Sex Chromosome Drive

Sex chromosome drivers are selfish elements that subvert Mendel''s first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species.Meiotic drivers are selfish genetic elements that subvert Mendelian segregation during gametogenesis for their own benefit. They are passed on to most, if not all, of the functional gametes produced by heterozygotes. Therefore, drivers can increase in frequency and invade populations even if they reduce individual fitness, which is usually the case. The drivers are typically expressed in one sex, of which fertility is impaired. This also has deleterious consequences for the opposite sex and is expected to promote adaptations to counteract drive through sexual selection and sexual conflict. Furthermore, sex-linked meiotic drivers expressed in the heterogametic sex typically lead to biased offspring sex ratios, which represents an additional cost and can exacerbate the sexual conflict.Morgan et al. (1925) were the first to observe sex-biased offspring, which turned out to be caused by a sex-linked meiotic driver. Unfortunately, the Drosophila affinis strain was lost before any conclusive study could be performed. Later, Gershenson (1928) found that the offspring of some Drosophila obscura males were female biased. He showed that these males carried an X-linked genetic element (hereafter “sex ratio” or SR) responsible for the sex-ratio distortion, and showed that the SR did not affect the viability of the male offspring but acted as a gametic killer of Y-bearing sperm. Gamete killing or disabling is observed in males; in females, meiotic drive is usually a result of centromere competition for access to the egg.In its original definition (from Gershenson''s work and others), the term meiotic drive applies to the consequences of the mechanics of the meiotic divisions (Sandler and Novitski 1957). Here, under the term “sex chromosome drive,” we will include more broadly any case of preferential transmission that results directly or indirectly from an event that took place before, during, or after meiosis. Sex chromosome drive is different from sex-ratio adjustment, in which the favored chromosome is not the actor of its drive (West and Sheldon 2002). As emphasized by Sandler and Novitski (1957), it is also different from selection in the haploid phase as a consequence of the gamete''s intrinsic fitness.Only a few dozen cases of sex chromosome drive have been described, mainly in Drosophila and other Diptera (reviewed in Jaenike 2001; Burt and Trivers 2006). One possible explanation for the rarity of reported cases is that a biased sex ratio is not evolutionarily stable. Fisher (1930) predicted that natural selection will favor a 1:1 sex ratio, and that any deviation will be counterselected. This means that variants with counteracting effects can be selected at unlinked loci. Consistent with this prediction, autosomal drive suppressors and resistant Y chromosomes have been found in several Drosophila species (De Carvalho and Klaczko, 1994; Carvalho et al. 1997; Cazemajor et al. 1997). Three different cryptic X-linked SR systems have been described in the same species (Drosophila simulans: Paris, Winters, and Durham systems), showing that they can evolve repeatedly and be completely neutralized in the wild, remaining undetectable unless appropriate genetic crosses are performed (Merçot et al. 1995; Tao et al. 2001, 2007a). D. simulans also teaches us that the time window leading up to neutralization can be very narrow (Bastide et al. 2013). However, variants that enhance distortion can be selected if they are linked to the distorter. Inversions should prevent recombination with nondriving X chromosomes and keep together the loci that interact to induce drive, as found in D. pseudoobscura (Wu and Beckenbach 1983). These examples illustrate the extended genetic conflict that can result from the evolution of sex chromosome drive.Among the known cases of sex chromosome drive, X chromosome drive is much more common than Y chromosome drive. This may be because Y-linked drivers are always expressed, at each generation, unlike X-linked drivers. All else being equal, Y chromosome drive spreads faster and leads to a higher risk of extinction owing to the lack of females (Hamilton 1967). Furthermore, when the sex chromosomes are well differentiated, the Y chromosome usually has many fewer genes, which may provide fewer opportunities for a driver to evolve. On the other hand, heteromorphic sex chromosomes are expected to facilitate the evolution of meiotic drive. Indeed, the more divergent the sex chromosomes are, the less they recombine, reducing the risk of producing a suicide chromosome that carries both the driver and a sensitive allele at the target locus (Charlesworth and Hartl 1978; Frank 1991; Hurst and Pomiankowski 1991).     

Is Sexual Conflict an “Engine of Speciation”?

At the end of the last century, sexual conflict was identified as a powerful engine of speciation, potentially even more important than ecological selection. Earlier work that followed—experimental, comparative, and mathematical—provided strong initial support for this assertion. However, as the field matures, both the power of sexual conflict and constraints on the evolution of reproductive isolation as driven by sexual conflict are becoming better understood. From theoretical studies, we now know that speciation is only one of several possible evolutionary outcomes of sexual conflict. In line with these predictions, both experimental evolution studies and comparative analyses of fertilization proteins and of species richness show that sexual conflict leads to, or is associated with, reproductive isolation and speciation in some cases but not in others. Increased genetic variation (especially in females) without reproductive isolation is an underappreciated consequence of sexually antagonistic selection.By the end of 1990s, studies of sexual conflict and sexually antagonistic coevolution moved to the forefront of experimental and theoretical research in evolutionary biology (Rice and Holland 1997; Holland and Rice 1998; Rice 1998). Although the potential evolutionary importance of sexual conflict was anticipated and articulated from a theoretical point of view by Geoff Parker 20 years earlier (Parker 1979), the explosive interest in this topic was a result of groundbreaking experimental work with Drosophila melanogaster by Bill Rice (1993, 1996), which directly showed high potential for sexually antagonistic coevolution.Sexual conflict is a special case of intragenomic conflict (Rice and Holland 1997; Rice 1998; Crespi and Nosil 2013). Sexual conflict occurs if the interests of the sexes with regard to certain aspects of reproduction differ (Parker 1979; Arnqvist and Rowe 2005). Ultimately, sexual conflict arises because of the differences in the roles played by the sexes in the process of reproduction, which in turn lead to the differences between the sexes in the costs and benefits of mating and reproduction (Bateman 1948; Trivers 1972; Parker 1979). Sexual conflict can occur over mating rate (Rice and Holland 1997; Holland and Rice 1998; Rice 1998), offspring size (Haig 2000), parental care (Smith and Härdling 2000; Barta et al. 2002), the use of sperm (Ball and Parker 2003), epigenetic control of development (Rice et al. 2012), etc.Sexual conflict can occur through two genetic routes (Chapman and Partridge 1996; Parker and Partridge 1998). Within-locus conflict occurs when the locus controls a trait expressed in both sexes and the optimum trait values differ between the sexes. As a result, optimizing the trait value in one sex will lead to a fitness reduction in the other sex. Within-locus conflict can be resolved via a number of mechanisms, including the evolution of sex linkage, sex-specific expression of genes, gene duplication, and condition dependence (Bonduriansky and Chenoweth 2009; van Doorn 2009). Between-locus conflict occurs when there are two different (sets of) traits each expressed in one sex only but affecting the fitness of both sexes in opposite directions. In this case, adaptive changes in a trait of one sex cause deleterious fitness consequences for the other sex, which can be negated by the evolution in a trait of the other sex, which in turn will cause deleterious fitness consequences for the first sex. For example, males can evolve adaptations increasing their mating rate, which would be detrimental for females who would then evolve some counteradaptations to decrease the mating rate (Rice 1996).One particularly exciting idea that has emerged from studies of sexual conflict and sexually antagonistic coevolution is that sexual conflict can be an important “engine of speciation” (Rice 1996, 1998; Howard et al. 1998; Parker and Partridge 1998). In standard modern perspective, speciation is a result of genetic divergence between populations accompanied by the evolution of reproductive isolation (Howard and Berlocher 1998; Schluter 2000; Coyne and Orr 2004; Dieckmann et al. 2004; Gavrilets 2004). Genetic divergence can be driven by a variety of evolutionary factors, including mutation, random genetic drift, and natural, sexual, and social selection. Reproductive isolation can follow from a variety of mechanisms, resulting in incompatibilities (including genetic, developmental, morphological, ecological, and behavioral) of males and females from diverging populations or in a reduced fitness of their offspring. As was argued by Rice (1998), Parker and Partridge (1998), and others (e.g., Howard et al. 1998), sexual conflict can contribute to these processes in a number of ways.Below, I briefly summarize several, mostly verbal, theories of biological diversification caused by sexual conflict and then move to discussing some of the more concrete mathematical models and empirical data and patterns.     

