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Sexual Conflict and Seminal Fluid : A Dynamic Landscape of Sexual Interactions

Laura K. Sirot1, Alex Wong2, Tracey Chapman3, and Mariana F. Wolfner4

1Department of Biology, College of Wooster, Wooster, Ohio 44691 2Department of Biology, Carleton University, Ottawa, Ontario K1S 5B6, Canada 3School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom 4Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853 Correspondence: [email protected]; [email protected]

Sexual reproduction requires coordinated contributions from both sexes to proceed efficient- ly. However, the reproductive strategies that the sexes adopt often have the potential to give rise to sexual conflict because they can result in divergent, sex-specific costs and benefits. These conflicts can occur at many levels, from molecular to behavioral. Here, we consider sexual conflict mediated through the actions of seminal fluid proteins. These proteins provide many excellent examples in which to trace the operation of sexual conflict from molecules through to behavior. Seminal fluid proteins are made by males and provided to females during mating. As agents that can modulate egg production at several steps, as well as reproductive behavior, “management,” and female feeding, activity, and longevity, the actions of seminal proteins are prime targets for sexual conflict. We review these actions in the context of sexual conflict. We discuss genomic signatures in seminal (and related) genes that are consistent with current or previous sexual conflict. Finally, we note promising areas for future study and highlight real-world practical situations that will benefit from understanding the nature of sexual conflicts mediated by seminal proteins.

oth sexes benefit from successful reproduc- (SFPs) that are made by males and transferred to Btion, but the different reproductive strate- females during mating. These proteins represent gies adopted by males and females may result a crucial interface of functional activity between in differential costs and benefits. This can result male and female. Transfer of SFPs can affect in sexual conflict before, during, and after mat- physiology and, in some animals, the behavior ing. Conflict in the more familiar form of com- and life span of mated females (reviewed in petition can also occur between females and Chapman 2001; Gillott 2003; Poiani 2006; Avila between males, with the latter situation includ- et al. 2011; Rodrı´guez-Martı´nez et al. 2011). Be- ing interejaculate competition. Of the many cause SFPs have important effects on the most “weapons” in these conflicts and competitions, intimate of interactions between the sexes, they this article focuses on the seminal fluid proteins are prime candidates to become subject to sex-

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ually antagonistic selection (Arnqvist and Rowe 2006; Sirot et al. 2009; Avila et al. 2011; Rodrı´- 2005). With increasing knowledge of the func- guez-Martı´nez et al. 2011; Ratto et al. 2012; tions of SFPs, their roles in inter- and intrasex- Bromfield et al. 2014). Most SFPs are the prod- ual conflict and their evolutionary responses to ucts of secretory glands in the male reproductive conflict are becoming ever more apparent. Here, tract; these include the prostate glands, epidi- we explore the roles, evolution, and significance dymi, and seminal vesicles of (Poiani of these male-derived players in sexual conflict. 2006; Rodrı´guez-Martı´nez et al. 2011) and the Werefer the reader to previous reviews for much male accessory glands and ejaculatory ducts/ of the detailed functional information on SFPs bulb of arthropods (Gillott 2003). These tissues (e.g., Chapman 2001; Gillott 2003; Kubli 2003; produce,modify,andstoresecretedproteinsthat Arnqvist and Rowe 2005; Poiani 2006; Sirot et al. are then transferred to females during mating, 2009; Avila et al. 2011; Rodrı´guez-Martı´nez et al. along with sperm. For some species there are 2011) and focus here instead on selected exam- comprehensive data on SFPs from large-scale ples, drawn largely from the study of . transcriptomic and/or proteomic analyses (e.g., Collins et al. 2006; Pilch and Mann 2006; Dottorini et al. 2007; Findlay et al. 2008, 2009; THE BATTLEGROUND Sirot et al. 2008, 2011; Walters and Harrsion The opportunity for postmating conflict is 2008, 2010; Baer et al. 2009; Dean et al. 2009; played out through the behavior and physiology Ramm et al. 2009; Rogers et al. 2009; Claw of the mated female and the fate of sperm in 2013). In others, only a partial complement of the female reproductive tract. After mating has SFPs has been identified so far (e.g., Andre´s et al. begun, male-derived molecules and sperm in- 2006, 2008; Davies and Chapman 2006; South teract with female-derived molecules, cells, and et al. 2011; Simmons et al. 2013). tissues both within the female reproductive In organisms in which SFPs have been glob- tract (e.g., Yapici et al. 2008; Hasemeyer et al. ally characterized, an amazing complexity is ap- 2009; Yang et al. 2009; Dean 2013; Rubinstein parent. First, they are numerous; latest estimates and Wolfner 2013; Bromfield et al. 2014) and, are just more than 200 different SFPs in Dro- in the case of some male-derived molecules, sophila melanogaster (Swanson et al. 2001; Ravi elsewhere in the female (e.g., Lung and Wolfner Ram and Wolfner2007; Findlay et al. 2008; Avila 1999). These interactions result in changes in et al. 2009); several hundred in mice (Dean et al. female gene expression, behavior, physiology, 2009) and humans (Pilch and Mann 2006); and life span, and morphology (reviewed in Gillott between 50 and 100 in honeybees (Baer et al. 2003; Poiani 2006; Robertson 2007; Avila et al. 2009) and in mosquitoes (Rogers et al. 2009; 2011). These changes, in turn, affect both male Sirot et al. 2011). Yet,even these SFP inventories and female reproductive success. As a result, the are likely incomplete. Second, the mole- battleground between males and females over cular characteristics of SFPs are fascinating. postmating responses occurs in several parts of On the one hand, many of the biochemical the female body including the reproductive tract classes of molecules in seminal fluids are similar and the nervous system. across all animals (Mueller et al. 2004; Baer et al. 2009). For example, seminal fluids contain many proteases and protease inhibitors, sugar- The Potential Weapons binding lectins, cysteine-rich secretory proteins The proteins that accompany sperm into the (CRISPs), antimicrobial and antioxidant pro- female—once dismissed as simply a supportive teins, and coagulation proteins such as trans- medium for sperm—are now known to be po- glutaminases, small peptides, and larger, pro- tent modulators of female reproductive biology; hormone-like, molecules (Avila et al. 2011). in some cases, they even have effects on offspr- On the other hand, although these conserved ing (reviewed in Martan and Shepherd 1976; types of proteins are observed in the seminal Chapman 2001; Gillott 2003; Kubli 2003; Poiani fluid of all animals examined to date, an unusu-

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Sexual Conflict and Seminal Fluid Proteins

ally high fraction of SFPs show rapid sequence features (rapid evolution and nonorthology, as evolution (e.g., Swanson and Vacquier 2002; well as the frequent presence of redundancy) Clark and Swanson 2005; Mueller et al. 2005; require explanation. One possibility is that this Clark et al. 2006; Haerty et al. 2007; Walters evolutionary exuberance is caused by coevolu- et al. 2010). SFPs of the same classes in different tionary arms races between SFPs in males and species are often not orthologous. For example, their receptors in females driven by sexual con- although the seminal fluid of two mosquito spe- flict. The evidence for this hypothesis is dis- cies and of D. melanogaster contains trypsin- cussed in a section further below (see Does Sex- class proteases that are predicted to have bio- ual Conflict Shape SFP Evolution?). chemically similar activities, those proteins are Another likely contributor to complexity is not orthologs (Findlay et al. 2008; Mancini et that multiple seminal proteins could be needed al. 2011; Sirot et al. 2011). Moreover, there is to accomplish a single functional goal. For ex- much redundancy in the types of protein pres- ample, a network of at least eight Drosophila ent in the seminal fluid. For example, there SFPs is required to bind a ninth SFP (the sex are more than 15 trypsin-class proteases in D. peptide, SP) to sperm. This binding to sperm melanogaster seminal fluid, and multiple serine prolongs the phenotypic effect of SP in females proteases in mammalian seminal fluid (see La- (Peng et al. 2005; Ravi Ram et al. 2009; Findlay Flamme and Wolfner 2012 for review). Al- et al. 2014). In another example from Dro- though each SFP may have particular target sophila, at least two SFPs (ovulin and Acp36DE) proteins, it seems likely that different SFPs can are proteolytically processed once inside the fe- also compensate for one another. These latter male (Fig. 1), and ectopic expression studies of

