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Darwin and the Origin of Interspecific Genetic Incompatibilities. Author(s): Daven C. Presgraves Reviewed work(s): Source: The American Naturalist, Vol. 176, No. S1, Darwinian Thinking: 150 Years after The Origin A Symposium Organized by Douglas W. Schemske (December 2010), pp. S45-S60 Published by: The University of Chicago Press for The American Society of Naturalists Stable URL: http://www.jstor.org/stable/10.1086/657058 . Accessed: 16/02/2012 17:24 Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact [email protected]. The University of Chicago Press and The American Society of Naturalists are collaborating with JSTOR to digitize, preserve and extend access to The American Naturalist. http://www.jstor.org vol. 176, supplement the american naturalist december 2010 Darwin and the Origin of Interspecific Genetic Incompatibilities Daven C. Presgraves* Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts 02138 abstract: Darwin’s Origin of Species is often criticized for having little to say about speciation. The complaint focuses in particular on Darwin’s supposed failure to explain the evolution of the sterility and inviability of interspecific hybrids. But in his chapter on hybridism, Darwin, working without genetics, got as close to the modern understanding of the evolution of hybrid sterility and inviability as might reasonably be expected. In particular, after surveying what was then known about interspecific crosses and the resulting hybrids, he established two facts that, while now taken for granted, were at the time radical. First, the sterility barriers between species are neither specially endowed by a creator nor directly favored by natural selection but rather evolve as incidental by-products of interspecific divergence. Second, the sterility of species hybrids results when their development is “disturbed by two organizations having been compounded into one.” Bateson, Dobzhansky, and Muller later put Mendelian detail to Darwin’s inference that the species-specific factors controlling development (i.e., genes) are sometimes incompatible. In this article, I highlight the major developments in our understanding of these interspecific genetic incompatibilities—from Darwin to Muller to modern theory—and review comparative, genetic, and molecular rules that characterize the evolution of hybrid sterility and inviability. Keywords: Darwin, speciation, hybrid incompatibility, postzygotic isolation. The importance of the fact that hybrids are very generally sterile, has, I think been much underrated by some late writers. On the theory of natural selection the case is especially important, inasmuch as the sterility of hybrids could not possibly be of advantage to them, and therefore could not have been acquired by the continued preservation of successive profitable degrees of sterility. I hope, however, to be able to show that sterility is not a specially acquired or endowed quality, but is incidental on other acquired differences. (Darwin 1859, p. 245) * Present address: Department of Biology, University of Rochester, Rochester, New York 14627; e-mail: [email protected]. Am. Nat. 2010. Vol. 176, pp. S45–S60. 䉷 2010 by The University of Chicago. 0003-0147/2010/176S1-51450$15.00. All rights reserved. DOI: 10.1086/657058 Introduction: A Strange Arrangement Despite its title, Darwin’s (1859) great book never really solved “that mystery of mysteries”—the origin of species. Or so it is often said. Shortly after The Origin appeared, none other than Darwin’s bulldog, T. H. Huxley (1894), complained that it had failed, in particular, to adequately explain the origins of hybrid sterility. Selective breeding of domesticated varieties, Huxley noted, had replicated all of the key evolutionary phenomena—mutation, heredity, response to selection—but one: no breeder, starting from a single progenitor, had ever produced varieties that when crossed gave rise to sterile hybrids. For Huxley, this was a serious problem. The worry was echoed 60 years later by William Bateson (1922, p. 58), who confessed that “that particular and essential bit of the theory of evolution which is concerned with the origin and nature of species remains utterly mysterious.”1 Neither Darwin, Huxley, nor Bateson advocated a sterility test to determine species status because from “the ascertained facts on the intercrossing of plants and animals, it may be concluded that some degree of sterility, both in first crosses and in hybrids, is an extremely general result; but that it cannot, under our present state of knowledge, be considered as absolutely universal” (Darwin 1859, p. 254). But, as Huxley (1894) argued, it hardly mattered that not all species pairs are isolated by hybrid sterility—so long as even one species pair is, any theory that fails to explain it must be considered incomplete. For Huxley and Bateson, then, the sterility of species hybrids stood as one of the great unsolved problems in evolutionary biology. Indeed, until the prob1 In a provocatively titled address, “Evolutionary faith and modern doubts,” made to the AAAS in 1921 (published in 1922), Bateson (1922, p. 61) offered a frank assessment of what he regarded as the most pressing unsolved problems facing evolutionary biologists. Recognizing the danger in this, he ended by saying: “When such confessions are made the enemies of science see their chance. … Let us then proclaim in precise and unmistakable language that our faith in evolution is unshaken. … Our doubts are not as to the reality or truth of evolution, but as to the origin of species, a technical, almost domestic, problem. Any day that mystery will be solved.” William Jennings Bryan and the prosecution in the Scopes trial would nevertheless use Bateson’s remarks to question the value of a theory that could not, after all, explain the origin of species (Weiss 2007). S46 The American Naturalist lem of hybrid sterility was solved, Bateson (1922, p. 59) said, “we have no acceptable account of the origin of ‘species.’” In the chapter on hybridism, Darwin’s (1859, p. 255) chief objective was not to provide a full account of the evolution of hybrid sterility but rather “to see whether or not the rules [governing the sterility of first crosses and their hybrids] indicate that species have specially been endowed with this quality, in order to prevent their crossing and blending together in utter confusion.” (The sterility of first crosses, unfortunately, conflates prezygotic and postzygotic isolation: “The early death of the embryo