Sexual Conflict between Parents: Offspring Desertion and Asymmetrical Parental Care

Parental care is an immensely variable social behavior, and sexual conflict offers a powerful paradigm to understand this diversity. Conflict over care (usually considered as a type of postzygotic sexual conflict) is common, because the evolutionary interests of male and female parents are rarely identical. I investigate how sexual conflict over care may facilitate the emergence and maintenance of diverse parenting strategies and argue that researchers should combine two fundamental concepts in social behavior to understand care patterns: cooperation and conflict. Behavioral evidence of conflict over care is well established, studies have estimated specific fitness implications of conflict for males or females, and experiments have investigated specific components of conflict. However, studies are long overdue to reveal the full implications of conflict for both males and females. Manipulating (or harming) the opposite sex seems less common in postzygotic conflicts than in prezygotic conflicts because by manipulating, coercing, or harming the opposite sex, the reproductive interest of the actor is also reduced. Parental care is a complex trait, although few studies have yet considered the implications of multidimensionality for parental conflict. Future research in parental conflict will benefit from understanding the behavioral interactions between male and female parents (e.g., negotiation, learning, and coercion), the genetic and neurogenomic bases of parental behavior, and the influence of social environment on parental strategies. Empirical studies are needed to put sexual conflict in a population context and reveal feedback between mate choice, pair bonds and parenting strategies, and their demographic consequences for the population such as mortalities and sex ratios. Taken together, sexual conflict offers a fascinating avenue for understanding the causes and consequences of parenting behavior, sex roles, and breeding system evolution.Sexual conflict over care is a type of evolutionary conflict that emerges from the different interests of males and females in regard to parental care (Trivers 1972; Clutton-Brock 1991; Chapman et al. 2003; Arnqvist and Rowe 2005). The conflict arises when the young benefit from the effort of either parent, but each parent pays only the cost of its own effort, so that each parent would have higher fitness if the other parent provides more care (Houston et al. 2005; Lessells 2006; Klug et al. 2012). Conflict refers to the way selection acts on the two sexes that have different optimum values in parental provisioning; between the two optima, sexually antagonistic selection operates (Lessells 2012). Sexual conflict over care can be seen as tug-of-war, because each parent is tempted to pull out of care leaving the other parent to provide more care for the young (Székely et al. 1996; Arnqvist and Rowe 2005; Lessells 2012).Sexual conflict over care seems to be the rule rather than the exception. The conflict may be resolved by one or both parents failing to adopt the optimal parenting for their mate and nonetheless remaining in conflict, or by both parents adopting the optima that suit their mate (i.e., exhibit the maximum provisioning possible). Examples of the latter conflict resolution (whereby the conflict is completely wiped out) are exceedingly rare and seem to be limited to three scenarios. First, conflict over care is not expected in obligate monogamy by both males and females so that the lifetime reproductive successes of both parents are identical. This may occur in semelparous organisms (i.e., both the male and the female put their resources into a single breeding event) or in iteroparous organisms with lifelong exclusive monogamy. Second, males and females might be genetically identical, so even though one or both sexes are polygamous, polygamy would benefit the same genome whether it is in the male or the female phenotype. Third, parental care is cost-free and thus parents provide maximum level of care (P Smiseth, pers. comm.). However, few, if any, organisms fit these restrictive assumptions, and thus conflict-free parenting seems exceedingly rare in nature: (1) some level of polygamy (by males, females, or both sexes) appears to be widespread; (2) the reproduction by genetically identical individuals (clones) as separate sexes (males and females) seems unlikely although not impossible if sex is determined environmentally; and (3) care provisioning, as far as we are aware, does have costs that discourage parents from providing their absolute maxima for a given batch of offspring.Parents may have conflicting interest over caring or deserting the young, the amount of care provided for each young, the number of simultaneous mates, the size and sex ratio of their brood, and the synchronization of birth for a clutch or litter of young (Westneat and Sargent 1996; Houston et al. 2005; Klug et al. 2012; Lessells 2012). Conflict between parents over care is usually labeled as a postzygotic conflict although resources had been already allocated into the gametes before fertilization as part of parental provisioning (Clutton-Brock 1991); other examples of postzygotic conflicts include infanticide and genomic imprinting (Chapman et al. 2003; Tregenza et al. 2006; Lessells 2012; see Palombit 2014).Studies of conflict over care are fascinating for at least four major reasons. First, parental care is diverse. There is great variation both between and within species in the types of care provided, duration of care, and the sex of the care-providing parent (Wilson 1975; Clutton-Brock 1991; McGraw et al. 2010; Royle et al. 2012), and sexual conflict is thought to be one of the main drivers of this diversity. Second, parental care is one of the core themes in breeding systems and sex role evolution, and it is increasingly evident that parental care can only be understood by dissecting the entangled relationships between ecological and life-history settings, and the variety of mating and parenting behavior (Székely et al. 2000; Webb et al. 2002; Wedell et al. 2006; Jennions and Kokko 2010; Klug et al. 2012). Third, parental care was (and is) one of the test beds of evolutionary game theory. Numerous models have been developed to understand how parents interact with each other and with their offspring (Trivers 1972; Maynard Smith 1977; Houston and Davies 1985; Balshine-Earn and Earn 1998; McNamara et al. 1999, 2000; Webb et al. 1999; Johnstone and Hinde 2006; Johnstone et al. 2014). Parental care research is one field in which empiricists are extensively testing the predictions of evolutionary game theoretic models in both the laboratory and wild populations (Székely et al. 1996; Balshine-Earn and Earn 1998; Harrison et al. 2009; Klug et al. 2012; Lessells 2012; van Dijk et al. 2012), although the congruence between theoretical and empirical work is not as tight as often assumed (Houston et al. 2013). Finally, parental care—wherever it occurs—is often a major component of fitness, because whether the offspring are cared for or abandoned has a large impact on their survival, maturation, and reproduction (Smiseth et al. 2012). Therefore, parental care (or the lack of it) may have an impact on population productivity and population growth and influences the resilience of populations to various threats (Bessa-Gomes et al. 2004; Veran and Beissinger 2009; Blumstein 2010). Thus, understanding the behavioral interactions between parents and the fitness implications of these interactions is highly relevant for population dynamics and biodiversity conservation (Alonzo and Sheldon 2010; Blumstein 2010).Sexual conflict over care has been reviewed recently (van Dijk and Székely 2008; Lessells 2012; Houston et al. 2013). Here, I focus on three issues that have not been extensively covered by previous reviews: (1) why sexual conflict over care occurs in some environments, whereas in others parental cooperation appears to dominate; (2) how can one detect sexual conflict over care; and (3) what are the implications of sexual conflict over care for macroevolution. I view causes and implications of parental care primarily from empirical perspectives; there are excellent reviews on the rich theoretical literature (Lessells 2006, 2012; Klug et al. 2012; Houston et al. 2013). My intention is not to be comprehensive; instead, I use selected examples to illustrate salient features of conflict over care. I focus on ecological and evolutionary aspects; for a discussion of the genetic and neuroendocrine bases of parental care, see Adkins-Regan (2005), McGraw et al. (2010), and Champagne and Curley (2012). I prefer to use the term “parental care” instead of “parental investment,” because the latter, as admitted by Trivers (1985), is extremely difficult to estimate empirically and thus may have a limited use in empirical studies (Mock and Parker 1997; McGraw et al. 2010). The term “parental investment” can be deceptive, if used without directly demonstrating the full costs of care. The term “parental care” is less restrictive, because it refers to any form of parental behavior that appears to increase the fitness of an offspring and is likely to have evolved for this function (Clutton-Brock 1991; Smiseth et al. 2012). In this review, I focus on families in the narrow sense (i.e., two parents and their offspring), although in numerous organisms the families are more extensive and may include several generations of offspring living together and/or unrelated individuals that assist the parents rearing the young.     

