Speciation genetics: current status and evolving approaches

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Phil. Trans. R. Soc. B (2010) 365, 1717–1733

doi:10.1098/rstb.2010.0023

Introduction

* Autho

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Speciation genetics: current status andevolving approaches

Jochen B. W. Wolf1,*, Johan Lindell1 and Niclas Backstrom1,2

1Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University,Norbyvagen 18D, 75236 Uppsala, Sweden

2Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street,Cambridge, MA 02138, USA

The view of species as entities subjected to natural selection and amenable to change put forth byCharles Darwin and Alfred Wallace laid the conceptual foundation for understanding speciation.Initially marred by a rudimental understanding of hereditary principles, evolutionists gainedappreciation of the mechanistic underpinnings of speciation following the merger of Mendelian gen-etic principles with Darwinian evolution. Only recently have we entered an era where decipheringthe molecular basis of speciation is within reach. Much focus has been devoted to the geneticbasis of intrinsic postzygotic isolation in model organisms and several hybrid incompatibilitygenes have been successfully identified. However, concomitant with the recent technologicaladvancements in genome analysis and a newfound interest in the role of ecology in the differen-tiation process, speciation genetic research is becoming increasingly open to non-modelorganisms. This development will expand speciation research beyond the traditional boundariesand unveil the genetic basis of speciation from manifold perspectives and at various stages of thesplitting process. This review aims at providing an extensive overview of speciation genetics. Startingfrom key historical developments and core concepts of speciation genetics, we focus much of ourattention on evolving approaches and introduce promising methodological approaches for futureresearch venues.

Keywords: selection; reproductive isolation; next generation sequencing; gene expression;hybrid; speciation research in the post-genomic era

1. INTRODUCTIONThe formation of new species lies at the very heart ofevolutionary biology. Indeed, the vast diversity of lifeon Earth can only be explained by speciation, a pro-cess that continuously generates independentlyevolving lineages. One and a half centuries ago, this‘mystery of mysteries’ was subject to bold speculation,as the philosopher John Herschel communicates in aletter to Charles Lyell (Herschel 1836). Several yearslater Charles Robert Darwin and Alfred Russell Wal-lace made a considerable contribution to demystifythe origin of new species and laid the foundation forevolutionary biology by suggesting natural selectionand common ancestry as cornerstones of organismicevolution (Darwin & Wallace 1858). Yet, despite itstitle, Darwin’s opus ‘On the Origin of Species byMeans of Natural Selection’ (Darwin 1859) did notfocus on the rise of new species, but instead empha-sized natural selection as a mechanism for theadaptive change of populations in response to the pre-vailing conditions. Furthermore, Darwin highlightedthe transition from populations to species as a gradual

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tribution of 11 to a Theme Issue ‘Genomics of speciation’.

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continuum (Mallet 2008) without formally treatingthe isolation factors that reduce gene flow amongpopulations (Mayr 1942; see also Barraclough 2010;Mallet 2010). However, Darwin lacked an under-standing of the genetic basis of heredity. This eludedevolutionary biology until four decades later, followingthe rediscovery of Mendelian principles of inheritancein 1900. Yet, it was not until the theoretical frameworkof population genetics was amalgamated with Darwi-nian evolution and gave rise to the Modern Synthesisduring the 1930s that the species problem wasseriously considered (Dobzhansky 1937; Mayr1942). This fusion put a premium on a populationgenetic viewpoint and hence allowed examining thespeciation process from a genic perspective. By explicitmodelling, the Modern Synthesis and influential deri-vates such as the Neutral and Nearly Neutral Theory(Kimura 1983; Ohta 1992) conceptually reduced theevolutionary process to several tractable parameterslike mutation, drift, selection and recombination,which can be estimated with empirical data. Fromthe excitement about modes and mechanisms of spe-ciation that characterized the Modern Synthesis, aconsensus had emerged that speciation representedcomplete reproductive isolation of biological species,which could most likely be acquired through

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1718 J. B. W. Wolf et al. Introduction. Speciation genetics


geographic isolation (Mayr 1942). Speciation researchfell into a state of dormancy and largely revolvedaround the relative importance of different geographicspeciation scenarios for several decades. However, oneand a half centuries after ‘On the Origin of Species’ thereis once again much excitement about speciation. Overthe last two decades, the spectrum of researchers withan interest in speciation has expanded considerably.Given the breadth of scientific disciplines that contrib-ute to contemporary speciation research, this review isnaturally limited in focus and will capitalize onresearch concerned with the genetics of speciation.

Genetic approaches have always been central to spe-ciation research, but despite significant progress overthe last years in speciation genetic research, many fun-damental questions about the molecular basis of thesplitting process await to be answered. Which geneticelements are of particular relevance to speciation?How many loci are involved, how large is the effectof a specific locus and how important is epistasis orpleiotropy? Where in the genome are the determinantslocated and what is the importance of the genomiclandscape? What is the role of recombination,mutation, chromosomal rearrangements, gene conver-sion and other molecular forces? How does divergencein gene expression compare with structural changes?How crucial is sex-linkage? Are different functionalclasses of genes relevant at different stages of the spe-ciation process? What is the role of natural selectionand how can we best detect its genetic footprints?