Inside the male Inside the female

Seminase

Inactive Active (cleaved) Ovulin But not if male metalloprotease (During metalloprotease cleavage is metalloprotease (in male transit enabled is absent accessory through gland) male)

Metallo- (Intact) (Cleaved) (Cleaved) (Absent) protease:

(Intact) (Intact)(Cleaved) (Intact) Ovulin:

Figure 1. The molecular cascade that governs the cleavage of the seminal protein ovulin. Biochemical studies show that ovulin cleavage requires activation of a male metalloprotease during transit through the male during mating (Park and Wolfner1995; Ravi Ram et al. 2006; LaFlamme et al. 2012, 2014). Ovulin and the two proteases that are needed to cleave it (seminase and the metalloprotease CG11864) are all made in the male’s accessory gland but are stored uncleaved in this tissue. During transit through the male, the metalloprotease is activated by cleavage that is initiated by the serine protease “seminase.” Although this metalloprotease is essential for ovulin cleavage within mated females, even after being activated, it does not cleave ovulin until all the proteins have entered females. (Western blot panels from Ravi Ram et al. 2006; reprinted, with permission, from the authors.)

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ovulin suggest that the processing generates a straints could open the door for other SFPs to more active portion of ovulin (Heifetz et al. evolve to target the pathway in other ways but 2005). The proteolytic processing only occurs with the same overall effect on the female. once the proteins are within the female, and is It is also important to note that there are mediated by at least two seminal proteases. other, nonproteinaceous molecules in seminal These proteases are made in the same tissue as fluid that could be players in postmating sexual their targets (i.e., the male accessory glands) conflict (e.g., steroid hormones [Baldini et al. and are kept inactive during storage. They are 2013], juvenile hormone in insects [Borovsky activated through sequential proteolysis as they et al. 1994; Clifton et al. 2014], prostaglandins and their targets move through the male and [Destephano et al. 1974; Loher et al. 1981; Rob- into and through the female reproductive tract ertson 2007], vesicles [Leiblech et al. 2012; Aal- (Park and Wolfner1995; Heifetz et al. 2005; Ravi berts et al. 2013], and noncoding RNAs such as Ram et al. 2006; LaFlamme et al. 2012, 2014). miRNAs [e.g., Li et al. 2012]). Much less is A proteolytic cascade involving multiple semi- known about the evolution, identity, and func- nal proteins is also observed in mammals: Liq- tion of these other molecules in comparison to uefaction of the seminal clot, a process that is SFPs, but their study promises a fruitful avenue thought to facilitate sperm movement, is regu- for future research. It is possible that, in some lated by a cascade of multiple seminal proteases species, these molecules play roles performed by and protease inhibitors (Pampalakis and Soti- SFPs in other species. It is tempting to speculate ropoulau 2007). Evolutionary pressures derived that such a situation might, in part, contribute from sexual conflict could affect various mem- to interspecific differences in the SFP composi- bers of the multiple proteins that regulate a spe- tion and complexity. cific effect on females, so interpreting data on the evolutionary dynamics of any one molecule DO SFPs CONTRIBUTE TO POSTMATING is complex. ? A further reason for complexity of SFPs is that different members of a given biochemical SFPs may serve as biochemical and physiologi- family could potentially be co-opted in different cal agents that manipulate female behavior and lineages to carry out a particular function. This physiology in ways that benefit males. Yet, fe- might reflect pressures to overcome female resis- males may also be taking advantage of SFPs as tance to more ancestral versions of SFPs. In this reliable cues for initiating physiological repro- sense, the apparent complexity of seminal fluid ductive processes to coordinate with the receipt may reflect previous conflicts. Finally, an aspect of sperm (Chapman 2001; Ratto et al. 2012; of the complexity of the action of SFPs is that Baldini et al. 2013). Below, we present the pro- they can, and often do, involve obligate partici- cesses over which postmating conflict is predict- pation of female molecules. Three examples, ed to occur and the evidence for roles of SFPs in from Drosophila, are that (1) ovulin processing each; these ideas are summarized in Table 1. cannot be completed without female contribu- tions (Park and Wolfner1995; Heifetz et al. 2005; Remating Ravi Ram et al. 2006; LaFlamme et al. 2012, 2014); (2) the effects of a sperm-bound seminal Females of many species show dramat- protein (sex peptide [SP]) require at least four ic changes in postmating behavior (reviewed female-expressed genes (Yapiciet al. 2008; Find- in Gillott 2003; Sirot et al. 2009; Avila et al. layet al. 2014); and (3) SFPs such as ovulin act by 2011). In some species, mated females do not turning up (or on) physiological pathways with- remate, or they remate at very low levels. These in females (Rubinstein and Wolfner 2013). That changes in female mating propensity could be certain SFPs interact in molecular pathways with advantageous to both sexes by reducing the risk female proteins may constrain the evolution of of further to males and re- those SFPs. Moreover, the existence of such con- ducing the costs of mating to females. However,

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Table 1. Summary of potential conflicts mediated by SFPs Trait over which Types of SFPs that are there is potential potentially responsible for conflict Nature of the potential conflict the conflict Remating Conflict over remating may occur between a female and her Those that modulate female previous mates and between a mated female and receptivity, attractiveness, courting males. Remating may benefit the female but at a activity levels, pheromone cost to her previous mates because there are potential production, and emission benefits for females of topping up or receiving better- quality, fresh sperm. These benefits may be at odds with the interests of males whose sperm are already in storage. There are also potential conflicts arising from the deleterious effects of male–male sperm competition. Yet, extensive remating could be costly to a female but beneficial to the males attempting to mate with her. Sperm transfer, Conflict may arise over how many sperm are transferred Those that mediate sperm storage, during mating, stored by the female, and released for transfer, sperm storage, retention, fertilization. The interests of the sexes over the efficiency sperm competition, the usage of individual sperm usage should be aligned. However, musculature of the female sperm usage may become inefficient as a result of reproductive tract, elevated rates of egg production, over which there is including the sperm separate potential conflict, see below. storage organs Egg production, Males mayoften gain from elevating current egg-production Those that mediate ovulation, egg oregg-provisioningrates more than isthe case for females. ovulation, release of provisioning, Females may trade off current versus future investment reproductive hormones, oviposition and gain from a longer-term strategy. Males, on the other egg production, and hand, may gain from increased current investment by the provisioning female, despite any future costs. Any divergence over the rate of ovulation may negatively impact the efficiency of fertilization, as noted above. Food intake Females may need to increase or change their nutrient Those that mediate feeding intake to support increased reproductive rate. This will behavior and nutrient be favored in an open-ended way by males, who may balancing have little interest in any future costs that the female might incur. However, increased nutrient trafficking decreases female life span, thus representing potential sexual conflict in terms of a female’s future reproductive capacity. Activity The female’s sleep/wake cycles can be altered by SFPs and Those that mediate activity could impact energy usage. Increased activity and patterns and circadian reduced siesta sleep in females (e.g., in Drosophila) could rhythms incur long-term costs for females but not males, reflecting a potential conflict. Immune Striking changes to the immune system occur during SFPs that have antimicrobial activation reproduction, the significance of which is not yet activity or that cause the globally clear. However, there is potential for conflict if expression of immune there is a suboptimal under- or overexpression of genes in females immunity in the female, with immune activity traded off against future reproductive capacity. Life span SFPs that reduce female life span can be selected because SFPs that either directly or any cost is incurred in the future. Therefore, the effect of indirectly exert costs leading such costs is felt unequally by males and females. toreducedfemalelifespan

