1059. spectacular outcomes. Bergerat A, de Massy B, Gadelle D, Varoutas PC, Nicolas A, Forterre P. 1997. An atypical topoisomerase II from Ar- chaea with implications for meiotic recombination. Na- ture 386: 414–417. ACKNOWLEDGMENTS Berman J. 2012. Candida albicans. Curr Biol 22: R620–R622. Wethank TomPetes, Kevin Roach, Alex Idnurm, Bloomfield G. 2011. Genetics of sex determination in the Jae-Hyeok Lee, and Sue Jinks-Robertson for social amoebae. Dev Growth Differ 53: 608–616. Bloomfield G, Skelton J, Ivens A, Tanaka Y, Kay RR. 2010. comments on the article, and, in particular, we Sex determination in the social amoeba Dictyostelium thank Sue Jinks-Robertson for suggesting that discoideum. Science 330: 1533–1536.

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Origins of Eukaryotic Sexual Reproduction

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Origins of Eukaryotic Sexual Reproduction

Ursula Goodenough and Joseph Heitman

Cold Spring Harb Perspect Biol 2014; doi: 10.1101/cshperspect.a016154

Subject Collection The Origin and Evolution of Eukaryotes

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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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