Finding full answers to even a subset of these ques-tions over a broad taxonomic range will probably bewishing for too much. Still, focusing on several well-chosen speciation models, we may come close to aneducated guess. Being empiricists, we will focus onthe empirical side by highlighting where recentadvancements have been and are expected to bemade and only mention the relevant theoretical workin passing. We provide the conceptual backgroundon general key concepts where deemed necessary. Asmuch of recent research has focused on the role ofnatural selection in speciation, the review reflects thisbias. We start by addressing research concerned withthe genetic basis of intrinsic postzygotic isolation,which has been the traditional stronghold of speciationgenetics. We then expand the framework of speciationgenetics into an ecological context and try to infer howthe field will be transformed, as novel genomic toolsallow for detailed analysis of organisms, where pre-viously no genomic resources have been available.

2. THE ROOTS OF SPECIATION GENETICSSpeciation involves the build-up of reproductive isolat-ing barriers between diverging populations which aremost palpable in malfunctional heterospecific hybrids.The evolution of postzygotic isolation giving rise tohybrid problems posed an important challenge toDarwinism: how can natural selection allow the pro-duction of maladaptive phenotypes and unfithybrids? Most speciation theories have subsequentlyfocused on resolving this dilemma. The theories canbe divided into two groups corresponding to distinctforms of postzygotic isolation. In extrinsic postzygotic

Phil. Trans. R. Soc. B (2010)

isolation, hybrid phenotypes fare poorly in their inter-action with the environment, falling between theniches of the parental phenotypes (Schluter & Conte2009). In intrinsic postzygotic isolation, hybrids areunfit because they suffer inherent developmentaldefects, resulting in partial or complete sterility orinviability (Orr & Turelli 2001). There are numerousexamples from nature where both extrinsic and intrin-sic postzygotic isolation appear to be at work (e.g.Rogers & Bernatchez 2006; Rieseberg & Willis 2007;Fuller 2008). Some recent work suggests that extrinsicpostzygotic isolation may be more common and moreimportant than intrinsic postzygotic isolation, specifi-cally in the early stages of divergence (Schluter 2009;Schluter & Conte 2009; Johannesson et al. 2010).However, given the relative ease with which the geneticbasis of reproductive isolation can be evaluated in lab-oratory model organisms, along with a great amount oftheoretical work on the topic, most of what we knowabout the genetics of speciation deals with intrinsicpostzygotic isolation.

Four kinds of genetic problems have been identifiedas the likely causes of intrinsic hybrid difficulties:ploidy levels, chromosomal rearrangements, genicincompatibilities and interaction between nuclear gen-omes and endosymbionts, which can arguably beregarded as a special case of the latter (Rieseberg2001; Coyne & Orr 2004; Hoffmann & Rieseberg2008). These mechanisms vary in importance depend-ing on the system. Ploidy levels, for example, are ofmajor importance in plant speciation (Rieseberg &Willis 2007), where chromosomal rearrangementshas also been extensively discussed (White 1969;Hoffmann & Rieseberg 2008). In research on geneticmodel organisms such as Drosophila (Kulathinal et al.2009), there has also been much interest in chromoso-mal rearrangements (Noor et al. 2001; Noor & Feder2006). Nevertheless, it appears that genic incompat-ibilities may be the most important cause of intrinsicpostzygotic isolation; they play a common role inboth hybrid sterility and inviability, and affect bothanimals and plants (Orr & Turelli 2001; Coyne &Orr 2004). Genic incompatibilities in hybrids mostcommonly involve between-locus interactions; anallele at one locus from one of the parental speciesdoes not interact well with an allele at another locusfrom the other parental species (Turelli & Orr 2000;Coyne & Orr 2004). This in line with early suggestionsof the Modern Synthesis that negative epistaticinteractions among genes constitute a plausible mech-anism that can cause hybrid sterility and inviability.The ‘Dobzhansky–Muller’ model, initially discussedby Bateson (1909) and later developed by Dobzhansky(1937) and Muller (1942) (we will refer to it asthe Bateson–Dobzhansky–Muller (BDM) modelthroughout), was proposed as a solution to the pro-blem of how hybrid sterility can evolve withoutselection opposing any intermediate step. In short,allopatric populations that evolve independently eachaccumulate different mutations that contribute to gen-etic differences between the populations. Subjected toevolutionary forces including genetic drift and naturalselection, specific mutations may function well inthe genetic make-up of their particular population.


Introduction. Speciation genetics J. B. W. Wolf et al. 1719


However, because alleles from different populationshave not been tested together, such mutations are onaverage less likely to function with alleles of a differentancestral background in hybrid individuals. Hybridsterility or inviability may therefore simply evolve as aby-product of genomic differentiation after extendedperiods of geographic separation. Accordingly, theevolution of BDM incompatibilities provides an ele-gant solution to the production of unfit hybrids,because natural selection need not oppose any stepin this process (Orr & Turelli 2001). BDM incompat-ibilities are expected to accumulate with the square ofthe number of substitutions separating two species(Orr & Turelli 2001). The emergence of reproductiveisolation through BDM is thus expected to be a slowprocess that gets ever more efficient as time progresses(Coyne & Orr 1997; Price & Bouvier 2002). If theevolution of epistatic BDM incompatibilities werecommonplace, this ‘snowball effect’ of acceleratingdecline in reproductive compatibility should generallybe visible. A recent exploratory meta-analysis byGourbiere & Mallet (2010), however, suggests thatfor most of the investigated taxa, the decay of repro-ductive compatibility is better predicted by linear orslowdown models. This finding calls the generalimportance of BDM compatibilities into questionand much rather suggests that incompatibilitiesaccumulate linearly without BDM effects and providesnovel evidence for a role of reinforcement. Furthermeta-analyses of this kind are needed to better judgethe relative contribution of these processes in generat-ing reproductive isolation.