is a very frequent cause of sterility in first crosses” [Darwin 1859, p. 264].) From Darwin’s (1859) survey of crosses between species, varieties, and their hybrids, several rules emerged: among different crosses, the degree of sterility graduates from zero to complete (p. 255); the fertility of the first cross and of hybrids depends largely on systematic affinity (p. 256); hybrid males are most liable to suffer sterility (p. 265); species that are difficult to cross generally produce sterile hybrids, but in some cases species that cross easily produce sterile hybrids, whereas in others species that cross rarely produce fertile hybrids (p. 256); and hybrids from reciprocal species crosses often differ in fertility (p. 258). The last observation, in particular, was especially problematic for creationist-naturalists of the day: if hybrid sterility was endowed by the creator to maintain the integrity of closely related species, then why make hybrids sterile in only one direction of the cross? Darwin’s (1859, p. 260) conclusion was firm: “Now do these complex and singular rules indicate that species have been endowed with sterility simply to prevent their becoming confounded in nature? I think not.” Indeed, why, Darwin asked, was the production of hybrids permitted at all? To grant to species the special power of producing hybrids, and then to stop their further propagation by different degrees of sterility, not strictly related to the facility of the first union between their parents, seems to be a strange arrangement. (Darwin 1859, p. 260) For Darwin, then, neither God’s design nor natural selection to maintain species boundaries explained the messy, seemingly capricious rules of speciation. Instead, the sterility barriers between species were not adaptive but “incidental on other acquired differences” (Darwin 1859, p. 245). Developing a Genetic Theory for Hybrid Sterility and Inviability For it is scarcely possible that two organisations should be compounded into one, without some disturbance occurring in the development. (Darwin 1859, p. 266) Darwin, of course, did not provide specifics on the genetic basis of hybrid sterility and inviability. But he got as close as one might, working as he did without Mendelian genetics. Hybrid sterility and inviability, he argued, result from a hybrid’s “organization having been disrupted by two organizations having been compounded into one” (Darwin 1859, p. 266). While Darwin saw that natural selection did not directly favor the evolution of hybrid sterility, he saw no impediment to its incidental evolution as a by-product of interspecific divergence. It was Bateson (1909) who first realized that evolution at a single locus could not result in hybrid sterility. Suppose two species with genotypes aa and AA evolve from a common ancestor with genotype aa, so that A arises and spreads in one lineage (aa r Aa r AA) and no change occurs in the other; their Aa hybrids cannot very well have been sterile or else the A mutation, arising in a heterozygous state, would never have spread in the first place. Bateson (1909) immediately saw the solution to this conundrum but then, it seems, promptly forgot or perhaps later doubted it (Orr 1996). Some 30 years would pass before Dobzhansky (1934, 1937) and then Muller (1939, 1940, 1942), both apparently unaware of Bateson’s forgotten solution (Orr 1996), would arrive at the same model: hybrid sterility and inviability result from incompatible epistatic interactions between two or more complementary factors (fig. 1). Unlike the single-locus case, incompatible interactions between loci can evolve readily, unopposed by natural selection within species (fig. 1). Just a few years earlier, Bonnier (1927) had come close to proposing what is now known as the Dobzhansky-Muller model, pointing out that aabb genotypes can evolve from AABB ones (AABB r aaBB r aabb) unopposed by selection and then, when crossed with AABB species, produce sterile AaBb hybrids due to an incompatibility between A and b alleles. “But,” Bonnier (1927, p. 140) wrote, “such intermediate genotypes [aaBB] are not to be found in Nature among the kind of organisms we are considering.” The lack of intermediate genotypes led Bonnier (1927, p. 143) to dismiss the two-locus model and “to assign the question as to the mode of occurrence of new species to the sphere of quite unknown things.” Hollingshead (1930) soon provided evidence for the missing intermediate genotypes in Crepis, showing that a hybrid inviability factor between Crepis tectorum and Crepis capillaris was not only polymorphic but also mendelized: some C. tectorum (LL) produced only lethal hybrids with C. capillaris, some (ll) produced only viable hybrids, and heterozygotes (Ll) produced one-half lethal and one-half viable hybrids. In his Genetics and the Origin of Species, Dobzhansky (1937, p. 255) cites Bonnier as one of those “inclined to believe that the known genetic principles are insufficient to account for [hybrid sterility and inviability]” Darwin and Interspecific Incompatibilities S47 DMIs and concluded, among other things, the following: DMIs accumulate gradually. Postzygotic isolation will approach completeness as divergence between species, and hence the number DMIs, increases (Muller 1942, p. 109). To Muller, the open-ended accumulation of DMIs even after reproductive isolation is complete proved that natural selection did not directly favor postzygotic isolation, just as Darwin (1859, p. 105) inferred. By formalizing the Dobzhansky-Muller model and thus pioneering the modern theory of DMIs, Orr (1995) showed that the number of DMIs not only increases but also accelerates as species diverge. Between two species separated by K fixed differences, there are () K 2 Figure 1: The Dobzhansky-Muller model for the evolution of interspecific genetic incompatibilities. A, In Dobzhansky’s (1937) version, an ancestral population with the two-locus genotype, aabb, splits into two allopatric populations; a new mutation, A, arises and spreads to fixation in one population (AAbb), and the B mutation does the same in the second population (aaBB). The key to the model is that during their entire evolutionary history, the derived A and derived B mutations have never been combined in a single individual, and, consequently, their genetic interaction has never been tested by natural selection. Thus, while both mutations are individually neutral or beneficial on their own genetic background, the A and B mutations may be incompatible when brought together in a hybrid, causing