Sexual Conflict Arising from Extrapair Matings in Birds

The discovery that extrapair copulation (EPC) and extrapair paternity (EPP) are common in birds led to a paradigm shift in our understanding of the evolution of mating systems. The prevalence of extrapair matings in pair-bonded species sets the stage for sexual conflict, and a recent focus has been to consider how this conflict can shape variation in extrapair mating rates. Here, we invert the causal arrow and consider the consequences of extrapair matings for sexual conflict. Extrapair matings shift sexual conflict from a simple two-player (male vs. female) game to a game with three or more players, the nature of which we illustrate with simple diagrams that highlight the net costs and benefits of extrapair matings to each player. This approach helps identify the sorts of traits that might be under selection because of sexual conflict. Whether EPP is driven primarily by the extrapair male or the within-pair female profoundly influences which players are in conflict, but the overall pattern of conflict varies little among different mating systems. Different aspects of conflict are manifest at different stages of the breeding cycle and can be profitably considered as distinct episodes of selection caused by conflict. This perspective is illuminating both because conflict between specific players can change across episodes and because the traits that evolve to mediate conflict likely differ between episodes. Although EPP clearly leads to sexual conflict, we suggest that the link between sexual conflict and multiple paternity might be usefully understood by examining how deviations from lifetime sexual monogamy influence sexual conflict.The development of genetic tools for determining parentage fundamentally altered our understanding of animal mating systems (Jeffreys et al. 1985; Avise 1996; Reynolds 1996) and provided invaluable insights into the consequences and causes of females mating with more than one male. Particularly for the study of birds, these methods revealed that social pair bonds often fail to match the actual patterns of copulations that produced offspring (Gowaty and Karlin 1984; Birkhead and Møller 1992; Reynolds 1996; Petrie and Kempenaers 1998), revolutionizing the study of avian mating systems. Extensive research and two recent reviews point out the progress we have made in this field and show how little we still understand extrapair behavior (Griffith et al. 2002; Westneat and Stewart 2003).In the 1960s, David Lack compiled what was then known about mating systems in birds and concluded that >90% of species were monogamous, a pattern that provided an early framework for the development of mating system theory (Lack 1968; Orians 1969; Emlen and Oring 1977). When it was later discovered that sexual mating patterns did not match the social mating systems that Lack described, the field was turned on its head (Westneat et al. 1990; Avise 1996; Reynolds 1996; Zeh and Zeh 2001). In extreme cases, the mismatch between the social and sexual mating systems is nothing short of spectacular; in fairywrens (Malurus species) that are socially monogamous, cooperatively breeding species with helpers, the extrapair paternity (EPP) rate can exceed 75% of all offspring and 95% of all broods (Mulder et al. 1994). In socially monogamous birds, in general, the rate of EPP is typically on the order of 10% of offspring and 20% of broods (Griffith et al. 2002), but variation among species, and even populations within species, is extensive (Arnold and Owens 2002; Griffith et al. 2002). The occurrence of EPP has profound consequences for the evolution of social behavior, both because it alters the scope for the action of sexual selection (Webster et al. 1995; Sheldon and Ellegren 1999) and because it results in males often providing parental care to offspring they have not sired (Davies et al. 1992; Westneat and Sherman 1993).Even in taxa with mating systems other than social monogamy, or in which there is no obvious pair bond, the ability to determine parentage genetically was revolutionary, allowing precise estimates of male reproductive success when females mate multiply. That focus on multiple mating also catalyzed an interest in sexual selection from the female’s perspective, whereas previous attention had been strongly biased toward males and male traits. More specifically, it raised the questions as to why females would pursue and benefit from matings outside the social pair bond (Westneat et al. 1990; Petrie and Kempenaers 1998), and why a female would benefit from mating with more than one male for a given clutch or litter. This new focus on females brought attention to the issue of polyandry more generally (Jennions and Petrie 2000; Simmons 2005; Parker and Birkhead 2013; Pizzari and Wedell 2013).Recently, the assumption that females control mating patterns, and thus that polyandry and EPP can be universally understood from the perspective of fitness benefits to females, has been questioned (Westneat and Stewart 2003). Focusing specifically on EPP, Westneat and Stewart (2003) suggested that, in some taxa, EPP could be driven entirely by benefits to the extrapair-seeking male. They also suggested that many aspects of EPP can be profitably explored from the perspective of sexual conflict, as had Petrie and Kempenaers (1998) before them. Previous interest in the relation between EPP and sexual conflict in birds was focused particularly on trying to explain the incidence and frequency of EPP within and among species. Westneat and Stewart (2003) recognized that that link was indirect. Instead, they suggested that sexual conflict theory might help us to identify traits that could arise from conflict and that those traits might inform the search for a general explanation of the huge variation in EPP rates both among and within bird species.Sexual conflict, the conflicting fitness interests of males and females during mating (Parker 1979; Rice 1998; Arnqvist and Rowe 2005), can lead to antagonistic coevolution between the traits expressed in males and those expressed in females, traits that in some way influence mating outcomes. Traits in males and females are ultimately the drivers of conflict, and, reciprocally, conflict fuels further trait evolution. Sexual conflict theory is useful because it can potentially explain the evolution and maintenance of traits that are otherwise difficult to understand (Arnqvist and Rowe 2005). Thus, studies often examine the factors and traits that underlie different aspects of sexual conflict, as well as the types of morphological and behavioral traits that result from selection caused by the sexual conflict itself.In this article, we build on the foundation provided by Westneat and Stewart (2003). They proposed that sexual conflict can help to explain variation in the occurrence of EPP among species and populations (Westneat and Stewart 2003). Here, we invert the focus and seek to understand the consequences that EPP can have for sexual conflict and the relation between EPP and other drivers of sexual conflict. Thus, we examine the players involved in the sexual conflict generated by EPP and the costs and benefits that underpin the conflicts among the different players. We point out that different conflicts are involved in the different stages of a single bout of reproduction, and we suggest that these represent sequential periods of conflict, each of which is a different episode of selection generated from that conflict. We then place these patterns of conflict into a broader context by contrasting how different patterns of fidelity and infidelity (including EPP) during a lifetime of mating can influence sexual conflict. Our review focuses on birds as examples, both because they have been extensively studied with respect to EPP and because they have been the subjects of most of our own research. Our goal, however, is to provide a framework for understanding trait evolution under the influence of sexual conflict caused by females mating multiply in any animal species.     

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

Sexual reproduction requires coordinated contributions from both sexes to proceed efficiently. 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, sperm “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 protein (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.Both sexes benefit from successful reproduction, but the different reproductive strategies adopted by males and females may result in differential costs and benefits. This can result in sexual conflict before, during, and after mating. Conflict in the more familiar form of competition can also occur between females and between males, with the latter situation including interejaculate competition. Of the many “weapons” in these conflicts and competitions, this article focuses on the seminal fluid proteins (SFPs) that are made by males and transferred to females during mating. These proteins represent a crucial interface of functional activity between male and female. Transfer of SFPs can affect physiology and, in some animals, the behavior and life span of mated females (reviewed in Chapman 2001; Gillott 2003; Poiani 2006; Avila et al. 2011; Rodríguez-Martínez et al. 2011). Because SFPs have important effects on the most intimate of interactions between the sexes, they are prime candidates to become subject to sexually antagonistic selection (Arnqvist and Rowe 2005). With increasing knowledge of the functions of SFPs, their roles in inter- and intrasexual conflict and their evolutionary responses to conflict are becoming ever more apparent. Here, we explore the roles, evolution, and significance of these male-derived players in sexual conflict. We refer the reader to previous reviews for much of the detailed functional information on SFPs (e.g., Chapman 2001; Gillott 2003; Kubli 2003; Arnqvist and Rowe 2005; Poiani 2006; Sirot et al. 2009; Avila et al. 2011; Rodríguez-Martínez et al. 2011) and focus here instead on selected examples, drawn largely from the study of insects.     

Origin and Evolution of the Self-Organizing Cytoskeleton in the Network of Eukaryotic Organelles

The eukaryotic cytoskeleton evolved from prokaryotic cytomotive filaments. Prokaryotic filament systems show bewildering structural and dynamic complexity and, in many aspects, prefigure the self-organizing properties of the eukaryotic cytoskeleton. Here, the dynamic properties of the prokaryotic and eukaryotic cytoskeleton are compared, and how these relate to function and evolution of organellar networks is discussed. The evolution of new aspects of filament dynamics in eukaryotes, including severing and branching, and the advent of molecular motors converted the eukaryotic cytoskeleton into a self-organizing “active gel,” the dynamics of which can only be described with computational models. Advances in modeling and comparative genomics hold promise of a better understanding of the evolution of the self-organizing cytoskeleton in early eukaryotes, and its role in the evolution of novel eukaryotic functions, such as amoeboid motility, mitosis, and ciliary swimming.The eukaryotic cytoskeleton organizes space on the cellular scale and this organization influences almost every process in the cell. Organization depends on the mechanochemical properties of the cytoskeleton that dynamically maintain cell shape, position organelles, and macromolecules by trafficking, and drive locomotion via actin-rich cellular protrusions, ciliary beating, or ciliary gliding. The eukaryotic cytoskeleton is best described as an “active gel,” a cross-linked network of polymers (gel) in which many of the links are active motors that can move the polymers relative to each other (Karsenti et al. 2006). Because prokaryotes have only cytoskeletal polymers but lack motor proteins, this “active gel” property clearly sets the eukaryotic cytoskeleton apart from prokaryotic filament systems.Prokaryotes contain elaborate systems of several cytomotive filaments (Löwe and Amos 2009) that share many structural and dynamic features with eukaryotic actin filaments and microtubules (Löwe and Amos 1998; van den Ent et al. 2001). Prokaryotic cytoskeletal filaments may trace back to the first cells and may have originated as higher-order assemblies of enzymes (Noree et al. 2010; Barry and Gitai 2011). These cytomotive filaments are required for the segregation of low copy number plasmids, cell rigidity and cell-wall synthesis, cell division, and occasionally the organization of membranous organelles (Komeili et al. 2006; Thanbichler and Shapiro 2008; Löwe and Amos 2009). These functions are performed by dynamic filament-forming systems that harness the energy from nucleotide hydrolysis to generate forces either via bending or polymerization (Löwe and Amos 2009; Pilhofer and Jensen 2013). Although the identification of actin and tubulin homologs in prokaryotes is a major breakthrough, we are far from understanding the origin of the structural and dynamic complexity of the eukaryotic cytoskeleton.Advances in genome sequencing and comparative genomics now allow a detailed reconstruction of the cytoskeletal components present in the last common ancestor of eukaryotes. These studies all point to an ancestrally complex cytoskeleton, with several families of motors (Wickstead and Gull 2007; Wickstead et al. 2010) and filament-associated proteins and other regulators in place (Jékely 2003; Richards and Cavalier-Smith 2005; Rivero and Cvrcková 2007; Chalkia et al. 2008; Eme et al. 2009; Fritz-Laylin et al. 2010; Eckert et al. 2011; Hammesfahr and Kollmar 2012). Genomic reconstructions and comparative cell biology of single-celled eukaryotes (Raikov 1994; Cavalier-Smith 2013) allow us to infer the cellular features of the ancestral eukaryote. These analyses indicate that amoeboid motility (Fritz-Laylin et al. 2010; although, see Cavalier-Smith 2013), cilia (Cavalier-Smith 2002; Mitchell 2004; Jékely and Arendt 2006; Satir et al. 2008), centrioles (Carvalho-Santos et al. 2010), phagocytosis (Cavalier-Smith 2002; Jékely 2007; Yutin et al. 2009), a midbody during cell division (Eme et al. 2009), mitosis (Raikov 1994), and meiosis (Ramesh et al. 2005) were all ancestral eukaryotic cellular features. The availability of functional information from organisms other than animals and yeasts (e.g., Chlamydomonas, Tetrahymena, Trypanosoma) also allow more reliable inferences about the ancestral functions of cytoskeletal components (i.e., not only their ancestral presence or absence) and their regulation (Demonchy et al. 2009; Lechtreck et al. 2009; Suryavanshi et al. 2010).The ancestral complexity of the cytoskeleton in eukaryotes leaves a huge gap between prokaryotes and the earliest eukaryote we can reconstruct (provided that our rooting of the tree is correct) (Cavalier-Smith 2013). Nevertheless, we can attempt to infer the series of events that happened along the stem lineage, leading to the last common ancestor of eukaryotes. Meaningful answers will require the use of a combination of gene family history reconstructions (Wickstead and Gull 2007; Wickstead et al. 2010), transition analyses (Cavalier-Smith 2002), and computer simulations relevant to cell evolution (Jékely 2008).     