Much of the research on intrinsic postzygotic iso-lation and genic incompatibilities has focused onHaldane’s rule, the preferential effect of sterility orinviability on hybrids of the heterogametic sex(Haldane 1922). Following decades of relative stasisin speciation genetics, the field was remarkably reinvi-gorated in the mid-1980s by newfound interest in thisphenomenon (Coyne 1985). Four main ideas havebeen suggested as general causes of Haldane’s rule:the dominance theory, the faster-male theory, thefaster-X theory and meiotic drive (Coyne & Orr2004), with the two former recognized as main factorsin causing Haldane’s rule. New genomic data haveunderscored the importance of sex chromosomes inspeciation (Mank et al. 2007; Presgraves 2008;Ellegren 2008a). While Haldane’s rule is commonlyviewed as important in the initial stages of speciation(Kulathinal & Singh 2008), it may, however, beargued that sex chromosomes are comparativelymore important in later stages of speciation, complet-ing the process following initial differentiation(Qvarnstrom & Bailey 2008).

There has also been considerable debate regardinghow many and what type of genes are important in caus-ing reproductive isolation. While the population geneticapproach of the Modern Synthesis held that adaptationand population differentiation was the cumulative effectof numerous genes, each with small effect (Fisher 1930),recent research on intrinsic postzygotic isolation hasfocused on the effect of a small number of genes eachwith large effect (Orr 2001). This view is taken to theextreme in research on bona fide speciation genes, of


which only a handful of examples are known (Wittbrodtet al. 1989; Ting et al. 1998; Barbash et al. 2000;Presgraves et al. 2003; Ortız-Barrientos & Noor 2005;Brideau et al. 2006; Mihola et al. 2009; Phadnis &Orr 2009; Tang & Presgraves 2009). Only recently,the first case was documented in which both genes ofa pair of epistatically interacting loci causing hybridincompatibility (Brideau et al. 2006; Presgraves 2007).While further research is needed to resolve the functionof factors causing intrinsic postzygotic isolation, excitingnew evidence points to a role both for epigenetic inter-actions and genetic conflict (Orr et al. 2007; Miholaet al. 2009; Phadnis & Orr 2009; Presgraves 2010).

A somewhat special case of gene–gene interactionsis given by mitonuclear interactions and may deservesome extra attention. Until lately, the effect of endo-symbionts on speciation has received comparativelylittle attention and has largely focused on incompat-ibilities caused by cytoplasmically inherited parasiteslike Wolbachia (Bordenstein et al. 2001). While mito-chondrial DNA was long regarded as a neutralmarker invaluable for tracing evolutionary history(Avise 2000), accumulating evidence questions theassumption of neutrality, with implications for evol-utionary biology including speciation (Meiklejohnet al. 2007; Dowling et al. 2008). Specifically, as mito-chondrial function is closely tied to energy productionthrough oxidative phosphorylation and organismal fit-ness (Rand et al. 2004), maladaptive combinations ofmitochondrial and nuclear genes in hybrids may actto reduce gene flow and drive population differen-tiation (Dowling et al. 2008). For example, hybridbreakdown owing to mitonuclear incompatibilities(leading to reduced energy production) has beenobserved in population crosses of marine copepods(Ellison & Burton 2008) and Nasonia parasitoidwasps (Ellison et al. 2008). Interestingly, large-scaleanalysis of the Nasonia nuclear genome impliesstrong effects of natural selection on nuclear genes ofrelevance for mitochondrial function, in line withstrong selection for mitonuclear coadaptation(TNGWG 2010). Incompatibilities between nuclearand mitochondrial genes have also been shown tocause hybrid sterility in yeast (Lee et al. 2008). Clearly,the role of mitochondrial DNA in speciation deservesfurther attention (Levin 2003; Gershoni et al. 2009)and may explain intriguing patterns such as asym-metric introgression between incipient species(Turelli & Moyle 2007).

The nature of hybrid sterility and infertility has notonly been elucidated by studies concerned with intrin-sic postzygotic isolation. Investigations of postmatingprezygotic isolation in externally fertilized organismssuch as sea urchins and mussels have importantly con-tributed (Palumbi 2009). A plethora of approachesover the last two decades have revealed that proteinson gamete surfaces (e.g. bindin and lysin) are ofmajor importance in reducing gene flow by disruptingfertilization (Lee et al. 1995; Metz & Palumbi 1996;McCartney & Lessios 2004). Egg and sperm proteinsseem to have engaged in an arms race driven by sexualconflict, which may accelerate the formation of repro-ductive isolation (Gavrilets 2000; Swanson & Vacquier2002). Considered in isolation this would make for a




simple story. A combination of ecological, genetic andphysiological approaches, however, suggests that spe-ciation in these systems include manifold processesthat may be simultaneously necessary for the emer-gence of discrete clusters. These include sexualconflict, sperm competition, cryptic female choice,frequency-dependent selection and reinforcement, aswell as ecological aspects such as individual densitydistributions (Birkhead & Pizzari 2002; Swanson &Vacquier 2002).