sterility or inviability. In this case, the incompatibility occurs between two derived alleles. B, In Muller’s (1942) version, both substitutions occur in the same lineage so that in the case shown, the B substitution occurs first in an aa genetic background, followed by the A substitution, which occurs in a BB genetic background. Note that the derived A substitution has never been tested in combination with the ancestral b substitution. In this case, the incompatibility occurs between the derived A and ancestral b alleles. before presenting his own version of the model with Crepis as supporting evidence. It would appear that Dobzhansky saw Bonnier’s misstep, how the Crepis work provided the missing intermediate genotypes, and how the two-locus model provided a feasible genetic basis for the evolution of hybrid sterility and inviability. While Dobzhansky (1934, 1937) first rediscovered and popularized Bateson’s solution, it was Muller (1942) who fully developed its implications in arguably the most important article ever written on the evolution and genetics of interspecific incompatibilities (hereafter, DobzhanskyMuller incompatibilities, or DMIs). In the curiously titled “Isolating mechanisms, evolution, and temperature,” Muller (1942) expanded on Darwin by surveying the comparative and genetic rules characterizing the evolution of possible pairwise interactions, each with a probability p of being incompatible. The expected number of incompatibilities, I, is thus () K p ≈ 1 K 2p. 2 2 (1) The number of two-locus DMIs thus increases with the square of, or snowballs with, the number of substitutions fixed between species (Orr 1995; Orr and Turelli 2001). Derived and ancestral alleles can contribute to DMIs. A two-locus DMI can occur between two derived alleles (fig. 1A, A and B) or, as Muller (1942) noted, between a derived allele and an ancestral allele (fig. 1B, A and b). Derived ancestral DMIs evolve when both the A and the B substitutions are fixed in a single lineage, as in figure 1B; Muller (1942, pp. 87–88) further saw that for these cases, the causative substitutions must occur in a particular order (in fig. 1B, the A substitution is permissible only after the B substitution has occurred). Derived ancestral DMIs might be expected if the A and B substitutions result from coevolution among interacting loci (Cattani and Presgraves 2009). An A substitution, for instance, could increase the probability of a B substitution at an interacting locus (Schlosser and Wagner 2008). DMIs tend to be recessive. Muller (1942, p. 89) was the first to suggest that Haldane’s (1922) rule—the preferential sterility and inviability of interspecific F1 hybrids of the XY (or ZW) sex—will result when recessive X-linked DMI alleles are expressed in hemizygous (XY or ZW) hybrids but masked in their heterozygous (XX or ZZ) hybrid siblings. Indeed, Haldane’s rule, along with the crude genetic data available at the time, convinced Muller (1942, p. 99) of “a large class of recessive complementary incapacitating S48 The American Naturalist genes, a class much larger than the dominants, which usually escapes observation, however, except where the gene is in a sex chromosome, because of the indetectability of (their) effects in the F1 generation.” Turelli and Orr (1995, 2000) have formalized what is now known as the dominance theory. Muller was careful to note that the dominance of deleterious DMI effects in hybrids says nothing about the dominance of any possibly favorable effects of the substitutions within species—the preponderance of recessive DMIs does not imply that adaptation involves recessive beneficial mutations. DMIs can be complex. Muller (1942, p. 93) noted that DMIs are often complex, so that “more than two genes interact to produce the harmful result.” Cabot et al. (1994) and, more formally, Orr (1995) argue that complex DMIs should be common, as there are more viable and fertile intermediate steps among the genotypic paths to the evolution of complex DMIs versus simple ones. Large-effect DMIs cause asymmetric isolation. Muller realized that the asymmetric sterility or inviability of hybrids from reciprocal crosses (termed “Darwin’s corollary” to Haldane’s rule; Turelli and Moyle 2007) implicates asymmetrically transmitted DMI factors, like those on sex chromosomes or in the cytoplasm (Sturtevant 1920; Turelli and Moyle 2007). He further realized, and Turelli and Moyle (2007) have confirmed, that Darwin’s corollary implies that species are often separated by a small number of largeeffect DMIs: “The difference in results of reciprocal crosses must therefore be an expression of the high statistical error to which the sampling of small numbers is subject. That is, the effects in question were in the main dependent on only a very few loci each which had considerable influence on viability or fertility” (Muller 1942, p. 101). DMIs can result from gene transposition. “By some types of transfers in the position of genes, effects similar to those of complementary genes can be produced in hybrid recombinants that come to contain the given gene in neither position” (Muller 1942, p. 88). One way gene functions can change position involves gene duplication, followed by the neutral degeneration (or functional divergence) of alternative, redundant duplicate gene copies (Werth and Windham 1991; Lynch and Force 2000). DMIs cause permanent reproductive isolation. Muller (1942, p. 83) argued that geographic or ecological isolation was important in facilitating divergence but often temporary: “Remove the outer source of discontinuity—bring together again forms that have been separated by physical barriers, or provide ecological bridges for those kept apart only by their mode of life—and a reversal can often set in if the isolation has not proceeded so far as to include more deepseated bars to crossing.” Of the different kinds of barriers between species, then—geographic or biological—intrinsic postzygotic barriers, while “very seldom a primary step in isolation” (p. 84), are the ones that “effect permanent genetic isolation in general” (p. 83). Once multiple DMIs have become established, causing complete postzygotic isolation between species, there is no going back. What evolutionary forces cause DMIs to evolve? Like Darwin, Muller (1942) avoided speculating about the specific forces driving the accumulation of DMIs, saying only that they arise “as an automatic consequence of evolution in general” (p. 103), with the causative substitutions coming about “either through selection … or through mere