Sexual Conflict,Life Span,and Aging

The potential for sexual conflict to influence the evolution of life span and aging has been recognized for more than a decade, and recent work also suggests that variation in life span and aging can influence sexually antagonistic coevolution. However, empirical exploration of these ideas is only beginning. Here, we provide an overview of the ideas and evidence linking inter- and intralocus sexual conflicts with life span and aging. We aim to clarify the conceptual basis of this research program, examine the current state of knowledge, and suggest key questions for further investigation.Sexual conflict arises because the sexes maximize their fitness via different, and often mutually incompatible, strategies, and its signature has been detected across a wide range of morphological, physiological, behavioral, and life-history traits in many species. A number of investigators have suggested that sexual conflict could play an important role in the evolution of two particularly interesting life-history traits: life span and aging (Svensson and Sheldon 1998; Promislow 2003; Bonduriansky et al. 2008; Maklakov and Lummaa 2013). Sexual conflict can affect life span and aging rate at both proximate (within-generation) and ultimate (evolutionary) scales. Sexually antagonistic behavioral or physiological interactions that increase mortality rate in one or both sexes (interlocus sexual conflict) could drive the evolution of faster life histories. Moreover, sex-specific optimization of reproductive strategies may often result in sex differences in life span and aging rates, and sexually antagonistic selection on shared genetic architecture can displace one or both sexes from their sex-specific optima for these traits (intralocus sexual conflict). Conversely, a change in life histories because of environmental fluctuations could affect the degree of sexual conflict in a population and influence sexual coevolution. Although evidence for sexual conflict is rapidly accumulating, our understanding of its relationship to life span and aging remains rudimentary. In this review, we provide a critical review of recent literature and highlight areas that require further investigation.     

Evolutionary Forces Shaping the Golgi Glycosylation Machinery: Why Cell Surface Glycans Are Universal to Living Cells

Despite more than 3 billion years since the origin of life on earth, the powerful forces of biological evolution seem to have failed to generate any living cell that is devoid of a dense and complex array of cell surface glycans. Thus, cell surface glycans seem to be as essential for life as having a DNA genetic code, diverse RNAs, structural/functional proteins, lipid-based membranes, and metabolites that mediate energy flux and signaling. The likely reasons for this apparently universal law of biology are considered here, and include the fact that glycans have the greatest potential for generating diversity, and thus evading recognition by pathogens. This may also explain why in striking contrast to the genetic code, glycans show widely divergent patterns between taxa. On the other hand, glycans have also been coopted for myriad intrinsic functions, which can vary in their importance for organismal survival. In keeping with these considerations, a significant percentage of the genes in the typical genome are dedicated to the generation and/or turnover of glycans. Among eukaryotes, the Golgi is the subcellular organelle that serves to generate much of the diversity of cell surface glycans, carrying out various glycan modifications of glycoconjugates that transit through the Golgi, en route to the cell surface or extracellular destinations. Here I present an overview of general considerations regarding the selective forces shaping evolution of the Golgi glycosylation machinery, and then briefly discuss the common types of variations seen in each major class of glycans, finally focusing on sialic acids as an extreme example of evolutionary glycan diversity generated by the Golgi. Future studies need to address both the phylogenetic diversity the Golgi and the molecular mechanisms for its rapid responses to intrinsic and environmental stimuli.Every eukaryotic cell is covered with a dense and complex array of glycans, which also feature prominently in extracellular matrix and secreted soluble molecules (Varki and Sharon 2009). The bulk of these glycans are synthesized by the Golgi (Emr et al. 2009; Varki et al. 2009a), and a significant percentage of the genes in the typical eukaryotic genome are dedicated to these glycosylation functions (Henrissat et al. 2009). Other articles on this topic address the primary biochemical pathways involved (Stanley 2011), transport mechanisms that expose the transiting cargo to the ordered sequence of glycosidases and glycosyltransferases that carry out the modifications to the bound oligosaccharides (Glick and Luini 2011; Banfield 2011), genetic diseases that can affect the Golgi glycosylation system (Freeze and Ng 2011), and the evolution and diversity of Golgi apparatus structure in eukaryotes (Klute et al. 2011). Here I consider the Golgi glycosylation machinery from an evolutionary perspective, asking why it is universal to eukaryotes, how it has changed and been modified over evolutionary time, and why this machinery has diverged so much between different taxa. Some figures in this article are from Essentials of Glycobiology, the first open access textbook (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=glyco2). The reader is referred to the relevant articles in Essentials of Glycobiology (Varki and Sharon 2009; Varki et al. 2009a; Freeze and Elbein 2009; Varki and Lowe 2009) for further information about some of the points made here, as well as to some other articles in the textbook on related topics (Stanley et al. 2009; Brockhausen et al. 2009; Schnaar et al. 2009; Ferguson et al. 2009; Freeze and Haltiwanger 2009; Stanley and Cummings 2009; Varki and Schauer 2009; Hascall and Esko 2009; Esko et al. 2009).     

Molecular Bases of Cell–Cell Junctions Stability and Dynamics

Epithelial cell–cell junctions are formed by apical adherens junctions (AJs), which are composed of cadherin adhesion molecules interacting in a dynamic way with the cortical actin cytoskeleton. Regulation of cell–cell junction stability and dynamics is crucial to maintain tissue integrity and allow tissue remodeling throughout development. Actin filament turnover and organization are tightly controlled together with myosin-II activity to produce mechanical forces that drive the assembly, maintenance, and remodeling of AJs. In this review, we will discuss these three distinct stages in the lifespan of cell–cell junctions, using several developmental contexts, which illustrate how mechanical forces are generated and transmitted at junctions, and how they impact on the integrity and the remodeling of cell–cell junctions.Cell–cell junction formation and remodeling occur repeatedly throughout development. Epithelial cells are linked by apical adherens junctions (AJs) that rely on the cadherin-catenin-actin module. Cadherins, of which epithelial E-cadherin (E-cad) is the most studied, are Ca²⁺-dependent transmembrane adhesion proteins forming homophilic and heterophilic bonds in trans between adjacent cells. Cadherins and the actin cytoskeleton are mutually interdependent (Jaffe et al. 1990; Matsuzaki et al. 1990; Hirano et al. 1992; Oyama et al. 1994; Angres et al. 1996; Orsulic and Peifer 1996; Adams et al. 1998; Zhang et al. 2005; Pilot et al. 2006). This has long been attributed to direct physical interaction of E-cad with β-catenin (β-cat) and of α-catenin (α-cat) with actin filaments (for reviews, see Gumbiner 2005; Leckband and Prakasam 2006; Pokutta and Weis 2007). Recently, biochemical and protein dynamics analyses have shown that such a link may not exist and that instead, a constant shuttling of α-cat between cadherin/β-cat complexes and actin may be key to explain the dynamic aspect of cell–cell adhesion (Drees et al. 2005; Yamada et al. 2005). Regardless of the exact nature of this link, several studies show that AJs are indeed physically attached to actin and that cadherins transmit cortical forces exerted by junctional acto-myosin networks (Costa et al. 1998; Sako et al. 1998; Pettitt et al. 2003; Dawes-Hoang et al. 2005; Cavey et al. 2008; Martin et al. 2008; Rauzi et al. 2008). In addition, physical association depends in part on α-cat (Cavey et al. 2008) and additional intermediates have been proposed to represent alternative missing links (Abe and Takeichi 2008) (reviewed in Gates and Peifer 2005; Weis and Nelson 2006). Although further work is needed to address the molecular nature of cadherin/actin dynamic interactions, association with actin is crucial all throughout the lifespan of AJs. In this article, we will review our current understanding of the molecular mechanisms at work during three different developmental stages of AJs biology: assembly, stabilization, and remodeling, with special emphasis on the mechanical forces controlling AJs integrity and development.     