Both the examples of intrinsic postzygotic isolationand postmating prezygotic isolation in external fertili-zers highlight a role for genic interactions in thebuild-up of reproductive isolation (referring in theformer case to epistatic interactions within onehybrid individual, in the latter between proteins rel-evant for communication between gametes). Theyalso strengthen the idea that only few genes of majorimportance may suffice in driving two populationsapart (Orr 2001).

3. EXTENDING THE FRAMEWORK OFSPECIATION GENETICSThe considerable amount of data that has been col-lected on the basis of genetically encoded hybridincompatibilities over the last decades has biased ourview of speciation towards the genetics of postzygoticisolation between rather divergent lineages. Concep-tually however, the genetics of speciation has a muchbroader definition, with speciation genes being func-tional genomic elements that convey some degree ofecological, sexual, pre- or postmating, pre- or post-zygotic isolation. Furthermore, as different genes willact during different stages of the speciation process,speciation research should encompass nascent speciesas well as species that have accomplished a certaindegree of reproductive isolation (Via 2009). Forexample, while understanding Haldane’s rule and theaction of BDM incompatibilities is undoubtedlyhighly relevant, it remains unclear to what extentobserved incompatibilities have contributed to theinitial branching of lineages or if they merely reflect asubsequent accumulation of incompatibility factorscompleting the speciation process. Research into thegenetics of intrinsic postzygotic isolation therefore rep-resents a retrospective look at the speciation process(Via 2009), and an exclusive focus on hybrid sterilityand inviability will impede a deeper understandingof the molecular basis of all aspects and stages of thespeciation process. Phylogenetic approaches includingtaxa which already have diverged significantly can giveimportant insight into the tempo and mode of specia-tion (Price 2010). However, a strict retrospectiveinference precludes a role of ecology a priori and canthereby only speculate about the conditions underwhich the speciation process was initiated. The evi-dence that prezygotic isolation seems to evolve fasterthan postzygotic isolation (Coyne & Orr 1997) andthat postzygotic isolation can be achieved much morereadily if driven by extrinsic factors (Schluter &Conte 2009) suggests that other approaches tounderstanding the speciation process are needed.


Fortunately, current speciation research is alsoembracing approaches that focus on the causes ofinitial divergence in populations that are only partlyisolated (Via 2009). From such work on evolutionaryyoung lineages that are at incipient states of diver-gence, it has increasingly been recognized thatbarriers to gene flow can evolve as a result of ecologi-cally based divergent or disruptive selection. Thisperception is bolstered both from theoretical workevaluating the role of natural selection in a growingnumber of empirical systems (Gavrilets 2004;Dieckmann et al. 2004a; Gavrilets & Losos 2009;Barton 2010). Clearly, a central limitation of thisforward-looking approach is that one cannot foreseewhether the speciation process will be driven to com-pletion. Still, we predict that an approach combiningboth ecology and genetics in young systems will befruitful, particularly so if the recently emerging geno-mic tools are applied to the well-establishedecological model systems with long study histories(Kruuk & Hill 2008). Merging both worlds will even-tually paint a broader picture of the relevantmechanisms involved in speciation. In the followingsections, we highlight some areas where recent pro-gress has been made towards understanding the roleof ecology and selection in speciation.

(a) Ecological speciation in a tube

One way to address the importance of ecologicallyimposed divergent selection in speciation is given byexperimental evolution studies on micro-organisms.This approach dates back to one of Darwin’s contem-poraries, William Dallinger, but had not gatheredweight until the early 1990s. A number of in vitroexperiments have demonstrated that fitness trade-offsbetween heterogeneous environments are easy toachieve and can be stably maintained (Rainey &Travisano 1998; Buckling et al. 2009). The genesinvolved in adaptations can potentially be mappedand in recent years it has become possible to monitorthe evolution of whole viral and prokaryotic genomesand this will likely be increasingly feasible in eukar-yotes (Bomblies & Weigel 2010). From these studiesit emerges that ecological adaptations often seem toentail lowered hybrid fitness between divergentlineages by negative epistatic interactions sensu BDMincompatibilities (Dettman et al. 2007; Duffy et al.2007; Barrick et al. 2009). This establishes the linkbetween ecological adaptation and postzygotic iso-lation and suggests that BDM incompatibilitities canarise as incidental by-products of positive naturalselection (Dettman et al. 2007; Bomblies & Weigel2010). The observation that most of the hybrid incom-patibility genes identified so far show signatures ofadaptive evolution further supports this idea (Orret al. 2007; but see Presgraves 2010).

(b) Ecology and the concept

of adaptive speciation

Darwin was a clear proponent of the idea that environ-mental differences can generate divergent selectionpressures that eventually drive two populations apart.He foreshadowed the idea that the splitting process




itself may be adaptive and not only a by-product ofgeographical isolation (Darwin 1859). However, incontrast to the experimental evolution studiesdescribed above (which are essentially allopatric intheir setup), natural populations might be connectedby gene flow for some period of time and experiencegradually changing environments. The only realisticscenario for the splitting process itself to be adaptivethen occurs by frequency-dependent intraspecificinteractions that can result in disruptive selection(Dieckmann & Doebeli 1999). The most radical rep-resentation of such ecologically mediated speciationis that of ‘adaptive speciation’, which refers to specia-tion processes in which the ‘splitting is an adaptiveresponse to disruptive selection caused by frequency-dependent biological interactions’ (Dieckmann et al.2004b). While this concept can, under specialcircumstances, also work in allopatry it is essentiallyrelated to speciation under conditions of gene flow(‘divergence-with-gene-flow’).