accidental multiplication [drift]” (p. 102). Dobzhansky (1937, p. 258) went further, calling our ignorance about the properties of DMI genes within species “the weakest point of the whole theory.” Muller’s (1942) treatise marks a major turning point in the development of a detailed genetic model of DMIs (Johnson 2002), inspiring much of modern theory (Orr 1993b; Turelli and Orr 1995, 2000; Orr and Turelli 2001; Turelli et al. 2001; Gavrilets 2003, 2004; Welch 2004; Turelli and Moyle 2007). In the sections that follow, I will review the comparative patterns, genetics, and molecular basis of hybrid sterility and inviability in the light of three major developments: Darwin’s chapter on hybridism, Muller’s 1942 article, and the new mathematical theory of DMIs. I will conclude that Darwin got more right than he is often credited with; that since Muller (1942), little has changed in our thinking about the genetics of hybrid sterility and inviability; and that emerging fine-scale and molecular genetic rules, while largely confirming Darwin and Muller, have nevertheless revealed surprises that neither anticipated. In particular, the comparative, genetic, and molecular patterns characterizing the evolution of hybrid sterility and inviability are best explained as by-products of recurrent genetic conflicts. Comparative Rules Postzygotic Isolation Accumulates Gradually Now the fertility of the first crosses between species, and of the hybrid produced from them, is largely governed by their systematic affinity. (Darwin 1859, pp. 256–257) The evolution of intrinsic postzygotic barriers between species follows several comparative rules. First, confirming Darwin’s inference, the strength of intrinsic postzygotic isolation affecting F1 hybrids increases gradually, from zero to complete, as species diverge from one another (fig. 2). Table 1 summarizes comparative studies from plants, fungi, insects, and vertebrates that show a positive relationship between the severity of hybrid fitness problems and the genetic distance between parent species. The Darwin and Interspecific Incompatibilities S49 Haldane’s Rule for Sterility versus Inviability When in the F1 offspring of two different animal races one sex is absent, rare, or sterile, that sex is the heterozygous sex. (Haldane 1922, p. 101) Figure 2: Postzygotic isolation speciation clock in Drosophila (Coyne and Orr 1989a, 1997). The strength of postzygotic isolation increases with genetic distance between species (each triangle represents a phylogenetically independent species pair). Similar relationships exist in fungi, plants, vertebrates, and other insects (table 1). roughly linear, clocklike accumulation of postzygotic isolation is consistent with any theory in which speciation results from gradual genetic divergence between species. As Coyne and Orr (1989a) conclude in their classic study of patterns of speciation in Drosophila, the only theories not consistent with these data are those predicting frequent instantaneous speciation—and special creation. While the generally linear accumulation of postzygotic isolation might appear inconsistent with predictions of the snowball theory, there are many reasons why comparative data do not allow an appropriate test (Sasa et al. 1998; Mendelson et al. 2004; Johnson 2006). The simplest and most trivial reason is that the data are, in most cases, very crude. Hybrid fitness data are typically gathered from literature spanning many labs and decades and then distilled down to simple isolation indices. Second, once a species pair is completely isolated, the continued accumulation of DMIs post-speciation goes unregistered in comparative data. Of several other reasons, the most important is that the snowball theory predicts how the number of DMIs, not the total strength of postzygotic isolation, increases over time. Strength will reflect number only under the unsafe assumption that DMIs tend to make individually small contributions to the cumulative strength of isolation. But comparative data suggest and genetic data show that complete F1 hybrid sterility or inviability can often result from one or a few strong DMIs. Consequently, there need not be a strong correlation between the number of DMIs and the strength of postzygotic isolation. Testing the snowball theory will therefore be difficult, as the relevant data are genetic, not comparative. As table 2 shows, Haldane’s rule is one of the strongest patterns characterizing the evolution of intrinsic postzygotic isolation (Coyne and Orr 1989b, 2004; Coyne 1992; Wu and Davis 1993; Turelli and Orr 1995, 2000; Wu et al. 1996; Laurie 1997; Orr 1997; Gérard and Presgraves 2009). Comparative analyses show that Haldane’s rule for sterility is an obligate, intermediate phase in the evolution of complete postzygotic isolation in both male and female heterogametic taxa: species pairs with intermediate genetic distances and levels of postzygotic isolation are almost always cases in which XY (or ZW) hybrids are sterile (Coyne and Orr 1989a, 1997; Presgraves 2002; Price and Bouvier 2002). The ubiquity of Haldane’s rule suggests that common evolutionary or genetic causes may characterize the evolution of postzygotic isolation in a wide range of taxa (Coyne 1992). The most general explanation is the dominance theory: Haldane’s rule will result so long as the alleles causing hybrid sterility and inviability are, on average, partially recessive (Turelli and Orr 1995, 2000). The power of the dominance theory is that it can explain Haldane’s rule for sterility and inviability in both maleand female-heterogametic taxa. The limits of the dominance theory, however, become evident when hybrid sterility and hybrid inviability are contrasted. As table 2 shows, Haldane’s rule for sterility is much stronger than that for inviability, especially in male-heterogametic taxa, and evolves earlier during the time course of speciation than does hybrid inviability. The evolutionary or genetic factors contributing to hybrid sterility and hybrid inviability must therefore differ. For starters, DMIs causing hybrid inviability, like lossof-function mutations within species, tend to affect both sexes, whereas those causing hybrid sterility tend to be sex-specific (Coyne 1985; Orr 1993a; Wu and Davis 1993). But since many fewer loci are mutable to sex-specific sterility than to lethality within species, the faster evolution of hybrid sterility requires one of two things: either fertility-related genes diverge between species faster than viability-essential ones or gametogenesis is more