Retrograde Traffic from the Golgi to the Endoplasmic Reticulum

Proteins to be secreted are transported from the endoplasmic reticulum (ER) to the Golgi apparatus. The transport of these proteins requires the localization and activity of proteins that create ER exit sites, coat proteins to collect cargo and to reshape the membrane into a transport container, and address labels—SNARE proteins—to target the vesicles specifically to the Golgi apparatus. In addition some proteins may need export chaperones or export receptors to enable their exit into transport vesicles. ER export factors, SNAREs, and misfolded Golgi-resident proteins must all be retrieved from the Golgi to the ER again. This retrieval is also part of the organellar homeostasis pathway essential to maintaining the identity of the ER and of the Golgi apparatus. In this review, I will discuss the different processes in retrograde transport from the Golgi to the ER and highlight the mechanistic insights we have obtained in the last couple of years.Proteins that are exposed at the plasma membrane or populate a membrane-bounded organelle are synthesized into the endoplasmic reticulum (ER). In the ER, the folding of these proteins takes place and posttranslational modifications such as N-glycosylation and disulfide bridge formation occur. Upon adopting a suitable, often correct, conformation, proteins destined to locations beyond the ER are concentrated at so-called ER exit sites (ERES) and incorporated into nascent COPII-coated vesicles. These COPII vesicles eventually bud off the ER membrane and are transported to the Golgi (in yeast, Drosophila, and C. elegans) or the ER-Golgi intermediate compartment (in mammalian cells) (Schweizer et al. 1990; Kondylis and Rabouille 2003; Spang 2009; Witte et al. 2011).It is assumed that the vesicle coat is at least partially destabilized through the hydrolysis of GTP by the small GTPase Sar1 (Oka and Nakano 1994; Springer et al. 1999). However, some of the destabilized coat components have to stay on the vesicle until it has reached the Golgi apparatus because coat components participate in the recognition and the tethering process (Barlowe 1997; Cai et al. 2007; Lord et al. 2011; Zong et al. 2012). Subsequently, SNARE proteins on the vesicles (v-SNAREs) zipper up with cognate SNAREs on the Golgi (target SNAREs, t-SNAREs) to drive membrane fusion (Hay et al. 1998; Cao and Barlowe 2000; Parlati et al. 2002). The content of the ER-derived COPII vesicles is thereby released into the lumen of the cis-cisterna of the Golgi apparatus. Most proteins will continue their journey through the Golgi apparatus and encounter further modifications such as extension of the glycosylation tree or lipidation. However, some proteins, especially those involved in the fusion process, i.e., the v-SNAREs or proteins that act as export factors of the ER, such as Vma21, which is essential for export of the correctly folded and assembled V0 sector of the V-ATPase, need to be recycled back to the ER for another round of transport (Ballensiefen et al. 1998; Malkus et al. 2004). Moreover, cis-Golgi proteins are returned to the ER for quality/functional control (Todorow et al. 2000; Sato et al. 2004; Valkova et al. 2011). Finally, some ER-resident proteins, such as the ER Hsp70 chaperone BiP/Kar2, can escape the ER, but are captured at the cis-Golgi by the H/KDEL receptor Erd2 and returned to the ER (Lewis et al. 1990; Semenza et al. 1990; Aoe et al. 1997).Unfortunately, the retrograde transport route is also hijacked by toxins. For example, endocytosed cholera toxin subunit A contains a KDEL sequence and can thereby exploit the system to access the ER (Majoul et al. 1996, 1998). From there, it is retro-translocated into the cytoplasm where it can exert its detrimental function.     

Sexual Cannibalism as a Manifestation of Sexual Conflict

Sexual cannibalism is a well-known example for sexual conflict and has many facets that determine the costs and benefits for the cannibal and the victim. Here, I focus on species in which sexual cannibalism is a general component of a mating system in which males invest maximally in mating with a single (monogyny) or two (bigyny) females. Sexual cannibalism can be a male strategy to maximize paternity and a female strategy to prevent paternity monopolization by any or a particular male. Considerable variation exists between species (1) in the potential of males to monopolize females, and (2) in the success of females in preventing monopolization by males. This opens up exciting future possibilities to investigate sexually antagonistic coevolution in a largely unstudied mating system.Sexual cannibalism, the killing and consumption of potential or actual mating partners in a mating context, has been termed a “pinnacle of sexual conflict” because of the dramatic ending of the act for one mating partner, mostly the male (Elgar and Schneider 2004). This contradiction of traditional sex roles may be one reason why the phenomenon of sexual cannibalism has intrigued naturalists for a long time. In the context of sexual conflict, sexually cannibalistic behavior of females is a harmful trait, and antagonistic traits are expected to evolve in males, which can be considered the reverse of most other examples in which females respond to male harm (see Perry and Rowe 2014). I will discuss potential antagonistic traits to sexual cannibalism in males but will also show that the above view is too simplistic when it comes to spider mating systems characterized by very low male mating rates.It is important to note that there are different kinds of sexual cannibalism based on very different evolutionary scenarios (Elgar and Schneider 2004; Prenter et al. 2006; Wilder et al. 2009). The most extreme divide exists between cannibalism before sperm transfer, which can only benefit the cannibal, and sexual cannibalism during or after sperm transfer (from here on termed postinsemination sexual cannibalism), which can benefit the cannibal and the victim (Elgar and Schneider 2004). Despite a longer history of research on preinsemination sexual cannibalism, the evolutionary causes and consequences of postinsemination sexual cannibalism are generally less debated.There are reports (often anecdotal) on the occurrence of sexual cannibalism from diverse invertebrate taxa (Elgar 1992) and it may well occur in all predatory invertebrates that are potentially cannibalistic (Polis 1981). It is beyond the scope of this brief review to list and evaluate all reported occurrences. Rather, I will start with a brief account of the generally discussed causes and consequences of sexual cannibalism and will then concentrate on the conflicting interests of the sexes regarding postinsemination sexual cannibalism in mating systems that are characterized by very low male mating rates.Studies that investigate sexual cannibalism experimentally are mostly concerned with (1) nutritional aspects, (2) the importance of sexual size dimorphism and sexual selection, and, increasingly, (3) behavioral syndromes. The aggressive spillover hypothesis suggests that preinsemination sexual cannibalism is part of a behavioral syndrome in which aggression against mating partners spills over from a foraging context (Arnqvist and Henriksson 1997). There is mixed support for this idea in the few species that have been looked at. In several spider species, females consistently differ in their aggressiveness and these differences affect sexual cannibalism (for a recent debate about the evidence for this hypothesis, see Johnson 2013; Kralj-Fišer et al. 2013b; Pruitt and Keiser 2013).A majority of studies have taken a unilateral view and have been concerned with the “motivation” of the cannibal; because sexual cannibalism generally occurs in predators, hunger is a well-supported motivation (Wilder et al. 2009). Many predators are food-limited, and, assuming a trade-off between foraging and mating, the balance may tilt toward foraging under particular circumstances (modeled by Newman and Elgar 1991). Food and mate availability will influence the costs and benefits of sexual cannibalism for females and have been one focus of a recent review on sexual cannibalism (Wilder et al. 2009).In all predatory and cannibalistic animals, mating partners impose selection on each other’s abilities to avoid or resist aggression. This selection pressure is asymmetrical if one sex is physically dominant. Indeed, the differences in size between females and males often determine the frequency of sexual cannibalism, perhaps because the potential to resist a cannibalistic attack is size-dependent (Elgar 1992; Wilder and Rypstra 2008). Usually, males are the victims and females are the cannibals. Yet, reversed sexual cannibalism has also been reported and appears to be associated with the reversed pattern in sexual size dimorphism. Examples are the water spider, Arygoneta aquatica (Schutz and Taborsky 2005, 2011) and role-reversed wolf spiders (Aisenberg et al. 2011). In the gnaphosid spider, Micaria sociabilis, large, young males cannibalize old and relatively smaller females (Sentenska and Pekar 2013). These examples further support the notion that the relative size differences of a mating pair play a part in determining the likelihood of sexual cannibalism. Patterns can be found both on a between-species comparative scale and on a within-species scale (Wilder and Rypstra 2008; Wilder et al. 2009), and they are also reported as an underlying pattern in cannibalism outside a mating context (Bleakley et al. 2013). Furthermore, there is anecdotal evidence for the same pattern in hermaphrodites (e.g., Goto and Yoshida 1985; Michiels et al. 2003), which may constitute a particularly interesting case to study, as the power asymmetries are less obviously related to the male or female role.In asymmetric encounters, the costs and risks of aggressive behavior toward potential mating partners are low for the dominant partner. Toward smaller males, females could use aggressiveness as a means of partner choice. Indeed, many studies suggest that sexual selection in addition to gaining a meal may be the adaptive value of sexual cannibalism (Prenter et al. 2006). From the female perspective, aggressive behavior directed toward males may serve as a general screening of partner quality, a mechanism often described as indirect mate choice (Elgar and Nash 1988; Prenter et al. 2006; Kralj-Fišer et al. 2012). A screening method implies that females attack every male, and suitors that cannot withstand and persist an attack will be killed and consumed; alternatively, females may differentiate between males and attack and consume only those males that do not meet certain quality criteria (reviewed in Prenter et al. 2006). The latter has been found in wolf spiders (Wilgers and Hebets 2012). The latter mechanism of direct choice is more complex than the indirect one as it requires perception and assessment of quality cues, and large enough benefits of choosiness are expected to match the costs. Mate rejection via sexual cannibalism is considered a particularly extreme case of sexual conflict mostly because rejection can lead to death. Although this may be true for the individual male that loses all future reproductive success, frequencies of preinsemination sexual cannibalism might be rather low (Kralj-Fišer et al. 2013b). Please note that in almost every species, a certain proportion of individuals will be excluded from the mating market and will have no mating success. The claim that prevention of mating success via sexual cannibalism results in more intense sexual conflict than exclusion from mating with less drastic measures has, to my knowledge, never been tested. Because of the scarcity of data on natural frequencies of preinsemination cannibalism, a meta-analysis would not reveal a realistic picture at this stage. Hence, to date, it is not feasible to compare the relative strength of selection imposed by a cannibalistic mate choice strategy against a strategy with less drastic consequences of mate rejection. More studies are needed to unravel the exact nature of sexual selection under the threat of ending as a meal. Below, I will briefly sketch possible responses to selection imposed by sexually cannibalistic females before or during insemination.     