While much of the literature on ‘ecological specia-tion’ revolves around similar ideas as in ‘adaptivespeciation’, ecological speciation is broader in its defi-nition (Rundle & Nosil 2005) and encompasses allinstances whereby reproductive isolation can evolveas a by-product of adaptation to different environ-ments (Schluter 2001, 2009; Rundle & Nosil 2005).Nonetheless, the two concepts have several featuresin common that make them explicitly different fromneutral speciation models in allopatry caused by therandom accumulation of negative epistatic mutations.A central theme of both is the importance of naturalselection acting on a set of few key traits associatedwith resource use, mate choice or, in plants, pollina-tion. Consequently, it is predicted that in the earlyphase of the divergence process, taxa are reproduc-tively isolated only at a small number of locallyconfined areas in the genome (‘genomic islands ofspeciation’), while remaining indistinguishablethroughout the parts of the genome that are unaffectedby selection (Turner et al. 2005; Harr 2006). Duringthe course of genomic differentiation, this divergencemix slowly attains a higher degree of phylogenetic con-cordance through independent responses to geneticdrift and selection within the new species (Nosilet al. 2009). Ecologically motivated speciation scen-arios are thus genic in their view and put a premiumon the early stages of speciation, where speciationboundaries are still porous and branching patternsare established by a few, but crucial changes.

(c) Establishing empirical evidence for

divergence-with-gene-flow

Quantification of divergent or disruptive selection inthe wild is not trivial. Therefore, indirect means areusually sought to evaluate the role of adaptation in spe-ciation. For example, evidence for prezygotic isolationbetween subpopulations from different environmentsis indicative of adaptive differentiation. Exampleswhere habitat-based prezygotic isolation has beendocumented include cichlid fish (Kocher 2004;Barluenga et al. 2006; Elmer et al. 2010), Galapagosfinches (Grant & Grant 2008), guppies (Reznick


et al. 2008), pea aphids (Hawthorne & Via 2001),butterflies (Jiggins et al. 2001), monkeyflowers(Bradshaw & Schemske 2003) and other floweringplant species (Lowry et al. 2008). Further evidencefor ecologically driven divergence comes from studiesexamining the level of differentiation between subpopu-lations that have adapted to different environments asopposed to subpopulations that reside in similarenvironments (Funk et al. 2006). With an increasingavailability of analytical tools (Foll & Gaggiotti 2006),we can expect that the environmental factors determin-ing genetic structure in populations will be identified innew systems.

An important observation that relies on a model ofspeciation that invokes adaptation is the phenomenonof parallel evolution, where similar ecotypes haveevolved repeatedly upon recurrent colonization ofnew habitats (Schluter & Nagel 1995). Hard evidencefor parallel evolution is difficult to collect as it needs tobe demonstrated that parallel divergence is the resultof independent colonization events and not of sub-sequent gene flow between similar ecotypes (Schluter2009). Still, there are examples from natural popu-lations indicating that parallel speciation may occur.A prominent case is given by the divergence of three-spined stickleback ecotypes (limnetic versus benthicand marine versus fresh water) (Rundle et al. 2000;McKinnon et al. 2004). Similar adaptations to limneticand benthic niches are observed in lake whitefish(Rogers & Bernatchez 2007; Whiteley et al. 2008;Bernatchez et al. 2010) and arctic char (Skulasonet al. 1996; Orr & Smith 1998). Other cases where par-allel speciation seems to be in progress includeadaptations to environments with and without preda-tors in mosquitofish (Langerhans et al. 2007),adaptations to areas of different wave exposure insnails (Sadedin et al. 2009; Johannesson et al. 2010;Butlin in press), and adaptations to different hostplants in walking sticks (Nosil et al. 2008) and peaaphids (Peccoud et al. 2009).

(d) Adaptations from novel mutations or

standing genetic variation?

Common to the examples listed above is that paralleldivergence occurred within thousands rather thanmillions of years. Given the speed of the process, it ismost probable that genetic variants underlying agiven adaptive phenotype are independently recruitedfrom standing genetic variation, since adaptationrestricted to selection of novel mutations would befar slower (Barrett & Schluter 2008). There areindeed some well-established cases of adaptive diver-gence occurring as a result of recent selection forparticular alleles recruited from ancestral polymorph-ism (Schluter & Conte 2009). For example,phylogenetic studies in sticklebacks have shown thatstream living, less-armoured ecotypes have arisenindependently several times at different locations, butthat the alleles contributing to body armouring(Ectodysplasin, Eda) were already present in theircommon ancestor (Colosimo et al. 2005). In the com-parable case of lake whitefish (Rogers & Bernatchez2007; Whiteley et al. 2008; Jeukens et al. 2009;




Bernatchez et al. 2010), it is likely that standing geneticvariation has contributed since the ecotypes evolvedrepeatedly, in parallel, in very recent times. A fascinat-ing case has been reported for the apple maggot,Rhagoletis pomonella. In this species, a particular eco-type started using domestic apple instead ofhawthorn and in less than two centuries this changein behaviour has caused almost complete reproductiveisolation between these ecotypes (Feder et al.2003a,b).