easily disrupted than viability in hybrids. Two models predict faster divergence of fertility-related genes. First, the faster-male theory posits that sexual selection drives the especially rapid divergence of male-specific fertility-essential genes between species (Coyne 1985; Orr 1993a; Wu and Davis 1993; Wu et al. 1996). Second, the drive theory posits that recurrent genetic conflicts over transmission of the sex chromosomes leads to arms races between selfish meiotic S50 The American Naturalist Table 1: Intrinsic postzygotic isolation increases with divergence between species Taxa Insects: Drosophila Lepidoptera Stalk-eyed flies Vertebrates: Teleost fishes Centrarchid fishes Frogs Toads Birds Birds Pigeons and doves Mammals Fungi: Microbotryum Plants: Glycine Silene Streptanthus Orchids Hybridizations Postzygotic isolation increases with divergence? Hybrid sterility evolves before hybrid inviability? References Sterility ⫹ inviability Sterility ⫹ inviability Sterility ⫹ inviability 171 212 8 Yes Yes Yes Yes Yes Yes Coyne and Orr 1989a, 1997 Presgraves 2002 Christianson et al. 2005 Sterility ⫹ inviability Inviability Sterility ⫹ inviability 37 130 116 Yes Yes Yes Yes NA Yes Sterility ⫹ inviability Inviability Sterility ⫹ inviability Inviability Inviability 680 36 254 21 31 Yes Yes Yes Yes Yes NA NA Yes NA NA Russell 2003 Bolnick and Near 2005 Sasa et al. 1998; see also Wilson et al. 1974 Malone and Fontenot 2008 Prager and Wilson 1975 Price and Bouvier 2002 Lijtmaer et al. 2003 Wilson et al. 1974; Fitzpatrick 2004 Yes NA de Vienne et al. 2009 Yes Yes No Yes NA NA NA No Moyle et al. 2004 Moyle et al. 2004 Moyle et al. 2004 Scopece et al. 2008 Hybrid fitness problem Inviability Sterility Sterility Sterility Sterility ⫹ inviability 20 29 61 136 Note: NA p no statistical test for selection available. drive elements and their suppressors (Hall 2004) that, in turn, cause perpetual divergence of genes affecting gametogenesis (Frank 1991; Hurst and Pomiankowski 1991a; Henikoff et al. 2001; Tao et al. 2001; Presgraves 2008a). There is a critical difference between the two models. Faster-male evolution should contribute to Haldane’s rule for sterility in male-heterogametic taxa but hinder it in female-heterogametic ones. The comparative data, however, show that Haldane’s rule for sterility not only is strong in female-heterogametic taxa but also, at least in Lepidoptera, evolves as fast as in male-heterogametic ones (Presgraves 2002; Price and Bouvier 2002). The drive theory, on the other hand, predicts faster evolution of fertilityrelated genes in male- and female-heterogametic taxa and thus contributes to Haldane’s rule for sterility in both (Hurst and Pomiankowski 1991a; Laurie 1997; Tao and Hartl 2003). This is the first hint that evolutionary conflict involving selfish genes may play an important role in the evolution of intrinsic postzygotic isolation. The implication of the drive theory of Haldane’s rule, if true, is that genetic conflict generally, and meiotic drive specifically, is a more pervasive force than previously imagined. Darwin’s Corollary It is also a remarkable fact, that hybrids raised from reciprocal crosses, though of course compounded of the very same two species … generally differ in fertility in a small, and occasionally in a high degree. (Darwin 1859, p. 258) Table 3 updates and quantifies Darwin’s corollary, the observation that reciprocal hybrids often differ in their degree of sterility or inviability. The simplest explanation for this asymmetry is that reciprocal hybrids are not genotypically identical. Reciprocal hybrids can differ for any number of uniparentally inherited factors, such as sex chromosomes, maternal factors, and cytoplasmic organelles. Perhaps the best-characterized example involving sex chromosomes is the hybridization between Drosophila melanogaster and Drosophila simulans: hybrid females from D. melanogaster mothers are viable, but those from D. simulans mothers are killed by a dominant factor on the D. melanogaster X chromosome that is incompatible with a D. simulans maternal factor(s) (Sturtevant 1920; Sawamura et al. 1993a, 1993b). In addition to these common asymmetrically inherited factors, angiosperm embryos also rely on a nutri- Darwin and Interspecific Incompatibilities S51 Table 2: Haldane’s rule Taxa, sex determination, and sterility/inviability Drosophila: XY/XX: Sterility Inviability Mammals: XY/XX: Sterility Inviability Anopheles: XY/XX: Sterility Inviability Aedes: XX/XX: Sterility Inviability Lepidoptera: ZW/ZZ: Sterility Inviability Birds: ZW/ZZ: Sterility Inviability Haldane’s rule (XY or ZW sex afflicted) Exceptions (XX or ZZ sex afflicted) Proportion obeying Haldane’s rule 199 14 3 9 .99 .61 Wu and Davis 1993 Wu and Davis 1993 25 0 0 1 1.00 .00 Wu and Davis 1993 Wu and Davis 1993 56 21 0 3 1.00 .88 Presgraves and Orr 1998 Presgraves and Orr 1998 11 1 0 1 1.00 .50 Presgraves and Orr 1998 Presgraves and Orr 1998 29 56 1 1 .97 .98 Presgraves 2002 Presgraves 2002 72 21 3 2 .96 .91 Price and Bouvier 2002 Laurie 1997 tive triploid (3N) endosperm during development that arises from the union of a paternally transmitted haploid genome (1N) and a maternally transmitted diploid one (2N). As DMIs that disrupt endosperm development in hybrids can cause inviability of hybrid seeds, this additional layer of potential DMIs may explain why asymmetry appears to be more common in plants than in animals (table 3). The very existence of Darwin’s corollary, along with direct evidence for large-effect DMIs from genetic analyses, substantiates the concern that comparative data on the strength of postzygotic isolation in F1 hybrids are inappropriate for tests of the snowball theory. Genetic Rules We know virtually nothing about the genetic changes that occur in species formation. (Lewontin 1974, p. 159) Speciation is an old but still unsolved problem. (Nei 1987, p. 430) The sad truth is that we know almost nothing about the genetics of species formation. (Hartl and Clark 1989, p. 587) Until the mid-1980s, genetic analyses of intrinsic postzygotic isolation languished. Since then, however, there has References been an explosion of work on hybrid sterility and inviability, with the Dobzhansky-Muller model forming the basis of virtually all genetic analyses. In this section, I review genetic estimates of the numbers and kinds of DMIs between species, their dominance, their distribution in the genome, and the potential forces driving their evolution. How Many DMIs? Direct estimates of the number of DMIs separating two species, and