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females may also experience costs from not re- also essential for female postmating responses mating, as this may prevent the acquisition from such as pheromone production (Fan et al. 1999; future mates of any direct (e.g., food or other Hanin et al. 2012). Recent studies suggest that resources) or indirect benefits (e.g., “better,” there may be additional receptors for SP, and more compatible, or diverse alleles for off- that SPR may facilitate access of SP to the ner- spring). Furthermore, conflict over remating vous system (Ja et al. 2009; Haussmann et al. can also occur when males attempt to mate 2013). Additional female-encoded molecules with previously mated females. Males that court have been identified that are also essential for and attempt to mate with unreceptive, recently SP effects (including on receptivity [Findlay et mated females may experience the costs of al. 2014]). Furthermore, recent evidence from courtship without the benefit of offspring pro- Drosophila suggests that there are female repro- duction. Additional costs can also arise; for ex- ductive proteins that promote rapid remating ample, D. melanogaster males that are rejected (Sirot et al. 2014). This finding is consistent when they attempt to mate with previously mat- with the hypothesis that females are in conflict ed females are less likely to court the females that with their mates over the frequency of remating. they subsequently encounter and regardless of whether those new females have mated (Siegel Sperm Transfer, Storage, Retention, and Hall 1979). and Usage SFPs influence female remating in a manner consistent with sexual conflict. In several insect Females of all internally fertilizing animals store species, receipt of SFPs decreases the probability the sperm that they receive during mating (Neu- of female remating (reviewed in Gillott 2003; baum and Wolfner 1999), for days (e.g., most Sirot et al. 2009; Avila et al. 2011). Initial de- mammals), weeks (e.g., Drosophila [Neubaum creases in remating may not involve SFPs and and Wolfner 1999]; some birds [Sasanami et al. can result from processes such as transfer of 2013]), or even years (e.g., some Hymenoptera cuticular pheromones (e.g., in Drosophila [Za- and reptiles [Gist and Congdon 1998]). Sperm wistowski and Richmond 1986]) or from phys- are stored in females in specialized organs (e.g., ical mate guarding. Longer-term changes in fe- spermathecae, seminal receptacles in insects male receptivity across a wide range of insects, [Neubaum and Wolfner 1999]) or in special however, derive from the actions of SFPs (re- regions of the reproductive tract (e.g., isthmus viewed in Gillott 2003; Arnqvist and Rowe in mammals [Suarez 2008]) and their release 2005; Avila et al. 2011). In species that form must be coordinated with the opportunity to mating plugs, specific mating plug proteins encounter eggs. Storage of sperm is potentially (e.g., PEB2 in Drosophila) can increase latency advantageous to both sexes by allowing for ex- to remating in females (Bretman et al. 2010). In tended progeny production after mating. How- all cases in which SFPs influence female remat- ever, it also provides the opportunity for con- ing, they appear to decrease the probability or flicts, such as those resulting from cryptic frequency of remating. Thus far, little is known female choice and sperm competition. More- about the role of female-derived molecules. One over, there could be sexual conflict over which exception, however, is the sex peptide receptor sex controls the rate of sperm release. For exam- (SPR) of D. melanogaster (Yapici et al. 2008). ple, it might be beneficial for the female to re- SPR is a G-protein-coupled receptor, and its place older sperm with newer, fresher sperm or activity in a set of reproductive tract neurons sperm from a better quality male (e.g., Lu¨pold in the female is necessary for sex peptide (SP), et al. 2013). This would be at odds with the a 36-amino-acid peptide with diverse pheno- male’s interest in maintaining his own sperm typic effects (Chen et al. 1988; Kubli 2003), to in storage so they can be used for fertilization. suppress receptivity through activation of SPR It might also be advantageous to the female to (Hasemeyer et al. 2009; Yang et al. 2009). The modulate the rate of sperm release to coordinate ortholog of SPR in Helicoverpa armigera is with the timing of egg production, whereas it

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Sexual Conflict and Seminal Fluid Proteins

might benefit the male to have his sperm used in molecules. Hymenopteran female spermathecal fertilizations as quickly as possible. secretions can act to diminish male–male con- SFPs play important roles in the transit of flicts by countering the negative viability effect sperm into storage. For example, transglutami- of seminal fluid on the sperm of different males nases—the cross-linking enzymes in the seminal (den Boer et al. 2009). This pattern could fluid of mice (Dean 2013) and anopheline mos- be consistent with an intense “conflict phase” quitoes (Rogers et al. 2009)—are necessary for between the males followed by a subsequent the coagulation of seminal fluids and the con- dampening down of conflict in order for the sequent efficient movement of sperm to storage female to retain viable sperm for a long time, sites. An SFP in D. melanogaster (Acp36DE) is hence prolonging progeny production over an necessary to regulate the uterine contractions extended period. In addition, several lines of that move sperm into storage (Avila and Wolfner evidence suggest that females play a physically 2009). SFPs in bovine seminal plasma bind to active role in influencing sperm use patterns. sperm (Gwathmey et al. 2006) and to annexins For example, genetic evidence and allelic corre- (Ignotz et al. 2007) on the oviductal epithelium. lations to sperm competition outcomes indicate This binding allows sperm to be stored in that in D. melanogaster, a functioning female the cows’sperm reservoirs. SFPs also are import- nervous system is necessary for proper sperm ant in regulating the release of sperm from stor- storage or to influence the outcome of sperm age for fertilization. In Drosophila, the lectin competition (Arthur et al. 1998; Chow et al. Acp29AB is required for maintenance of sperm 2013). In another example, sperm storage is in the female’s storage organs (Wonget al. 2008), compromised in dead or anesthetized Tribolium and SP is required for efficient rate of release of castaneum females, again suggesting an active sperm from storage in mated females (Avila et al. role for the female in sperm management 2010). Furthermore, several other SFPs are nec- (Bloch Qazi et al. 1998). essary to transport SP to the necessary location to exert its effects. In cows, SFP-mediated release Egg Production of sperm from storage allows the sperm to move to the fertilization site (Hung and Suarez 2010). The reproductive success of both sexes depends During the process of sperm storage, SFPs have largely on the quantity and quality of fertilized the potential to directly affect the sperm of a eggs. The female has to make eggs that are pro- female’s previous mates. In vitro studies in Hy- visioned for future embryonic development, re- menoptera (den Boer et al. 2010) and Diptera lease them from the ovaries (ovulation), and (Holman and Snook 2008) show that incubat- move them through the reproductive tract to ing sperm in SFPs affects their viability. In Hy- the correct location for further development menoptera, SFPs from one male can decrease (either inside or outside of the female, depend- the viability of rival males’ sperm and thus the ing on the species). We consider these events ability of those sperm to successfully fertilize together as the “egg-production process” (see eggs (den Boer et al. 2010). In sum, SFPs affect Heifetz et al. 2000). In species with little or no the ability of a male’s sperm to survive and trav- oogenesis, ovulation or (if appropriate) egg lay- el to the appropriate storage sites to be stored, ing before mating, egg production must in- retained, and released for fertilization (Xue and crease after mating. Noll 2000). They can also negatively impact the Increased egg production should benefit survival or success of competitor sperm in the both female and male if more progeny are pro- female. In this capacity, SFPs can play important duced. In an additional benefit to the female, by roles in sexual conflict over sperm use patterns coupling her level of egg production to mating, (also see work by Edward et al. 2014). she does not “waste” resources making eggs A female may also benefit by influencing when she lacks sperm to fertilize them. Once sperm use patterns (Eberhard 1996). This phe- she has mated, however, it pays to increase egg nomenon may be mediated by female-derived production (all steps) because those eggs can be