While many of the examples of parallel speciationmight be indicative of selection on standing geneticvariation, caution needs to be taken. In sticklebacks,the Pituitary homeobox transcription factor 1 (Pitx1)locus has been shown to be involved in the develop-ment of the pelvic apparatus. Comparable to thesituation of armour plating described above, moststicklebacks develop a normal pelvic apparatus. Inover a dozen widely distributed populations, however,phenotypes with reduced spines seem to have evolvedin parallel and seem to be under selection as a responseto habitat-related factors such as predator pressure orcalcium availability (see Shapiro et al. 2006 and refer-ences therein). Chan et al. (2010) have recentlydemonstrated that recurrent deletions in a highlymutable enhancer region of the Pitx1 gene, ratherthan recruitment from ancestral variation, areresponsible for a phenotype with reduced pelvicspines.

(e) The problem of recombination

In the early stages of adaptive divergence, reproductiveisolation is expected to be concentrated around a smallnumber of locally adapted genes. It remains an impor-tant challenge to understand how reproductiveisolation progresses from a genetic mosaic pattern togenome-wide divergence. Particularly, under con-ditions with homogenizing gene flow, the associationbetween genes involved in local adaptation and thoseinfluencing premating isolation are generally con-sidered to be vital (Rundle & Nosil 2005; Bolnick &Fitzpatrick 2007). A key problem in speciation-with-gene-flow models is therefore to understand hownatural selection can maintain adaptive gene combi-nations when faced with the deteriorating force ofrecombination. Several possibilities to overcome thedisruptive influence of recombination have beensuggested, including close physical linkage (Butlin2005), reduction in effective recombination rate inthe regions under diversifying selection (Via & West2008) and pleiotropy (Kirkpatrick & Barton 1997;Kirkpatrick & Ravigne 2002). These scenarios arehard to disentangle as long as the causative variantsfor both isolation and adaptation have not been eluci-dated (Rundle & Nosil 2005). Still, to understand thestrength of selection needed to result in the build-upof reproductive isolation, an effort to discriminatethem is essential. At present, the genetic elements gov-erning the traits involved in ecological speciation remainlargely unknown. Chromosomal speciation modelspostulate an important role for rearrangements in thebuild-up of reproductive isolation among incipientspecies (Rieseberg 2001; Hoffmann & Rieseberg


2008). Indeed, rearrangements have been found to beassociated with hybrid inviability for example inHelianthus sunflowers (Rieseberg et al. 1999) andDrosophila (Noor et al. 2001; Brown et al. 2004).Chromosome rearrangements definitely provide ameans to resolve the problem of linkage, but ofcourse require that major causative variants for bothisolation and adaptation are located within the invertedregion.

Pleiotropic genes are particularly attractive candi-dates, as they entirely bypass the problems of linkageand recombination. By definition, pleiotropy occurswhen a single gene influences several phenotypictraits. Translated into the speciation context, theyconvey habitat-specific selective advantage and at thesame time ensure assortative mating with referenceto the trait under selection. Examples from severalstudies point towards their existence. Beak size inDarwin’s finches is both relevant to ecologically mediatedfitness and species recognition (Grant & Grant 2008);the genetic background to beak shape seems to be largelyconfined to one locus involved in the calmodulin pathway(Abzhanov et al. 2006). Empirical data also indicatethat pleiotropy might govern copper tolerance and polli-nator shifts in monkeyflowers (Macnair & Christie1983; Bradshaw & Schemske 2003), and the couplingof reproductive isolation and host switch in pea aphids(Hawthorne & Via 2001). In addition, wing colour andmate preference actually map to the same gene (wingless)in butterflies (Kronforst et al. 2006) and many floral traitsthat affect pollinator shift in columbines seem to berestricted to a small genomic region (Hodges et al.2002). However, causative variants are not fine-mappedand verified and the results could also be explained ifthere is tight linkage between the locus governing localadaptation and the locus governing reproductive isolation(Rundle & Nosil 2005). Another way of establishingevidence for pleiotropic genes could potentially comefrom candidate gene approaches. While rapidly develop-ing genomic tools will soon allow examining classes ofcandidate genes (e.g. pigmentation genes, early develop-ment genes) or entire gene families (Mamanova et al.2010), candidate gene approaches are at present still lim-ited to a handful of genes. For example, the majorhistocompatibility locus (MHC) has been extensivelystudied in a behavioural ecological framework. Pleiotropywith regard to parasite resistance and signal for matechoice make it a good candidate for studies on ecologicalspeciation under conditions of gene flow (Eizaguirre et al.2009). Another extensively studied class of genes thatmay be relevant to speciation are pigmentationgenes like the melanocortin-1-receptor (MC1R) or theAgouti signalling protein (ASIP1) that have beenshown to influence coat and plumage colour in severalorganisms (Mundy et al. 2004; Hoekstra et al. 2006;Linnen et al. 2009). It is intuitively clear that thematch between body coloration and substrate is rel-evant to predator-mediated selection, as has beenrecently shown for Peromyscus mice (Mullen et al.2009). Another convincing non-genic mechanismthat generates an immediate association betweenecological adaptation and mate choice is habitatlearning (Beltman & Haccou 2005), which has beensuggested to be relevant in several vertebrate systems




(Musiani et al. 2007; Wolf et al. 2008). One has to becareful, however, to a priori attribute the link betweenecological adaptation and assortative mating tolearning, as simple non-genic mechanism of assortativemating, in which the mating trait arises as a pleiotropiceffect of genes responsible for ecological adaptation,is also credible in viral evolution (Duffy et al. 2007).