hence the rate at which DMIs accumulate, remain scarce, as few fine-scale genome-wide analyses exist. The most high-resolution genome-wide screens for DMIs come from two sets of hybridizations in Drosophila. The first set involves crosses between Drosophila melanogaster and Drosophila simulans (Sturtevant 1920; Sawamura et al. 1993a, 1993b), which split from one another ∼3 million years ago. Although F1 hybrids from this species cross are normally sterile or dead, hybrid rescue mutations (Watanabe 1979; Hutter and Ashburner 1987) and the genetic tools of D. melanogaster have allowed a thorough dissection of lethal DMIs. These analyses suggest that ∼190 hybrid-lethal DMIs separate D. melanogaster and D. simulans (Coyne et al. 1998; Presgraves 2003). The second set of genetic analyses involves the three species of the D. S52 The American Naturalist Table 3: Incidence of asymmetric postzygotic isolation Taxon and hybrid phenotype Drosophila: Hybrid male sterility Hybrid female inviability Anopheles: Hybrid male sterility Hybrid female inviability Lepidoptera: Hybrid female inviability Centrarchid fishes: Hybrid viability Angiosperms: F1 seed viability Hybrid male sterility Asymmetric (%) References 15 25 Coyne and Orr 1989a, 1997; Turelli and Orr 1995 Coyne and Orr 1989a, 1997; Turelli and Orr 1995 16 27 Presgraves and Orr 1998 Presgraves and Orr 1998 60 Presgraves 2002 6 45 35 Bolnick et al. 2008 Tiffin et al. 2001 Tiffin et al. 2001 Note: All data, except those for centrarchids, were compiled by Turelli and Moyle (2007). simulans clade—D. simulans, Drosophila sechellia, and Drosophila mauritiana—which split from one another ∼250,000 years ago (Kliman et al. 2000; McDermott and Kliman 2008). All pairwise crosses between these species produce sterile hybrid sons but fertile hybrid daughters (Lachaise et al. 1986). Introgression analyses (True et al. 1996; Tao and Hartl 2003; Tao et al. 2003a, 2003b; Masly and Presgraves 2007) show that ∼15 different D. mauritiana regions cause complete hybrid male sterility (HMS) when made homozygous in the genomes of its sister species, few (D. simulans) or no (D. sechellia) regions cause hybrid female sterility, and few cause hybrid inviability (Cattani and Presgraves 2009). Genetic analyses in plants are also consistent with the faster accumulation of DMIs that reduce hybrid male (pollen) fertility versus other aspects of hybrid fitness (Moyle and Graham 2005; Moyle and Nakazato 2008). The Dominance of DMIs The same genetic analyses allow tests of the dominance theory. For two-locus DMIs, there are three kinds of incompatible interactions: those in which the incompatible effects of both alleles are dominant (denoted H0, following Turelli and Orr 2000), those in which one is dominant and the other recessive (H1), and those in which both are recessive (H2). Between D. melanogaster and D. simulans, there are no H0 DMIs (but see Barbash et al. 2000), ∼22 H1 DMIs (H1), and ∼169 H2 DMIs (Presgraves 2003). These results confirm Muller’s (1942, p. 99) inference that there must be “a large class of recessive complementary incapacitating genes, a class much larger than the dominants, which usually escapes observation.” The genetic analyses of D. mauritiana and its sister species provide similar support for the dominance theory: there is not one case of a fully dominant HMS factor (Tao and Hartl 2003). But, while confirming the relative abundance of recessive DMIs, these findings raise a new question. If Haldane’s rule results from incompatibilities between recessive Xlinked factors and dominant autosomal ones, then why are the dominant autosomal HMS factors missing from introgression analyses? Chang and Noor (2009) may provide the answer: individually recessive autosomal HMS factors can become partially dominant when co-introgressed into hybrids—that is, epistasis modifies the dominance of HMS factors. Complexity of DMIs Complex epistasis—in which a DMI involves three or more loci—has been the rule for HMS for some time (Wu et al. 1993; Wu and Hollocher 1998; Tao et al. 2003b). The D. mauritiana allele of Odysseus (Odsmau), for instance, causes complete HMS only when co-introgressed into D. simulans with another D. mauritiana factor (Perez and Wu 1995). It is becoming increasingly clear, however, that complex epistasis is the rule for hybrid lethality as well (see below). In F1 hybrid males from D. melanogaster mothers and D. simulans fathers, the wild-type D. simulans allele of Lethal hybrid rescue (Lhrsim) causes lethality (Watanabe 1979), but expressing a Lhrsim transgene in a pure D. melanogaster genetic background does not (Brideau et al. 2006). These findings imply that additional factors are required from D. simulans for Lhrsim to produce its lethal effect. Why complex epistasis is the rule for DMIs is unclear (but see Cabot et al. 1994; Orr 1995). Darwin and Interspecific Incompatibilities S53 Figure 3: The large X-effect for hybrid male sterility in Drosophila. Backcross hybrid male genotypes with chromosomes X, Y, 2, 3, and 4 are shown (the small dot for 5 is not shown; white p Drosophila pseudoobscura chromosomes, black p Drosophila persimilis chromosomes; Orr 1987). The percent of hybrid males with motile sperm is shown on the X-axis. Introduction of a foreign (D. persimilis) X chromosome reduces fertility far more than does introduction of foreign autosomes. The Large X-Effect Dobzhansky’s (1936) groundbreaking backcross analysis of DMIs in Drosophila—the first to show that HMS factors localize to chromosomal regions—showed that the X chromosome has a disproportionately large effect on the fertility of hybrid males (Orr 1987). This large X-effect has since been replicated in backcross analyses of hybrid sterility in other male-heterogametic taxa (e.g., Good et al. 2008) and in female-heterogametic taxa (reviewed in Coyne and Orr 1989b; Coyne 1992; Presgraves 2008b). While the large X-effect could imply that there is something special about the X chromosome during speciation, its meaning and significance have been disputed. The reason is that in backcross analyses, the hemizygous effects of a foreign X chromosome are usually contrasted with the heterozygous effects of foreign autosomes (fig. 3). If DMIs are generally recessive, then the effects of autosomal ones will be mostly hidden and those on the X fully expressed (Wu and Davis 1993; Turelli and Orr 2000). Several genetic analyses have nevertheless hinted at a higher density of HMS factors on the X (Naveira and Fontdevila 1986; True et al. 1996; Tao et al. 2003a), a finding