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fertilized. Yet, even these apparently mutually and Wolfner 1995; Heifetz et al. 2000). In- beneficial changes may engender potential con- creased ovulation triggered by SFPs is not, flicts: Mating may induce a higher short-term however, restricted to insects. For example, al- level of egg production in the female than that though many mammals are spontaneous ovu- which maximizes her lifetime reproductive suc- lators (i.e., independent of mating or SFPs), cess. Females risk trading off resources that they camelid ovulation is induced by the nerve might otherwise have used for defense against growth factor in seminal fluid (Kershaw et al. pathogens or for other survival traits. Further- 2012; Ratto et al. 2012), analogous in outline to more, in species that lay eggs, oviposition can be the situation found in Drosophila. Therefore, costly to females in terms of time allocation, through their effects on egg production and re- energy expenditure, and exposure to predators lease, SFPs may mediate conflict over these steps and parasites. Thus, the optimal rate of egg pro- in the egg-production process. duction is a source of sexual conflict. Recent evidence from dipteran insects has Ovulation frequency is perhaps a less obvi- provided insights into how seminal fluid mole- ous arena than overall egg production for sexual cules interact with female molecules to influ- conflict (particularly in mammals without in- ence specific steps in egg production. For exam- duced ovulation, in which ovulation does not ple, D. melanogaster ovulin stimulates ovulation increase after mating). Ovulation could, how- by increasing the amount or activity of a female- ever, be a source of sexual conflict in insects derived neuromodulator (octopamine) that (and potentially in mammals who are induced modulates muscle contractions that accompany ovulators; e.g., camelids [Adams and Ratto ovulation (Rubinstein and Wolfner 2013). In 2013]). For example, in Drosophila, the buildup the mosquito, Anopheles gambiae, a seminal flu- of many mature (but unovulated) oocytes in the id derived hormone induces increased produc- ovaries of unmated females feeds back to arrest tion of a female reproductive tract protein that is oogenesis (Chapman et al. 2001; Drummond- necessary for mating-induced changes in egg Barbosa and Spradling 2001). So, males could development (Baldini et al. 2013). Such molec- benefit by increasing ovulation rates, thereby ular interactions between male- and female-de- relieving this feedback inhibition and thus ac- rived molecules provide opportunities for both celerating the increase in oogenesis. The result- partners to adjust egg-production rate toward ing increased egg production can exert a phys- their own optima and, therefore, create an op- iological cost on females and thus, as noted portunity for sexually antagonistic coevolution. above, represents a source of sexual conflict. In insects, SFPs influence the egg-produc- Food Intake and Processing tion process, at several stages (reviewed in Gil- lott 2003; Arnqvist and Rowe 2005; Avila et al. The nutritional needs of females change once 2011). For example, D. melanogaster SP in- they are reproductively active. For example, in creases the number of eggs made, consistent arthropods, the increased production of eggs with its effects in raising juvenile hormone titers requires increased food resources to provide (Moshitzky et al. 1996), and also through effects and sustain energy. In mammals, the physio- on specific neurons that innervate the re- logical demands of pregnancy also impact the productive tract (Hasemeyer et al. 2009; Yang amount of food needed by the female. Consis- et al. 2009). D. melanogaster SP can also increase tent with the idea that increased egg production egg production in the moth H. armigera on requires additional resources, mating can alter injection (Fan et al. 2000), and knockdown of food preferences in arthropods. Mated D. mel- the H. armigera ortholog of the sex peptide re- anogaster females eat more protein (Ribeiro and ceptor blocks postmating increases in egg pro- Dickson 2010), mated Aedes aegypti mosquito duction (Hanin et al. 2012). In D. melanogaster, females take larger blood meals (Houseman and an SFP has been identified (ovulin) that in- Downe 1986), and a male-derived factor stim- creases ovulation rate specifically (Herndon ulates blood feeding and engorgement in ticks

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(Weiss and Kaufman 2004; Donohue et al. Ae. aegypti, mated females are less likely than 2009). unmated females to fly toward a host. Injections Conflicts may occur in this arena as well. of male accessory glands into unmated females For example, it could be beneficial to the male decrease their response to host cues, suggest- to increase food consumption by his mate if it ing this change is mediated, in part, by seminal allowed her to produce more eggs and hence fluid molecules (Fernandez and Klowden 1995). more progeny. But increased food consump- Consistent with this hypothesis, male Ae. ae- tion is associated with a decrease in longevity gypti transfer an SFP that can change host-seek- (in flies, nematodes, and mice [Chapman and ing behavior when applied topically to females Partridge 1996; Partridge and Gems 2002; Gems (Naccarati et al. 2012). and Partridge 2013]) and thus may be costly to the female. In addition, the increased time Immune Activation spent eating, or finding different food sources, can potentially expose females to predation Mating causes changes in immune capacity in a and pathogens, providing additional potential number of animals, although the ultimate rea- sources of conflict. sons are as yet poorly understood. Immune The role of SFPs in feeding related processes changes could protect the female from microbes is clear in some insects. For example, receipt of introduced during mating, could reflect trade- SP increases the amount of food consumed by offs occasioned by the need to produce eggs D. melanogaster females (Ribeiro and Dickson (insects), or could lessen the probability of re- 2010) and changes the female’s food prefer- jecting the fetus (mammals). These changes ences. SPalso affects the rate of intestinal transit, provide another arena for conflict; whatever with mated D. melanogaster females having benefits changes in immunity might have for slower intestinal transit than virgins, producing male (or female) fertility might be accompanied more concentrated excreta, presumably because by negative effects on the female’s immune ca- they have absorbed more water (and nutrients) pacity or by trade-offs with other physiological from their food (Cognigni et al. 2011; Apger- processes. For example, a Drosophila female’s McGlaughon and Wolfner 2013). In contrast, immunity to systemic infection drops after mat- mated female Ae. aegypti mosquitoes digest their ing (Fedorka et al. 2007; Short and Lazzaro blood meals more rapidly than virgins, an effect 2010; but see also Zhong et al. 2013) and up- that has also been attributed to SFPs (Downe regulation of female immunity has been pro- 1975). posed to generate a hostile environment for sperm. That seminal fluid plays a role in mating related immunity is known in Drosophila, mice, Activity Level and humans (Robertson et al. 2009; Guerin Mated D. melanogaster females sleep less and et al. 2009, 2011; Sharkey et al. 2012; Short et move around more than do unmated females al. 2012), and seminal fluid of all animals tested (Isaac et al. 2010). This postmating response, to date includes predicted antimicrobial com- dependent on SP, also could result in conflict. pounds (e.g., see Poiani 2006; Avila et al. 2011). The additional movement could be detrimental The effect of SFPs on immunity is complex, at for females by decreasing their regenerative least in Drosophila. Although numerous studies sleep time, taking energy that could be used have indicated that mating, and SFPs in partic- for somatic maintenance or to produce eggs, ular, induce an increase in expression of antimi- and potentially exposing them to predation. In crobial peptide (AMP) genes, or in AMP pro- the tephritid fruit fly (Ceratitis capitata), mating duction, mated female Drosophila show an SFP- (or injection with seminal fluids) changes the induced decrease in systemic immunity after attraction of females from a preference for male mating (Short et al. 2012). It is possible that odors to a preference for fruit used for ovipo- there are tissue-specific differences in immune sition (Jang 1995). Similarly, in the mosquito response to mating—perhaps the AMPs protect