Metabolic Stress in Autophagy and Cell Death Pathways

Growth factors and oncogenic kinases play important roles in stimulating cell growth during development and transformation. These processes have significant energetic and synthetic requirements and it is apparent that a central function of growth signals is to promote glucose metabolism to support these demands. Because metabolic pathways represent a fundamental aspect of cell proliferation and survival, there is considerable interest in targeting metabolism as a means to eliminate cancer. A challenge, however, is that molecular links between metabolic stress and cell death are poorly understood. Here we review current literature on how cells cope with metabolic stress and how autophagy, apoptosis, and necrosis are tightly linked to cell metabolism. Ultimately, understanding of the interplay between nutrients, autophagy, and cell death will be a key component in development of new treatment strategies to exploit the altered metabolism of cancer cells.Although single-celled organisms grow and proliferate based on nutrient availability, metazoan cells rely on growth factor input to promote nutrient uptake, regulate growth and proliferation, and survive (Raff 1992; Rathmell et al. 2000). Access and competition for these signals are critical in developmental patterning and to maintain homeostasis of mature tissues. Cells that do not receive proper growth factor signals typically atrophy, lose the ability to uptake and use extracellular nutrients, and instead induce the self-digestive process of autophagy as an intracellular energy source before ultimately undergoing programmed cell death. Cancer cells, in contrast, often become independent of extracellular growth signals by gaining mutations or expressing oncogenic kinases to drive intrinsic growth signals that mimic growth factor input, which can be the source of oncogene addiction. Growth factor input or oncogenic signals often drive highly elevated glucose uptake and metabolism (Rathmell et al. 2000; DeBerardinis et al. 2008; Michalek and Rathmell 2010). First described in cancer by Warburg in the 1920s, this highly glycolytic metabolic program is termed aerobic glycolysis and is a general feature of many nontransformed proliferative cells (Warburg 1956; DeBerardinis et al. 2008).Nutrient uptake and aerobic glycolysis induced by growth signals play key roles in cell survival (Vander Heiden et al. 2001). Manipulating cell metabolism as a means to promote the death of inappropriately dividing cells, therefore, is a promising new avenue to treat disease. Targeting the altered metabolism of cancer cells in particular is of great interest. It is still unclear at the molecular level, however, how inhibiting or modulating cell metabolism leads to apoptosis, and how these pathways may best be exploited (Dang et al. 2009; Wise and Thompson 2010).Growth factor or oncogenic kinases promote multiple metabolic pathways that are essential to prevent metabolic stress and may be targets in efforts to link metabolism and cell death (Vander Heiden et al. 2001). Decreased glucose metabolism on loss of growth signals leads to decreased ATP generation as well as loss in generation of many biosynthetic precursor molecules, including nucleic acids, fatty acids, and acetyl-CoA for acetylation (Zhao et al. 2007; Wellen et al. 2009; Coloff et al. 2011). Glucose is also important as a precursor for the hexosamine pathway, to allow proper glycosylation and protein folding in the endoplasmic reticulum (Dennis et al. 2009; Kaufman et al. 2010). If glucose metabolism remains insufficient or disrupted, the cells can switch to rely on mitochondrial oxidation of fatty acids and amino acids, which are energy rich but do not readily support cell growth and can lead to potentially dangerous levels of reactive oxygen species (Wellen and Thompson 2010). Amino acid deficiency can directly inhibit components of the signaling pathways downstream from growth factors and activate autophagy (Lynch 2001; Beugnet et al. 2003; Byfield et al. 2005; Nobukuni et al. 2005). Finally, hypoxia induces a specific pathway to increase nutrient uptake and metabolism via the hypoxia-inducible factor (HIF1/2α) that promotes adaptation to anaerobic conditions, but may lead to apoptosis if hypoxia is severe (Saikumar et al. 1998; Suzuki et al. 2001; Fulda and Debatin 2007).Typically a combination of metabolic stresses rather than loss of a single nutrient input occur at a given time (Degenhardt et al. 2006) and autophagy is activated to mitigate damage and provide nutrients for short-term survival (Bernales et al. 2006; Tracy et al. 2007; Altman et al. 2011; Guo et al. 2011). Autophagy is a cellular process of bulk cytoplasmic and organelle degradation common to nearly all eukaryotes. Unique double-membraned vesicles known as autophagosomes engulf cellular material and fuse with lysosomes to promote degradation of the contents (Kelekar 2005). Described in greater detail below, autophagy can reduce sources of stress, such as protein aggregates and damaged or dysfunctional intracellular organelles, and provide nutrients during times of transient and acute nutrient withdrawal.Despite the protective effects of autophagy, cells deprived of growth signals, nutrients, or oxygen for prolonged times will eventually succumb to cell death. Apoptosis is the initial death response on metabolic stress and is regulated by Bcl-2 family proteins. In healthy cells, antiapoptotic Bcl-2 family proteins, such as Bcl-2, Bcl-xl, and Mcl-1, bind and inhibit the multidomain proapoptotic proteins Bax and Bak (van Delft and Huang 2006; Walensky 2006; Chipuk et al. 2010). In metabolic stress, proapoptotic “BH3-only” proteins of the Bcl-2 family are induced or activated and bind to and inhibit the antiapoptotic Bcl-2 family proteins to allow activation of the proapoptotic Bax and Bak (Galonek and Hardwick 2006). The BH3-only proteins Bim, Bid, and Puma can also directly bind and activate Bax and Bak (Letai et al. 2002; Ren et al. 2010). Active Bax and Bak disrupt the outer mitochondrial membrane (termed mitochondrial outer-membrane permeabilization, or MOMP) and release several proapoptotic factors including cytochrome-C that activate the apoptosome that in turn activates effector caspases to cleave a variety of cellular proteins and drive apoptosis (Schafer and Kornbluth 2006). In cases in which these apoptotic pathways are suppressed, metabolic stress can instead lead to necrotic cell death (Jin et al. 2007).     

Conflict on the Sex Chromosomes: Cause,Effect, and Complexity

Intralocus sexual conflict and intragenomic conflict both affect sex chromosome evolution and can in extreme cases even cause the complete turnover of sex chromosomes. Additionally, established sex chromosomes often become the focus of heightened conflict. This creates a tangled relationship between sex chromosomes and conflict with respect to cause and effect. To further complicate matters, sexual and intragenomic conflict may exacerbate one another and thereby further fuel sex chromosome change. Different magnitudes and foci of conflict offer potential explanations for lineage-specific variation in sex chromosome evolution and answer long-standing questions as to why some sex chromosomes are remarkably stable, whereas others show rapid rates of evolutionary change.Compared to the autosomes, the unique inheritance pattern of the sex chromosomes is often thought to intensify evolutionary conflict (Rice 1984; Frank 1991; Jaenike 2001). Sex chromosomes are therefore hot spots for two specific types of conflict: intralocus conflict, in which an allele confers different fitness effects depending on the sex in which it is found, and intragenomic conflict, in which selfish genetic elements (SGEs) promote their own transmission at the expense of unlinked regions of the genome. These conflicts act in distinct but complementary ways. Not only do they shape sex chromosome and genome evolution, but in some cases, they also have the power to cause complete turnover of sex chromosomes.Unlike the autosomes, because the sex chromosomes are unevenly transmitted between males and females and are also unevenly distributed between the sexes (Fig. 1), the relative effect of male- and female-specific selection acting on them is unbalanced. The inherent differences in sex-specific selection on the sex chromosomes themselves, and between the sex chromosomes and the autosomes, form the basis of a large and often compelling body of evolutionary theory that predicts the ways that intralocus sexual conflict will arise, play out, and in some cases potentially be resolved. This theory predicts that, under some conditions, the sex chromosomes are hot spots of intralocus sexual conflict (Rice 1984; Albert and Otto 2005; Connallon and Clark 2010), and in some cases alleles that harm one sex more than they benefit the other can still reach high frequencies if they are sex-linked (Rice 1984; Dean et al. 2012). All this theory predicts that although the sex chromosomes generally represent a small proportion of the genome, they should play a disproportionately large role in sexual conflict, sexual dimorphism, and sexual selection. There is substantial empirical evidence supporting at least some of this theory (Dean and Mank 2014).Open in a separate windowFigure 1.Transmission of the sex chromosomes. Females are shown in red, males in blue. In male heterogamety (A), the Y chromosome is passed through the patriline and limited to males. The maternal X chromosome is passed from mother to both sons and daughters, but the paternal X can only be transmitted to daughters. Additionally, the X is present two-thirds of the time in females. In female heterogamety (B), the W chromosome is limited to females and passed solely from mother to daughter. The paternal Z chromosome can be passed from father to both daughters and sons; however, the maternal Z chromosome is only passed to sons. Converse to the X chromosome, the Z chromosome is resident in males two-thirds of the time.