Pleiotropy certainly is an appealing idea, but to dateit remains unclear to what extent the different mechan-isms of coupling the trait under selection andassortative mating are involved. Regardless, the studiesmentioned above show that the coupling seems to bepossible and rather widespread.

(f) A role for sexual selection

While sexual selection in itself need not be linked toecological speciation (Schluter 2001, 2009), it hasbeen discussed as a means to enhance divergence inan ecological context (Grant & Grant 1997; Edwardset al. 2005; Ritchie 2007; van Doorn et al. 2009).Under certain circumstances, the effect of a sexuallyselected trait depends on the environment in which itis displayed, so that the divergence in mating traitswill eventually be governed by adaptation to theenvironment (‘sensory drive’; Boughman 2002). In arecent study, Seehausen et al. (2008) established thelink between colour variants in cichlid fishes andwater turbidity and provided compelling evidence forspeciation through sensory drive in sympatry.Although sensory drive may promote speciation insome systems, it is conceivable that other modes ofsexual selection are the driving forces of speciation(e.g. good genes (Andersson 1994) or Fisherian run-away selection (Fisher 1930; Kirkpatrick & Hall2004)). Specific examples where sexual selection hasbeen argued to promote divergence include the rapiddiversification of cichlid fish (Seehausen et al. 1999;Kocher 2004; Elmer et al. 2010) and cricket species(Shaw & Parsons 2002; Mendelson & Shaw 2005).Theory predicts that sexual selection is expected tobe more powerful in organisms with female hetero-gamety (Reeve & Pfennig 2003), such as birds andlepidopterans. There is indeed some empirical indi-cation that traits of importance for speciesrecognition are sexually selected in Heliconius butter-flies (suggesting a role for the wingless locus;Kronforst et al. 2006) and Ficedula flycatchers(Sæther et al. 2007; Qvarnstrom et al. 2010). Interest-ingly, in the case of flycatchers there is characterdisplacement, presumably driven by reinforcement(Sætre et al. 1997), and in crickets, butterflies and fly-catchers there is also evidence for physical linkage oftrait and preference loci, which could partly resolvethe problem of recombination. One important pointis that in most cases where sexual selection has beenthe suggested force of speciation, it is still to beresolved if the differentiation has evolved as aby-product of diversifying selection driven by environ-mental factors (ecological speciation) or throughfixation by sexual selection of different mutations inpopulations with similar selection regimes (Ritchie2007).


A fresh perspective on how sexual selection couldfacilitate speciation under sympatric conditions hasbeen put forth by van Doorn et al. (2009). In asimple model, the authors explore how sexual selec-tion and disruptive ecological selection can joinforces to curtail gene flow, promote local adaptationand eventually lead to speciation. Key to theirmodel is the incorporation of condition-dependentmate choice, which only involves a pre-existingmate choice machinery instead of having to relyon concomitant divergence of ecologically and arbi-trary sexually selected traits. By the introduction ofthis genotype-by-environment interaction theyentirely circumvent the problem of earlier modelsto link ecological performance and assortativemating without having to invoke the presence offortuitous pleiotropy between ecological andmating traits.

4. GETTING TO THE GENES UNDER SELECTIONMuch progress has been made over the last years inidentifying the genes responsible for BDM incompat-ibilities in model organisms (see above), but thequest for genes underlying adaptive divergence inorganisms of ecological interest where few geneticresources are available has only begun. Bringing wildstrains into the laboratory will not yield the sameclear-cut insights as in the study of postzygotichybrid breakdown even if the same genetic toolsexisted as for model species like Drosophila. The fitnesseffect of a given trait (and its underlying genetic basis)should preferably be investigated under the full set ofenvironmental conditions in the wild and will be diffi-cult to study under laboratory conditions (Calisi &Bentley 2009). The quest is further exacerbated bythe fact that traits important for local adaptation arelikely to be quantitative and are hence thought tohave a complex genetic background (Weedon &Frayling 2008; Hendry 2009). In the years to come,many efforts will nonetheless be devoted to decipher-ing the genetic basis of speciation driven by adaptivedivergence. Although getting to specific genes willunderstandably be difficult in most cases, much pro-gress is expected in finding candidate regions ofinterest and in answering more general questionsabout the underlying genetic mechanisms. Is extensiveadaptive divergence based on few loci with major effect(Gavrilets & Losos 2009) or by many loci of smalleffect (Fisher 1930)? Do gene interactions betweentraits undergoing adaptive divergence also lead tointrinsic postzygotic isolation? Are candidate genesspecial with regard to the level of pleiotropy or theirposition in protein networks? How is the homogeniz-ing effect of gene flow and recombination overcome?In the following, we will shortly mention somepromising avenues for addressing these questions.