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the reproductive tract at the expense of systemic as Jiang et al. (2011) found no changes, using immunity. the same approach and source population. However, to date no study has explicitly exam- ined the effects of SFPs on the evolution of male Life Span harm (or female resistance). That such effects Reductions in life span associated with elevated might be mediated by SFPs is suggested by the reproduction are common in both sexes, but the finding that experimental evolution under al- nature of those costs often differs substantially tered adult sex ratios (and hence opportunities between males and females. Sexual conflict can for sexual conflict) can result in divergent ejac- occur because adaptations that increase the re- ulate allocation strategies (Linklater et al. 2007). productive success of males can be selected even SFPs are thought to be involved in the con- if they also cause decreased life span in females, flict between adaptations that increase male and vice versa. Females are expected to, and reproductive success and decrease female life indeed do, have the capacity to evolve to ame- span because receipt of high levels of SFPs can liorate these costs. This leads to adaptation and be costly to females, causing a decrease in female counter adaptation (i.e., sexually antagonistic longevity and reproductive success (Chapman coevolution). et al. 1995). The shortening of female life span Laboratory experimental evolution in in response to SFPs could be a side effect of SFP D. melanogaster provides some support for function (e.g., of increased male permating fit- the idea that sexual conflict can be manipulated ness or a direct “toxic” effect that is selected to experimentally, over evolutionary time, with reduce the likelihood of female remating and/ predictable outcomes for life span. For example, or to increase current investment in reproduc- the level of sexual conflict can be manipulated tion (Johnstone and Keller 2000; Lessells 2005). in the laboratory by altering sex ratios. A high Support for the “side effect” idea comes from ratio of males to females is expected to increase data that some SFP-mediated fitness traits are the opportunity for sexual conflict over the op- directly linked to reductions in female life span. timum value of reproductive traits such as the Such a relationship is observed between in- frequency of mating in this species. In popu- creased male sperm defense (success of a first lations of D. melanogaster evolving under con- mating male after subsequent matings) and ear- ditions with elevated potential for sexual con- ly female mortality in D. melanogaster (Civetta flict (arising from increased mating frequency), and Clark 2000). Furthermore, SFPs with iden- females evolved to live longer in the presence tified or predicted reproductive functions of males (Wigby and Chapman 2004). This that benefit males are implicated in causing fe- suggests that females evolved resistance to the male mating costs in Drosophila (SP [Wigby and harmful (i.e., life-span-shortening) effects of Chapman 2005]) or have been suggested to play elevated mating frequency. The evidence that such a role (e.g., SP, CG8137, and CG10433 females can evolve to minimize male-imposed [Mueller et al. 2007]; Acp62F [Lung et al. costs suggests the strong potential for sexual 2002; Civetta et al. 2005]). However, the situa- conflict, in particular over optimum female life tion may be complex, as a recent study in D. span. In terms of corresponding male adapta- melanogaster found no evidence that elevation tions, there are conflicting reports, with either of sexual conflict, via increased male to female no differences in male-induced harm (Wigby sex ratio, affected the frequency of a null allele of and Chapman 2004) or reduced harm under Acp62F (Wong and Rundle 2013). low-conflict conditions (Nandy et al. 2013). Ex- Evidence for the idea that SFPs are directly periments in which selection is limited to selected to be “toxic” is difficult to gather un- males, which predict the evolution of male ben- ambiguously, as the toxic effect must be linked efit phenotypes, have also given various results. to some male benefit (otherwise it would not be Rice (1998) reported the evolution of increased selected). One possible line of evidence for a male harm under male limited selection, where- direct toxic effect of SFPs would be if the toxic-

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ity occurred via a different pathway from the evidence of sexually antagonistic selection. This effect of the SFP on male reproductive success. evidence could include changes in sequence or To our knowledge, however, there is little evi- expression level between the interacting loci. dence for this possibility. Although the toxicity These changes, in turn, could result in modifi- of ectopic expression of SFPs (e.g., Lung et al. cations in seminal fluid composition over time 2002; Mueller et al. 2007) could represent such (Perry et al. 2013). evidence, it must be noted that that the ectop- ic expression was at very high levels in those Molecular Signatures of Conflict experiments. Studies are needed in which po- tential toxicity of these SFPs is measured in sit- A general prediction (Parker 1979) is that sexual uations in which their ectopic expression is at conflict can, under some conditions, lead to levels closer to those delivered during mating. continual evolutionary chases between the ad- It should also not be ruled out that longevity aptations in one sex and the counteradapta- “costs” may be lower than first perceived if there tions in the other (Tregenza et al. 2006). Such are beneficial effects of SFPs on females earlier chases can result in coevolution between the in their lives. Although no such benefits have genes in males and females that encode these yet clearly been identified (e.g., Brommer et adaptations and counteradaptations. This co- al. 2012), costs to females could be lowered if evolution could involve changes in protein se- SFPs caused early life egg production to in- quence or in expression level of genes subject to crease, minimizing the fitness effect of life span sexual conflict. Theory predicts that this type of reduction (Edward et al. 2011). Males may also coevolution between males and females can lead suffer longevity costs from ongoing SFP-related to diversification in the sequences of the inter- sexual conflict. For example, if females evolve acting loci involved. If this diversification oc- decreased sensitivity to SFPs, selection may act curs in reproductive genes in individuals from on males for increased SFP production, which, different populations of the same species, it can in turn, could result in decreased male life span. facilitate reproductive isolation between popu- So far, this prediction has not been tested. The lations, and ultimately speciation, owing to finding that males that invest in longer matings breakdown in reproductive processes. Dynamic throughout their lives can suffer reduced life change in expression levels could also result in span and late life mating capacity (Bretman et rapid diversification between different popula- al. 2013) suggests that such effects could occur. tions if it promoted regulatory incompatibilities between the reproductive genes of individuals from different populations. However, this pos- DOES SEXUAL CONFLICT SHAPE SFP sibility has not yet been considered in any detail. EVOLUTION? Theory since Parker’s original formulation Sexual conflict can occur in two modes—intra- (Parker 1979), from simple to multilocus mod- and interlocus; these terms define whether the els, quantitative to explicit genetics, predicts conflict occurs between the same or different that sexual conflict can lead to five different loci, respectively. Sexual conflict mediated by types of dynamic outcomes between interacting SFPs is likely to be exclusively in the interlocus loci in males and females (Parker 1979; Frank mode, because SFPs generally interact with 2000; Rowe et al. 2003, 2005; Gavrilets and Ha- non-SFP proteins encoded by different loci (in- yashi 2005; Hayashi et al. 2007). These outcomes cluding female-encoded proteins) to influence are continuous evolutionary chases, cyclic co- the outcome of male–female encounters (e.g., evolution, evolution toward an equilibrium, timing or amount of remating or egg produc- differentiation in female traits, and differentia- tion). If SFPs participate in ongoing sexual con- tion in male and female traits (Fig. 2). In addi- flicts described above (see the section Do SFPs tion, females could vary in their sensitivity to Contribute to Postmating Sexual Conflict?), SFPs (or in their activation threshold to SFPs). then the genes that encode them should show Theory predicts that when this occurs female