now confirmed by recent fine-scale genetic analyses that control for introgression size: the density of HMS factors is approximately three or four times higher on the X than on the autosomes (Masly and Presgraves 2007). The high density of HMS factors, coupled with dominance, provides a proximate explanation for the large Xeffect, but why the X is a hot spot for hybrid sterility remains unclear (Presgraves 2008b). The drive theory of- S54 The American Naturalist fers one (but not the only) explanation (Tao et al. 2003a; Presgraves 2008b; Meiklejohn and Tao 2010). If X-linked meiotic drive elements arise and spread to fixation more readily than do autosomal ones, then species will tend to accumulate functional divergence (and hence DMIs) at Xlinked loci affecting gametogenesis (Frank 1991; Hurst and Pomiankowski 1991a; Tao and Hartl 2003). While the first tests of the drive theory failed to turn up evidence of drive in hybrid genotypes (Coyne 1986; Johnson and Wu 1992; Coyne and Orr 1993), there are now several examples of cryptic drive systems, suppressed within species but unleashed in species hybrids (Tao et al. 2007a, 2007b; Presgraves 2008a). Two of these show a clear association with HMS. First, the D. mauritiana allele of Tmy, when homozygous in a D. simulans background, contributes to HMS and exposes otherwise cryptic X chromosome drive (Tao et al. 2001). Second, the genetic factors causing HMS in F1 hybrid males from Drosophila pseudoobscura bogotana mothers and D. p. pseudoobscura fathers also cause hybrid meiotic drive (Orr and Irving 2005; Phadnis and Orr 2009). The rapid accumulation of HMS factors, their concentration on the X chromosome, and their occasional association with meiotic drive phenotypes further implicate evolutionary conflict as a force in speciation. Molecular Rules Direct molecular evolutionary data now support one of the central tenets of the neoDarwinian view of speciation—that reproductive isolation results from natural selection within species. This may well represent the most important finding to emerge from the last decade of work on the genetics of speciation. (Coyne and Orr 2004, p. 319) Determining the molecular genetic basis of hybrid sterility and inviability provides information on the functions of DMI genes within species (and hence the development of postzygotic isolation), as well as the forces driving their divergence between species. Twelve speciation genes that cause sterility or inviability in species hybrids have now been identified (table 4). From this small but rapidly growing sample, tentative molecular genetic rules that characterize the evolution of DMIs are beginning to emerge. First, 11 of 12 genes are protein-coding genes, with a scattershot of functions, from cell signaling to DNA binding and modification. Second, of the eight genes for which population genetic or molecular evolutionary analyses have been performed, all show patterns of substitution consistent with recurrent positive selection. These episodes of positive selection occurred in one species’ lineage in some cases (e.g., Ods, Ovd) but in both lineages in other cases (e.g., Hmr, Lhr, Nup96, Nup160). Why should two species living in different locations often experience, at the same time during their short histories, recurrent bouts of adaptation at the same loci? These patterns of substitution seem most consistent with evolutionary conflicts that might be expected from antagonistic interactions of a host genome with its pathogens and selfish genes. In Drosophila, the functions of some DMI genes further suggest a role for conflicts involving, specifically, the regulation of heterochromatin, viruses and retrotransposons, and meiotic drive elements (Sawamura and Yamamoto 1997; Brideau et al. 2006; Presgraves 2007; Presgraves and Stephan 2007; Phadnis and Orr 2009; Bayes and Malik 2009; Ferree and Barbash 2009; Tang and Presgraves 2009). In the clearest case, evolution at Ovd, a gene causing hybrid sterility in F1 males between Drosophila pseudoobscura bogatana and D. p. pseudoobscura, involved the fixation of selfish substitutions that cause segregation distortion (Phadnis and Orr 2009). The mouse HMS gene Prdm9 appears to disrupt meiotic sex chromosome inactivation (MSCI)—the transcriptional silencing of the X (or Z) chromosome in the germline of the XY (or ZW) sex (Mihola et al. 2009). MSCI is thought to be a generalized system for suppressing selfish elements on the sex chromosomes (Hurst and Pomiankowski 1991b; Tao et al. 2007b; Meiklejohn and Tao 2010). Thus, in Drosophila, and possibly mouse, genetic conflict is emerging as an important evolutionary force in the molecular evolution of DMIs (table 5). Similar molecular arms races between plants and their pathogens may drive the evolution of incompatibilities among genes with immune functions (Bomblies and Weigel 2007; Bomblies et al. 2007). Not all DMIs are necessarily by-products of evolutionary conflict. As Muller (1939; 1942, pp. 88–89) pointed out, DMIs can also result from the transposition of gene function from one genomic address to another in different lineages so that “the original and the transferred loci (or rather, their ‘absences’) operate as complementary factors”; as in the Dobzhansky-Muller model, gene transposition “occurs in two steps, each individually innocuous or nearly so: first, the addition of the gene or block of genes in the new position … and second, the loss of one or more of the genes in the old position [by gene mutation or deficiency].” Lynch and Force (2000) developed population genetic theory for this plausibly neutral evolution of DMIs via gene transposition, and in at least one case, gene transposition has given rise to an interspecific DMI: the Drosophila male fertility-essential gene JYalpha, located on chromosome 4 in Drosophila melanogaster, has moved to chromosome 3 in the Drosophila simulans clade species. As a result, recombinant hybrid males homozygous for the D. melanogaster third chromosome and D. simulans fourth chromosome are sterile because they completely lack JYalpha (Masly et al. 2006). Similar gene transpositions appear to contribute to lethal gene combinations segregating JYalpha Overdrive Zygotic hybrid rescue Hybrid male rescue Lethal hybrid rescue Nucleoporin96 Nucleoporin160 Ovd Zhr Hmr Lhr Nup96 Nup160 PR domain containing 9 kinase 2 M. m. domesticus Mus musculus musculus/ Xiphophorus helleri X. maculatus receptor tyrosine Xiphophorus maculatus/ S. cerevisiae/S. bayanus S. bayanus/S. cerevisiae D. simulans/D. melanogaster D. simulans/D. melanogaster