Table 1.

Studies showing a disproportionate role of the sex chromosomes in sexual dimorphism, fitness, or fertility

Glial Cell Development and Function in Zebrafish

The zebrafish is a premier vertebrate model system that offers many experimental advantages for in vivo imaging and genetic studies. This review provides an overview of glial cell types in the central and peripheral nervous system of zebrafish. We highlight some recent work that exploited the strengths of the zebrafish system to increase the understanding of the role of Gpr126 in Schwann cell myelination and illuminate the mechanisms controlling oligodendrocyte development and myelination. We also summarize similarities and differences between zebrafish radial glia and mammalian astrocytes and consider the possibility that their distinct characteristics may represent extremes in a continuum of cell identity. Finally, we focus on the emergence of zebrafish as a model for elucidating the development and function of microglia. These recent studies have highlighted the power of the zebrafish system for analyzing important aspects of glial development and function.Following the pioneering work of George Streisinger in the early 1980s, the zebrafish has emerged as a premier vertebrate model system (Streisinger et al. 1981). A key strength of the zebrafish is that the embryos and early larvae are transparent, allowing exquisite cellular analysis of many dynamic processes, including cell migration, axonal pathfinding, and myelination, among many others (e.g., Gilmour et al. 2002; Lyons et al. 2005; Czopka et al. 2013). The zebrafish also has many advantages for large-scale genetic studies, including relatively small size and rapid development, high fecundity, and the ability to manipulate the ploidy of gametes and early embryos (Kimmel 1989). Through the 1980s and early 1990s, insightful studies of several interesting mutations elegantly exploited these experimental advantages (e.g., Kimmel et al. 1989; Ho and Kane 1990; Hatta et al. 1991; Grunwald and Eisen 2002), attracting many researchers from other fields to the zebrafish system. Following the explosion of interest in the zebrafish in the 1990s, advances in many areas have added to the strengths of the system, including large-scale screens that identified thousands of new mutations (Driever et al. 1996; Haffter et al. 1996), rapid transgenesis (Kawakami et al. 2004), new methods for imaging and tracking all cells during development (Huisken 2012), genetic mapping and sequencing to identify genes and mutated loci (Postlethwait et al. 1994; Howe et al. 2013), optogenetic methods to control neural activity (Portugues et al. 2013), the advent of targeted nucleases to create mutations in genes of interest (Huang et al. 2011; Sander et al. 2011; Bedell et al. 2012; Chang et al. 2013; Hwang et al. 2013), and small molecule screening approaches to isolate compounds with novel biological activities in vivo (Peterson and Fishman 2011).Many fundamental similarities in physiology and body plan unite the zebrafish and other vertebrates (Kimmel 1989). In addition, analysis of genes and genomes has revealed that sequence, expression, and function of many genes are conserved among zebrafish and other vertebrates (Postlethwait and Talbot 1997; Howe et al. 2013). Thus, insights from studies in zebrafish will apply broadly to other vertebrates, including humans. On the other hand, there are important genetic, genomic, and physiological differences among vertebrates. It is, therefore, important to keep possible differences in mind and to recognize that analyzing the diversity among different species may enhance overall understanding of important processes. For example, zebrafish and other teleosts have a much more extensive regenerative ability than mammals, so that studies of fin, heart, and spinal cord regeneration in zebrafish may suggest avenues toward new therapeutic approaches in humans (Gemberling et al. 2013; Becker and Becker 2014).In this review, we provide an overview of different types of glia in the zebrafish, with a focus on some recent studies that highlight the power of the zebrafish system to analyze different aspects of glial development and function.     

Molecular Mechanisms of Fibroblast Growth Factor Signaling in Physiology and Pathology

Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understanding of the mechanism of FGF signaling in human health and development, and has provided novel concepts in receptor tyrosine kinase (RTK) signaling. Among these contributions are the elucidation of HS-assisted receptor dimerization, delineation of the molecular determinants of ligand–receptor specificity, tyrosine kinase regulation, receptor cis-autoinhibition, and tyrosine trans-autophosphorylation. These structural studies have also revealed how disease-associated mutations highjack the physiological mechanisms of FGFR regulation to contribute to human diseases. In this paper, we will discuss the structurally and biophysically derived mechanisms of FGF signaling, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases.Fibroblast growth factor (FGF) signaling fulfills essential roles in metazoan development and metabolism. A wealth of literature has documented the requirement for FGF signaling in multiple processes during embryogenesis, including implantation (Feldman et al. 1995), gastrulation (Sun et al. 1999), somitogenesis (Dubrulle and Pourquie 2004; Wahl et al. 2007; Lee et al. 2009; Naiche et al. 2011; Niwa et al. 2011), body plan formation (Martin 1998; Rodriguez Esteban et al. 1999; Tanaka et al. 2005; Mariani et al. 2008), morphogenesis (Metzger et al. 2008; Makarenkova et al. 2009), and organogenesis (Goldfarb 1996; Kato and Sekine 1999; Sekine et al. 1999; Sun et al. 1999; Colvin et al. 2001; Serls et al. 2005; Vega-Hernandez et al. 2011). Recent clinical and biochemical data have uncovered unexpected roles for FGF signaling in metabolic processes, including phosphate/vitamin D homeostasis (Consortium 2000; Razzaque and Lanske 2007; Nakatani et al. 2009; Gattineni et al. 2011; Kir et al. 2011), cholesterol/bile acid homeostasis (Yu et al. 2000a; Holt et al. 2003), and glucose/lipid metabolism (Fu et al. 2004; Moyers et al. 2007). Highlighting its diverse biology, deranged FGF signaling contributes to many human diseases, such as congenital craniosynostosis and dwarfism syndromes (Naski et al. 1996; Wilkie et al. 2002, 2005), Kallmann syndrome (Dode et al. 2003; Pitteloud et al. 2006a), hearing loss (Tekin et al. 2007, 2008), and renal phosphate wasting disorders (Shimada et al. 2001; White et al. 2001), as well as many acquired forms of cancers (Rand et al. 2005; Pollock et al. 2007; Gartside et al. 2009; di Martino et al. 2012). Endocrine FGFs have also been implicated in the progression of acquired metabolic disorders, including chronic kidney disease (Fliser et al. 2007), obesity (Inagaki et al. 2007; Moyers et al. 2007; Reinehr et al. 2012), and insulin resistance (Fu et al. 2004; Chen et al. 2008b; Chateau et al. 2010; Huang et al. 2011), giving rise to many opportunities for drug discovery in the field of FGF biology (Beenken and Mohammadi 2012).Based on sequence homology and phylogeny, the 18 mammalian FGFs are grouped into six subfamilies (Ornitz and Itoh 2001; Popovici et al. 2005; Itoh and Ornitz 2011). Five of these subfamilies act in a paracrine fashion, namely, the FGF1 subfamily (FGF1 and FGF2), the FGF4 subfamily (FGF4, FGF5, and FGF6), the FGF7 subfamily (FGF3, FGF7, FGF10, and FGF22), the FGF8 subfamily (FGF8, FGF17, and FGF18), and the FGF9 subfamily (FGF9, FGF16, and FGF20). In contrast, the FGF19 subfamily (FGF19, FGF21, and FGF23) signals in an endocrine manner (Beenken and Mohammadi 2012). FGFs exert their pleiotropic effects by binding and activating the FGF receptor (FGFR) subfamily of receptor tyrosine kinases that are coded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) in mammals (Johnson and Williams 1993; Mohammadi et al. 2005b). The extracellular domain of FGFRs consists of three immunoglobulin (Ig)-like domains (D1, D2, and D3), and the intracellular domain harbors the conserved tyrosine kinase domain flanked by the flexible amino-terminal juxtamembrane linker and carboxy-terminal tail (Lee et al. 1989; Dionne et al. 1991; Givol and Yayon 1992). A unique feature of FGFRs is the presence of a contiguous segment of glutamic and aspartic acids in the D1–D2 linker, termed the acid box (AB). The two-membrane proximal D2 and D3 and the intervening D2–D3 linker are necessary and sufficient for ligand binding/specificity (Dionne et al. 1990; Johnson et al. 1990), whereas D1 and the D1–D2 linker are implicated in receptor autoinhibition (Wang et al. 1995; Roghani and Moscatelli 2007; Kalinina et al. 2012). Alternative splicing and translational initiation further diversify both ligands and receptors. The amino-terminal regions of FGF8 and FGF17 can be differentially spliced to yield FGF8a, FGF8b, FGF8e, FGF8f (Gemel et al. 1996; Blunt et al. 1997), and FGF17a and FGF17b isoforms (Xu et al. 1999), whereas cytosine-thymine-guanine (CTG)-mediated translational initiation gives rise to multiple high molecular weight isoforms of FGF2 and FGF3 (Florkiewicz and Sommer 1989; Prats et al. 1989; Acland et al. 1990). The tissue-specific alternative splicing in D3 of FGFR1, FGFR2, and FGFR3 yields “b” and “c” receptor isoforms which, along with their temporal and spatial expression patterns, is the major regulator of FGF–FGFR specificity/promiscuity (Orr-Urtreger et al. 1993; Ornitz et al. 1996; Zhang et al. 2006). A large body of structural data on FGF–FGFR complexes has begun to reveal the intricate mechanisms by which different FGFs and FGFRs combine selectively to generate quantitatively and qualitatively different intracellular signals, culminating in distinct biological responses. In addition, these structural data have unveiled how pathogenic mutations hijack the normal physiological mechanisms of FGFR regulation to lead to pathogenesis. We will discuss the current state of the structural biology of the FGF–FGFR system, lessons learned from studying the mechanism of action of pathogenic mutations, and how the structural data are beginning to shape and advance the translational research.     