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AB

C D

E Frequency of initial major allele Frequency

Time (generations)

Figure 2. The simplified dynamic outcomes of sexual conflict between SFPs and their receptors in females, based on data adapted from the predictions of Parker (1979) and Hayashi et al. (2007). In this case, sexually antag- onistic coevolution is occurring between different loci in males and females, each with two alleles. The frequency of the initial most frequent allele for each of the loci in males (blue) versus females (red) is shown. (A)A continuous coevolutionary chase, in which the frequency of the female allele tracks that of the male, with no underlying pattern, through time. (B) Cyclic coevolution, in which the female allele frequency tracks that of the male, with the coevolution having a cyclical pattern through time. (C) Evolution toward an equilibrium, in which the frequency of the female allele tracks that of the male toward a stable invariant frequency. (D) Differentiation in female, but not male allele frequency (an example of Buridan’s ass). Here, the frequency of the major male allele continues to fluctuate through time, but that of the female, though initially tracking that of the male, diverges and in this case significantly decreases in frequency. Therefore, the coevolution has led to divergence in the frequencies of the two female alleles. (E) Differentiation in male and female allele frequencies. The frequency of the major male and female alleles initially show coevolutionary fluctuations; however, over time there is divergence in the frequency of both male and female alleles, with, in this case, the initial major allele in males becoming more frequent and that of the female becoming less so. Therefore, the initial coevolution has led to divergence in the frequencies of the two male and the two female alleles.

traits can evolve to “ignore” male adaptations to to become more resistant to the effects of such sexual conflict (Rowe et al. 2005). For example, SFPs (Rice 1996; Pitnick et al. 2001). We would females might become completely resistant to therefore expect rapid sequence and/or expres- a male SFP that induces high levels of egg pro- sion changes in these molecules. There is sub- duction. Expression level variation could medi- stantial evidence for rapid SFPevolution, both at ate this type of regulatory change (e.g., through the sequence level and with respect to seminal down-regulation of a female receptor). fluid composition. Sequence-based studies in a To date, four kinds of evidence for signa- wide range of species, including insects (e.g., tures of sexual conflict have been described. Aguade´ et al. 1992; Swanson et al. 2001; Begun et al. 2000) and mammals (Ramm et al. 2008, (i) Rapid Evolution, in Sequence or Regulation, 2009; Karn et al. 2008), have identified SFP loci in Some SFP Loci and Their Receptors that diverge rapidly between species and/or in Females whose patterns of sequence evolution are indic- Sexual conflict involving SFPs is expected to re- ative of positive selection. Furthermore, in line- sult in selection for male molecules with increas- ages for which genome-wide evolutionary com- ingly “manipulative” (male benefit/female det- parisons have been performed, SFPsare typically riment) functions, and for female SFP receptors found to evolve more rapidly, on average, than

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other functional classes of protein (e.g., Clark tion of SFP loci, this would predict a correlation and Swanson 2005; Haerty et al. 2007; Dean between measures of the intensity of postcopu- et al. 2009; Findlay and Swanson 2010; Wong latory selection (such as mating system) and 2010). Similarly, SF composition appears to rate of SFP evolution. Mating system can be a change particularly rapidly in a number of spe- good proxy for tests of such correlations be- cies. For example, many genes encoding known cause the intensity of postcopulatory sexual se- SFPs in D. melanogaster are undetectable in oth- lection is generally expected to increase with er members of the genus (Mueller et al. 2005; female promiscuity. A number of studies have Wagstaff and Begun 2005; Haerty et al. 2007), sought to test these ideas, and specifically, the and novel species-specific SFP genes have been hypothesis that rates of SFP sequence evolution described in Drosophila (Wagstaff and Begun should correlate with measures of female pro- 2007; Findlay et al. 2008, 2009; Almeida and miscuity and/or sperm competition risk. The Desalle 2009). Systematic characterization of results of these studies are, however, mixed. seminal fluid composition in other groups of Some SFP genes show clearly elevated rates of animals (e.g., mammals) will help to determine amino acid substitution in species in which fe- the generality of this trend. males mate with many males (polyandry); how- It is worth noting that, along with sequence ever, many SFP loci do not show this pattern level changes, there can also be significant vari- (reviewed in Wong 2011; see also Claw 2013; ation in the expression level of SFP loci and of Schumacher et al. 2014). The reason for this SFP receptors within and between populations inconsistency could be that the strength of se- (Smith et al. 2009; Ayroles et al. 2011). Studies lection may not be consistent for the same SFP of this type of variation in the context of sexual across multiple species, perhaps because differ- conflict have not yet been reported. The extent ent signals and pathways may operate in differ- to which expression level variation occurs in ent lineages. This would obscure correlations genes encoding female proteins that interact between mating system and SFP evolution in with SFPs is of significant interest. It could, for studies that focus on a few or single loci. This example, represent some of the “missing” vari- problem could be avoided if the average rates of ation that is evident in comparisons between the evolution for multiple SFPs in monandrous ver- rapid evolution of male-expressed SFPs versus sus polyandrous species were compared. Such the typically lower levels of sequence variation analyses should include investigations of se- seen within the female-expressed loci with quence variation across different members of which SFPs potentially interact (e.g., Swanson the same biochemical gene family. This can re- et al. 2004; Prokupek et al. 2009). Females might veal whether different family members are co- respond to new SFP sequence variants by chang- opted for similar functions in different species. ing the expression level or sensitivity of existing Studies using these approaches and including receptors and interacting molecules. This could multigene comparisons report a higher average subsequently select for ever-newer SFP sequence rate of evolution for testis-biased or testis-spe- variants in the male, or “improved” versions cific genes in chimpanzees (in which sperm of old SFPs. We suggest that further work into competition is more intense) in comparison the extent and significance of expression level to humans (Wong 2010; see Turner and Hoek- variation in genes encoding SFPs and the female stra 2008 for a similar comparison in ). proteins with which they interact will prove very informative. (iii) Coevolution between the Genes Encoding Interacting Male and (ii) Correlations between Rates of SFP Female Proteins Evolution and Mating Systems In addition to affecting the rate of sequence If the intensity of sexual conflict or sexual selec- evolution of SFPs, sexual conflict is expected tion is responsible for driving the rapid evolu- to result in the coevolution of SFPs and recep-