D. simulans/D. melanogaster D. melanogaster/D. simulans D. melanogaster/D. simulans D. p. pseudoobscura D. pseudoobscura bogatana/ D. simulans/D. melanogaster D. mauritiana/D. simulans Species Hybrid phenotype F1 hybrid males F2 hybrids F2 hybrids F2 hybrids F2-like hybrids F2-like hybrids F1 hybrids F1 hybrids F1 hybrids Hybrid sterility Hybrid inviability Hybrid sterility Hybrid sterility Hybrid inviability Hybrid inviability Hybrid inviability Hybrid inviability Hybrid inviability 17 X Mito. 13 2 3 2 X X X F1 hybrid males Hybrid male sterility 4 X Chrom. Introgression hybrid males Hybrid male sterility Introgression hybrid males Hybrid male sterility Affected hybrids Note: Chrom. p chromosome; mito. p mitochondrion; NA p no statistical test for selection available. Prdm9 Xmrk2 Vertebrates: ATPase ExPression OLIgomycin resistance AEP2 OLI1 Yeast (Saccharomyces): Odysseus JYalpha Gene name Ods Drosophila: Locus Table 4: Hybrid incompatibility genes positive trimethyltransferase Histone 3 lysine 4 Receptor tyrosine kinase F0-ATP synthase subunit Nuclear pore protein Nuclear pore protein DNA-binding DNA-binding Repetitive DNA DNA-binding activity NA Yes NA NA Yes Yes Yes Yes NA Yes Yes NA DNA-binding selection? Na⫹/K⫹-exchanging ATPase Molecular function Evidence for Mihola et al. 2009 Wittbrodt et al. 1989 Lee et al. 2008 Lee et al. 2008 Tang and Presgraves 2009 Presgraves et al. 2003 Brideau et al. 2006 Barbash et al. 2003 1997 Sawamura and Yamamoto Phadnis and Orr 2009 Masly et al. 2006 Ting et al. 1998 References S56 The American Naturalist Table 5: Emerging molecular rules for DMIs in Drosophila Gene Hybrid phenotype Ods JYAlpha Ovd Hmr Lhr Nup96 Nup160 Zhr HMS HMS HMS HI HI HI HI HI Protein coding Complex DMI Positive selection Genetic conflict References Yes Yes Yes Yes Yes Yes Yes Het Yes No Yes Yes Yes Yes Yes ? Yes GTr Yes Yes Yes Yes Yes ? ? No Yes Yes Yes Yes Yes Yes Ting et al. 1998; Bayes and Malik 2009 Masly et al. 2006 Phadnis and Orr 2009 Barbash et al. 2003 Brideau et al. 2006 Presgraves et al. 2003 Tang and Presgraves 2009 Sawamura and Yamamoto 1997; Ferree and Barbash 2009 Note: HMS p hybrid male sterility. HI p hybrid inviability. GTr p gene transposition. Het p heterochromatin. within Arabidopsis (Bikard et al. 2009) and may have contributed to a burst of speciation in yeast (Scannell et al. 2006). Conclusions Darwin’s chapter on hybridism was a first attempt to synthesize the information available on the fitness of interspecific hybrids in plants and animals so that the rules governing the sterility of hybrids might be inferred. From Darwin’s survey, two general rules emerged. First, he recognized that the sterility of hybrids results from “two organizations having been compounded into one” (Darwin 1859, p. 266). Dobzhansky, and especially Muller, added the Mendelian genetic details to Darwin’s intuition, and modern genetic analyses confirm that hybrid sterility and inviability are caused, by and large, by incompatible epistatic interactions. More than that, genetic analyses show that DMIs tend to be complex, that the alleles involved tend to be partially recessive, and that DMIs causing HMS preferentially accumulate on the X chromosome. Second, Darwin (1859) saw “that some degree of sterility, both in first crosses and in hybrids, is an extremely general result” (p. 254) and that interspecific sterility barriers must be “incidental on other acquired differences” (p. 245). Darwin thus believed that speciation—at least when it involves postzygotic isolation—occurs as a by-product of interspecific divergence. He might well have been satisfied by the molecular genetic data, which show that hybrid sterility and inviability evolve as by-products of recurrent positive selection. But Darwin, Dobzhansky, and Muller might have been surprised at the causes of selection. There is an emerging consensus that the comparative, genetic, and molecular rules characterizing the evolution of hybrid sterility and inviability are most consistent with pervasive, recurrent conflicts between host genomes and their selfish genes. Two questions seem especially important as work on hybrid sterility and inviability moves forward. First, the case for conflict, while clear-cut for particular examples (e.g., Ovd, Tmy), is far from certain. To further test the veracity and generality of the conflict hypothesis, detailed molecular characterization of more speciation genes from a wider range of taxa—especially ZW ones—is needed. Establishing the reasons why selection caused particular DMI genes to diverge between species will, however, often prove difficult. The reason is that selfish genetic elements may frequently arise and run their course, spreading to fixation or coming under the control of suppressors, and ultimately leave no phenotype behind except sterility or inviability in hybrids (Presgraves 2010). Second, the direct evidence for natural hybridization (Grant and Grant 1992; Presgraves 2002), the existence of hundreds of hybrid zones (Barton and Hewitt 1985; Harrison 1993; Price 2008), and molecular population genetics analyses (Hey 2006) together suggest that gene flow between partially reproductively isolated species may be common. Recent whole-genome sequence analyses from multiple closely related species further suggest that speciation often may be complex, involving hybridization and gene flow, and that DMIs affect which regions of the genome can pass between species and which cannot (Noor et al. 2001; Rieseberg 2001; Wu 2001; Wu and Ting 2004). The sex chromosomes (Tucker et al. 1992; Llopart et al. 2005; Bachtrog et al. 2006; Putnam et al. 2007; Geraldes et al. 2008; Storchova et al. 2009) and regions of the genome with low rates of recombination (Turner et al. 2005; Noor et al. 2007; Carneiro et al. 2008), for instance, show especially reduced propensity for gene flow between species. These patterns are consistent with the higher density of (and hemizygous selection against) DMIs on sex chromosomes and the greater likelihood of linkage to DMIs for low-recombination regions (Noor et al. 2001; Rieseberg 2001). Going forward, whole-genome studies that combine high-resolution mapping of DMIs with complementary population genomics analyses of the history of speciation will be enormously valuable. The integration of fine-scale genomewide mapping and population genomics data will put historical inferences about the impact of DMIs on the cessation of gene flow, and hence speciation, on solid footing. 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