Paradox of Mother's Curse and the Maternally Provisioned Offspring Microbiome

Strict maternal transmission creates an “asymmetric sieve” favoring the spread of mutations in organelle genomes that increase female fitness, but diminish male fitness. This phenomenon, called “Mother''s Curse,” can be viewed as an asymmetrical case of intralocus sexual conflict. The evolutionary logic of Mother''s Curse applies to each member of the offspring microbiome, the community of maternally provisioned microbes, believed to number in the hundreds, if not thousands, of species for host vertebrates, including humans. Taken together, these observations pose a compelling evolutionary paradox: How has maternal transmission of an offspring microbiome become a near universal characteristic of the animal kingdom when the genome of each member of that community poses a potential evolutionary threat to the fitness of host males? I review features that limit or reverse Mother''s Curse and contribute to resolving this paradox. I suggest that the evolution of vertical symbiont transmission requires conditions that mitigate the evolutionary threat to host males.The genomes of mitochondria, chloroplasts, and many symbiotic microbes are transmitted maternally by host females to their offspring. Maternal transmission can be transovariole (intracellular, within the egg) or contagious, during gestation, birth, or feeding (Sonneborn 1950; Smith and Dunn 1991; Gillham 1994; O’Neill et al. 1997). Vertically transmitted (VT) symbiont lineages tend to be genetically homogeneous within hosts (Birky et al. 1983, 1989; Funk et al. 2000). Maternal uniparental transmission creates an “asymmetric sieve” wherein mutations advantageous for females, but harmful for males, can spread through a population (Cosmides and Tooby 1981; Frank and Hurst 1996; Zeh and Zeh 2005; Burt and Trivers 2006). Such mutations spread because deleterious male-specific fitness effects do not affect the response to natural selection of the maternally transmitted entities. This adaptive process favoring the transmitting sex is called Mother''s Curse (MC) (Gemmell et al. 2004) and it has been referred to as an irreconcilable instance of intralocus conflict: “… exclusively maternal transmission of cytoplasmic genes (e.g., in mitochondria) can result in suboptimal mitochondrial function in males … a form of [intralocus sexual conflict] that apparently cannot be resolved, because selection on mitochondria in males cannot produce a response” (Bonduriansky and Chenoweth 2009, p. 285).Mitochondria are ubiquitous in animals and despite the indisputable evolutionary logic of MC (Frank and Hurst 1996) there are no reported cases of sperm-killing or son-killing mitochondria (Burt and Trivers 2006). Moreover, many species of animals possess an offspring microbiome, a community of microbes transmitted uniparentally from mother to offspring at some point in development, whether prefertilization, postfertilization, or postnatal (Funkhouser and Bordenstein 2013). In some vertebrates, including humans, this community is believed to number in the hundreds of species (Funkhouser and Bordenstein 2013). Prolonged periods of maternal care, as in mammals and birds, as well as kin-structured sociality, afford many opportunities for maternal provisioning of microbes to developing offspring. The social insects, in particular, show obligate mutualisms with a microbiome that confers important nutritional benefits for its host (Baumann 2005; Engel and Moran 2013), the termites being a classic example (Ikeda-Ohtsubo and Brune 2009).Together, the evolutionary logic of MC and the widespread existence of maternally transmitted hereditary symbioses pose a paradox for evolutionary biology. The maternally provisioned microbiome (MC) consists of tens to hundreds of genomes affording ample opportunity, along with mitochondrial and organelle genomes, for the occurrence of mutations that benefit females while harming host males. Assembling a VT community as a host nutritional or defensive adaptation requires evading MC not once, but from a continuous siege over evolutionary time. This is the Mother''s Curse–microbiome (MC–MB) paradox. It conceptually affiliated with the “paradox of mutualism,” the persistence of interspecific mutualisms despite the advantages of cheating by one or the other member of the mutualism (Heath and Stinchcombe 2014). Symbiont “cheating” on only half the members of a host species, the males, might offer marginal benefits relative to wholesale cheating on both host sexes. Nevertheless, the MC–MB paradox deserves research attention.In this review, I discuss inbreeding, kin selection, compensatory evolution, and defensive advantages against more virulent pathogens (or predators and herbivores) as means for resolving the MC–MB paradox. First, I review the simple population genetics of MC. I discuss how host inbreeding and kin selection (Unckless and Herren 2009; Wade and Brandvain 2009), alone or in concert, allow for a response to selection on male fertility and viability fitness effects of maternally transmitted genomes. As a result, inbreeding and kin selection can limit or prevent the spread of mutations in a hereditary symbiosis (Cowles 1915) that are harmful to males. I will show that, for both inbreeding and kin selection, there exist conditions that “favor the spread of maternally transmitted mutations harmful to females”; a situation that is the reverse of MC. However, many outbreeding, asocial species harbor maternally provisioned microbiomes and these solutions cannot be applied to them.I also consider the evolution of compensatory nuclear mutations that mitigate or eliminate the harm to males of organelles or symbionts, spreading via MC dynamics. However, I find that the relative rate of compensatory evolution is only 1/4 the rate of evolution of male-harming symbionts. Thus, an evolutionary rescue of host males via compensatory host nuclear mutations requires that there be fourfold or more opportunities for compensation offered by a larger host nuclear genome. The larger the number of species in a host microbiome, the more difficult it is to entertain host nuclear compensatory mutations as a resolution of the MC–MB paradox.Next, I consider the situation in which a deleterious, VT symbiont harms its host but prevents host infection by a more severely deleterious contagiously transmitted pathogen (Lively et al. 2005; see also Clay 1988). This is a case in which absolute harm to a host by a maternally provisioned symbiont becomes a “relative” fitness advantage. This is a scenario that may be common in hosts with speciose microbial communities, especially if each microbial species increases host resistance or outright immunity to infectious, virulent pathogens.Finally, I discuss models of symbiont domestication and capture via the evolution of vertical transmission from an ancestral state of horizontal transmission (Drown et al. 2013). I show that the evolution of vertical transmission requires conditions that tend to restrict the capacity for male harming by symbionts. Each of these scenarios significantly expands the range of evolutionary possibilities permitted for the coevolution of host–symbiont assemblages, especially those microbial communities that are maternally, uniparentally transmitted across host generations. Unfortunately, current data do not permit discriminating among these various evolutionary responses to MC, so none can be definitively considered a resolution of the MC–MB paradox.     

Heparan Sulfate Proteoglycans

Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein–heparan sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, heparan sulfate proteoglycans have profound effects at the cellular, tissue, and organismal level.Heparan sulfate proteoglycans (HSPGs) are glycoproteins, with the common characteristic of containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG) (Esko et al. 2009). Cells elaborate a relatively small set of HSPGs (∼17) that fall into three groups according to their location: membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored proteoglycans (glypicans), the secreted extracellular matrix HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin (Esko et al. 1985), which allowed functional studies in the context of a cell culture model (Zhang et al. 2006). A decade later, the first HSPG mutants in a model organism (Drosophila melanogaster) were identified (Rogalski et al. 1993; Nakato et al. 1995; Häcker et al. 1997; Bellaiche et al. 1998; Lin et al. 1999), which was followed by identification of mutants in nematodes, tree frogs, zebrafish, and mice (​and3).3). HS is evolutionarily ancient and its composition has remained relatively constant from Hydra to humans (Yamada et al. 2007; Lawrence et al. 2008).

Table 1.

Heparan sulfate proteoglycans