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tors in females. This process can be character- dence for coevolution at the intrapopulation ized by successive waves of directional selection and between-species levels (Clark et al. 2009), or fluctuating selection, leading to continual including correlated rates of amino acid substi- evolutionary chases (Fig. 2). In the simplest sce- tution. nario, in which sexual conflict is mediated by Sexually antagonistic interactions are, how- interactions between a single SFP and a single ever, unlikely to be limited to the simple sce- female receptor, it is expected that these two nario above, in which the interaction is only molecules should coevolve over time. Such sig- between one SFP and its female receptor. For natures should, in theory, be detectable, given example, sexual conflict could be mediated by knowledge of pairs of loci in males and females SFPs that do not have a receptor, as in coevolu- that are subject to sexually antagonistic selec- tion between SFPs that coagulate to form a mat- tion, and robust methods for identifying coevo- ing plug and the female proteases that degrade lution (Clark and Aquadro 2010; Findlay et al. the plug. Conflicts could also be mediated 2014). Unfortunately, it has been difficult to test through interactions between SFPs and female this prediction, because female receptors have morphology or behavioral traits. This type of been identified for only a very few SFPs (Yapici conflict could be evident, for example, in coevo- et al. 2008; Haussmann et al. 2013). In addition, lution between mating plug-forming SFPs and there is a lack of population genomic studies female plug removal behaviors, or female geni- targeted at detecting potentially divergent evo- tal tract morphology changes. Such female traits lutionary trajectories between different popula- may indeed be easier to identify than SFP re- tions of the same species. ceptors themselves and should be more widely Even when a receptor has been identified, considered. A second example is that antago- detecting coevolution is not straightforward. nistic interactions between males and females For example, SPR, the D. melanogaster SP recep- could be impacted by interactions of either sex tor, has nonreproductive ligands in addition with pathogens that access the reproductive to SP (the myoinhibitory peptides, MIPs [Kim tract or cells. There is evidence that some im- et al. 2010; Poels et al. 2010; Vandersmissen munity genes evolve more rapidly in promiscu- et al. 2013]). This may constrain its ability ous species, consistent with the idea that multi- to coevolve with SP potentially independent of ple mating is associated with increased immune whether it is subject to sexual conflict. Another challenge (Wlasiuk and Nachman 2010). In confounding situation would occur if the re- such a situation, it could be difficult to differ- ceptor and ligand interact through molecular entiate antagonistic coevolution between SFPs features that are not directly reflected in the pri- and their receptors from antagonistic coevolu- mary amino acid sequence of either protein. tion between female receptors and the patho- For example, in cows, annexins in the oviducts gens. This would be particularly difficult if interact with BSP seminal proteins to mediate the pathogen interacted directly with the SFP sperm storage—but this molecular interaction receptor in the female, because coevolution be- involves the annexins binding to sugar (fucose) tween the female receptor and the pathogen modifications on the BSPs—modifications that could also “drag along” SFP coevolution to re- are added posttranslationally (Ignotz et al. tain SFP function through the female receptor. 2007). Although it has not yet been possible to The primary driving interaction in this scenar- test the hypothesis of coevolution with SFPs and io would be the host–pathogen interaction, not their receptors, some ideas of what might be the male–female conflict. However, without found come from results on coevolving egg (vi- knowledge of host–pathogen interactions, the telline envelope) and sperm ligand/receptor correct explanation for any coevolutionary pat- pairs in abalone (VERL and lysin, respective- terns observed between SFPs and receptors ly [Clark et al. 2009]). VERL and lysin are in could be hard to pin down. linkage disequilibrium, even though their loci One outcome of sexual conflict, predicted are not physically linked. They also show evi- by theory when the intensity of sexual conflict

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between males and females is relatively weak, is (iv) Chromosomal Distribution of SFP Loci the differentiation of reproductive traits in one sex but not in the other (the so-called Buridan’s In organisms with chromosomal-based sex de- ass outcome, Fig. 2) (Gavrilets and Waxman termination, there is an inevitable asymmetry 2002; Parker 2006; Hayashi et al. 2007). If this of passage of sex chromosomes through the process occurs within a species, it could assist in sexes (see work by Mank et al. 2014). In XX/ the evolution of divergent reproductive forms, female and XY/male systems, for example, X and hence reproductive isolation via the sym- chromosomes are present more often in females patric mode (i.e., in the absence of physical than in males. In such a situation, there is a barriers to gene flow [Gavrilets and Waxman greater chance for selection for genes of benefit 2002]). Interestingly, there is empirical evidence to females on the X chromosome and less for Buridan’s ass in the apparently antagonistic chance to select for genes of benefit to males. interactions concerning the speed and efficiency This would be predicted to lead to a situation in of sperm entry into the egg; this evidence con- which female benefit genes should be X-en- cerns the abalone sperm protein lysin, and the riched (Rice 1984). Consistent with this idea, egg protein VERL to which it binds, as discussed the gene for SPR is X-linked in D. melanogaster. above (Clark et al. 2009). The empirical obser- As additional SFP receptors are discovered it vation is that male-derived lysin has low genetic will be interesting to see whether they, too, are variability and hence shows little phenotypic X-linked. variation, whereas its female partner VERL Genes encoding D. melanogaster SFPs are shows abundant polymorphism and manifests predominantly located on the autosomes. This multiple different phenotypes in females, asso- could reflect that alleles of genes that more of- ciated in some cases with incipient speciation. ten benefit males can accumulate more easily These data have been interpreted as evidence for on the autosomes, or perhaps that sex limita- Buridan’s ass in that the invariant male lysin is tion in males is easier to evolve on autosomes, “stranded” between the divergent female VERLs because of additional requirements for dosage- (Panhuis et al. 2006). A Buridan’s ass situation compensation control of X-linked genes in male appears to be a unique signature of sexual con- Drosophila. flict. Further work will show whether this phe- nomenon is seen for SFPs. Evidence for Conflict Resolution It is important to note that, although each of the evolutionary patterns described so far In addition to evidence for ongoing conflict could arise as a result of sexually antagonistic mediated by SFPs, it should be possible to detect coevolution, none is a unique signature of sex- signatures of previous, but resolved, conflicts. ual conflict, with the possible exception of the These resolutions might, of course, themselves Buridan’s ass scenario, as discussed above. As open up alternative possibilities, or routes for, such, the presence or absence of rapid SFP evo- novel sexual conflicts. Signatures of previous lution is consistent with sexual conflict but does sexual conflict in the genome are predicted to be not rule out other selective regimes. Further- detectable as genomic “baggage” such as pseu- more, even where sexual conflict over a partic- dogenes, gene redundancy, duplication, and/or ular outcome (e.g., egg-laying rate or remating) gross genome rearrangements between sibling is expected to result in coevolution between an species. Examples of all of these phenomena SFP and its receptor, coevolution may be im- are observed among genes encoding SFPs. peded by pleiotropy (where the loci involved One line of evidence for resolution of con- have additional, potentially nonreproductive, flict could be the loss of function of SFP genes, functions) or if the conflict is mediated by mul- as females overcome or avoid their effects. The tiple interacting loci. Thus, care must be taken “lost” genes could be replaced by others, in- in interpreting patterns of SFP molecular evo- cluding by co-option of other members of the lution in the light of sexual conflict. same biochemical family, in response. Such SFP

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turnover appears to be particularly rapid in sexual conflict but also show signatures at the Drosophila species subgroups and in the pri- gene sequence and expression level of past and mate copulatory plug protein SEMG2 (Kingan current conflict. In this section, we conclude by et al. 2003; Carnahan and Jensen-Seaman considering additional aspects of the interface 2008). Female gorillas, unlike their chimpanzee between SFPs and sexual conflict and proposing cousins, are usually monandrous during each future research directions. reproductive bout, removing the opportunity for postcopulatory sexual conflict. Because pri- Is It All Conflict? mate copulatory plug proteins are thought to be maintained, at least in part, owing to the advan- The evidence provided in the sections above can tage they provide males in preventing sperm be interpreted as indicating the presence of sex- competition, in species with monandrous fe- ual conflict. However, we do not yet know to males, selection is expected to be relaxed on what extent conflict actually operates and how such proteins, and thus loss-of-function muta- important it is in relation to processes such as tions within them would not be removed from sexual selection. As noted above (in the section the population (see also Claw 2013). The Potential Weapons), there are examples of Resolution of one type of conflict can also biochemical pathways that include contribution provide conditions for new conflicts to emerge. by males and females (e.g. proteolytic process- For example, intralocus sexual conflict, which ing of Drosophila ovulin, Fig. 1), males turning results from differing “demands” by males and on molecular pathways in females (e.g., Rubin- females on a single gene, is often proposed to be stein and Wolfner 2013), males activating al- resolved by the evolution of sex-limited expres- ready prepared pools of preexisting RNAs or sion of the relevant gene (see work by Ingleby proteins in females (e.g., Heifetz and Wolfner et al. 2014). Sex limited expression for SFPs 2004; Lawniczak and Begun 2004; McGraw would have released SFPs from any functional et al. 2004; Mack et al. 2006; Kapelnikov et al. constraint imposed by having to operate in fe- 2008; Rubinstein and Wolfner 2013), and ap- males. It may also have allowed the effects of parent male/female synergy in achieving sperm SFPs to be more easily tailored to coordinate storage (e.g., Ignotz et al. 2007). These examples reproductive processes. Forexample, an SFP sig- may reflect the requirement to coordinate the nal from males received by females only once many complex processes needed in order for sperm transfer has been achieved would be an reproduction to be successful. It is worth con- efficient way of activating reproductive pro- sidering, however, that sexual conflict can occur cesses in females at the correct time and in the within even the most complex and apparently correct sequence (Chapman 2001). This mech- mutually beneficial of these interactions. SFPs anism benefits both sexes. However, once pres- have the potential to engage females in a “sen- ent, sex limitation instantly opens up the sory trap” (West Eberhard 1979) through the possibility for relatively unconstrained direct use of SFP signals to which females “must” re- manipulation of reproduction in the female by spond to reproduce successfully, but which can males, with the possibility of initiating a new then be used to divert females from their opti- interlocus sexual conflict. Hence, new routes mal investment in reproduction. Females can- for sexual conflict via the interlocus mode may not evolve complete insensitivity; otherwise emerge following resolution of intralocus sexual they achieve lower fitness (hence “trapped”). conflict via the evolution of sex limitation. Only a combination of mechanistic knowledge with manipulative experiments can determine whether such a scenario exists. CONCLUDING REMARKS Further, the intensity of sexual conflict me- SFPs provide an informative molecular system diated by SFPs may vary over time, both across in which to study sexual conflict because they and within generations. The intensity of conflict not only provide mechanisms that can underlie now may not indicate its relative importance in

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the past or future. Resource levels may also be used to make SFPs more stable in females cause variability in the extent to which conflict so that their effects persist, or to allow them to is expressed (Fricke et al. 2010). For example, be effective even in the absence of sperm (in the when food is scarce, females may be unable to case of SFPs, like SP, whose effects are sperm exhibit increased egg laying following mating, dependent). Another logical application of the no matter how much SF has been received. Ad- use of SFPs in pest management would be to ditional experiments into the lifetime costs and chemically interfere with the production of benefits of SFP transfer from both the male and particular SFPs in males or their receptors in the female’s perspective, made under a range of females. This approach may be successful for biologically relevant conditions, are now neces- effects in females that are mediated by a single sary to resolve the extent of sexual conflict me- SFP–receptor pair, but as noted earlier there diated by SFPs. is significant redundancy in SFP functional classes and/or lack of specificity in SFP recep- tors that might make such interference with a Practical Applications single SFP or receptor less effective. Moreover, Understanding how SFPs shape and are shaped the rapid rate of SFPevolution suggests that pest by sexual conflict has numerous potential prac- species may evolve resistance to such strategies, tical applications, and also provides cautionary as these strategies simulate what might happen insights. For example, this knowledge could under conflict scenarios. Rapid SFP evolution provide insights for the control of pest insects. also makes it unlikely that SFP-based molecules One option for increased efficiency of insect used to target one species would negatively af- control is to select for, or genetically engineer, fect other species. males that have a greater effect on female repro- In addition to controlling pest populations, ductive physiology and/or behavior. This ma- our knowledge of the role of sexual conflict nipulation could be coupled with pest control in shaping SFPs could also inform strategies strategies such as the sterile male technique or to promote successful reproduction outcomes release of genetically modified strains that are in species of conservation concern, agricultur- altered in such a way to reduce damage (e.g., Fu al animals (e.g., honey bees and farm animals), et al. 2007). Proof of principle for the use of and even humans. For example, for nonhuman artificial selection in creating more “manipu- animals, SFPs from males in populations in lative” males comes from studies in D. mela- which females mate promiscuously may en- nogaster. For example, female D. melanogaster hance the fertilizing ability of sperm used in mated to males that had experimentally evolved assisted reproduction. Similarly, exposure of in a polygamous mating system took longer to males to cues of sperm competition could in- remate and produced fewer offspring after crease the quantity or fertilizing ability of mating than females mated to males that had sperm in theirejaculates (Wedellet al. 2002; Kill- evolved in a monogamous mating system (Hol- gallon and Simmons 2005; Bretman et al. 2009, land and Rice 1999; Pitnick et al. 2001). Fur- 2011). thermore, D. melanogaster males selected for increased accessory gland size produced and Future Prospects transferred more SP and sired more offspring when in competition with other males than SFPs are experimentally accessible molecules control males (Wigby et al. 2009). The results that exert precise and measurable effects on of these studies suggest that standard artificial the female—yet are made by the male. These selection could increase the ability of laborato- characteristics make them a fascinating and ry-reared males to induce postmating responses tractable system for dissecting molecular inter- in their mates. Similar effects can be achieved actions that can participate in, and underlie, simply by exposing males to rivals (Bretman et sexual conflict. In the sections above, we have al. 2009). Selection or genetic engineering could highlighted some of these interactions and how

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L.K. Sirot et al.

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Sexual Conflict and Seminal Fluid Proteins: A Dynamic Landscape of Sexual Interactions

Laura K. Sirot, Alex Wong, Tracey Chapman and Mariana F. Wolfner

Cold Spring Harb Perspect Biol published online December 11, 2014

Subject Collection The Genetics and Biology of Sexual Conflict

Mechanisms and Evidence of Genital Infanticide as Sexual Conflict: Coevolution of Coevolution: The Roles of Natural Selection, Mate Male Strategies and Female Counterstrategies Choice, and Sexual Conflict Ryne A. Palombit Patricia L.R. Brennan and Richard O. Prum The Evolution of Sexually Antagonistic Copulatory Wounding and Traumatic Phenotypes Insemination Jennifer C. Perry and Locke Rowe Klaus Reinhardt, Nils Anthes and Rolanda Lange Reproductive Parasitism: Maternally Inherited Sexual Conflict in Hermaphrodites Symbionts in a Biparental World Lukas Schärer, Tim Janicke and Steven A. Ramm Gregory D.D. Hurst and Crystal L. Frost Sex-Biased Gene Expression and Sexual Conflict Sexual Conflict and Sperm Competition throughout Development Dominic A. Edward, Paula Stockley and David J. Fiona C. Ingleby, Ilona Flis and Edward H. Morrow Hosken Human Homosexuality: A Paradigmatic Arena for Sexually Antagonistic Zygotic Drive: A New Form Sexually Antagonistic Selection? of Genetic Conflict between the Sex Andrea Camperio Ciani, Umberto Battaglia and Chromosomes Giovanni Zanzotto Urban Friberg and William R. Rice Sexual Conflict Arising from Extrapair Matings in Sex Chromosome Drive Birds Quentin Helleu, Pierre R. Gérard and Catherine Alexis S. Chaine, Robert Montgomerie and Bruce Montchamp-Moreau E. Lyon Sexual Conflict and Seminal Fluid Proteins: A Is Sexual Conflict an ''Engine of Speciation''? Dynamic Landscape of Sexual Interactions Sergey Gavrilets Laura K. Sirot, Alex Wong, Tracey Chapman, et al. Conflict on the Sex Chromosomes: Cause, Effect, Sexual Cannibalism as a Manifestation of Sexual and Complexity Conflict Judith E. Mank, David J. Hosken and Nina Wedell Jutta M. Schneider

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