(a) Phenotype–genotype association

Most investigations conducted in natural populationsso far have used a limited number of genetic markers,typically tens to thousands of microsatellites or ampli-fied fragment-length polymorphisms (AFLPs), whichare suboptimal with regard to large-scale genome




scans (Butlin in press). The advent of massively paral-lel sequencing technologies holds much promise forspeeding up the progress in understanding the geneticbasis of (ecological) speciation (Noor & Feder 2006;Ellegren 2008b; Vera et al. 2008; Gilad et al. 2009).The scope of these recent fast developing methods isnicely illustrated by a collation of 21 articles on nextgeneration molecular ecology (Tautz et al. 2010).Once statistical challenges of how to appropriatelydeal with short-read shotgun sequences in a popu-lation genetic context are overcome, populationgenomic analysis will be directly based on the sequen-cing data itself and replace the marker-basedapproaches. At present still, the most straightforwardapplication consists in scanning large proportions ofthe genome for polymorphisms that may be used asgenetic markers for subsequent genotyping usingarray-based high-throughput genotyping techniques(Syvanen 2005). The increase of genetic markers byorders of magnitudes is expected to boost geneticmapping studies that have been so far often limitedby the number of available markers. The first step inestablishing the link between phenotype and genotypeusually involves obtaining a detailed linkage map. In afew natural populations, this has already been achieved(e.g. Wang & Porter 2004; Stemshorn et al. 2005;Gharbi et al. 2006; Akesson et al. 2007; Rogers et al.2007; Backstrom et al. 2008). Nonetheless, such pedi-gree-based approaches require access to multi-generation samples of related individuals; that can beextremely challenging in natural populations, andagain stresses the importance of long-term ecologicalmodel systems for the study of speciation.

With the availability of larger marker sets one couldanticipate that mapping efforts will be focused onother methods, such as association scans (linkage dis-equilibrium mapping) using population samples, anapproach most well developed in model species withthe available genome sequences (Nordborg & Weigel2008; Goddard & Hayes 2009; Bomblies & Weigel2010). In divergent natural populations or hybridzones, it may be of particular interest to make use ofthe extended linkage disequilibrium resulting fromthe admixture of differentiated populations (Rieseberg& Buerkle 2002; Smith & O’Brien 2005). Recent pro-gress in analytical approaches (Gompert & Buerkle2009) further increases the applicability of thismethod making a strict geographical sampling regimedispensable. A striking example demonstrating thepotential of this approach comes from a study on thegenetics of introgression across Cottus hybrid zones,which basically suggests that different forms of selec-tion affect much of the genome and providesnumerous candidate regions for future studies (Nolteet al. 2009). While extended linkage after admixtureis useful for identifying the genomic regions of interest,short-range linkage disequilibrium is needed to be ableto resolve selection at the level of the gene. However,adaptive divergence may put a lower boundary onthe resolution with which genes can be mapped, asselection can reduce the effective (interspecific/inter-population) recombination rates in regionsharbouring genetic determinants of local adaptation(‘divergence hitchhiking’; Via & West 2008). This


results in large regions spanning significant portionsof the genome increasing the degree of differentiationat marker loci located far from the target of selection(but see Yatabe et al. 2007; Wood et al. 2008). Never-theless, as exemplified in disease-mapping studies indog, there may still be potential for designing mappingstudies so that within-breed long-range linkage dis-equilibrium (admixture or divergence hitchhiking inthe case of incipient species) is used to find candidateregions and then between-breed short-range linkagedisequilibrium (within species) allows for moredetailed searches (Sutter et al. 2004; Lindblad-Tohet al. 2005).

Additional possibilities to characterize the genesinvolved in early speciation spring from the everincreasing characterization of gene function in modelspecies from where it will be possible to extract candi-date loci for investigation in the focal species (Hoekstraet al. 2004; Mundy 2005). This approach certainlytakes the risk that there might be different geneticbackgrounds to similar phenotypes also between clo-sely related species or between populations withinspecies (Hoekstra & Nachman 2003).

(b) Phenotype uninformed methods:

evolutionary genomics

All the above-mentioned approaches require some pre-vious knowledge about the phenotype involved in theadaptive process (top down; mapping). An alternativeapproach lies in the application of population geneticapproaches to detect selection directly from DNAsequence data without a priori knowledge of the phe-notypic effect (bottom-up; evolutionary genomics).With an ever increasing availability of genome-widepolymorphism and divergence data, it will be possibleto scan genomes of diverging populations for regionswith higher than expected differentiation indicativeof ongoing or recent diversifying selection (Akeyet al. 2004; Beaumont 2005; Excoffier et al. 2009).Additionally, high-density marker data can be usedto trace regions indicative of recent directional selec-tion (selective sweeps) within populations (Nielsen2005; Nachman 2006). An example of where thisapproach has been successfully applied comes fromwild mice populations (Harr 2006; Teschke et al.2008). However, it is well recognized that populationstructure and other demographic scenarios canseverely affect the expected distribution of parametervalues (Thornton & Andolfatto 2006; Pool & Nielsen2007; Excoffier et al. 2009; Hermisson 2009).Encouragingly, numerous methods have been devel-oped to estimate the demographic scenario underwhich to search for the footprints of selection (Hey &Nielsen 2004; Hey 2006; Becquet & Przeworski2007). Clearly, studies on rich datasets that infer selec-tion under detailed demographic scenarios will set thefuture standards (Nielsen et al. 2009).

Valuable insights into the genetic basis of adap-tation may further come from comparative genomicstudies that set out to find signatures of selection bycomparing sequences of orthologous genes from twoor more organisms (Ellegren 2008a). Genes affectedby diversifying selection on protein structure are




expected to have a higher ratio of non-synonymous tosynonymous differences among taxa than genes thatevolve under purifying selection. For this approachto be meaningful, however, the number of fixedmutations must clearly exceed the numberof polymorphisms, which restricts it to comparisonsof lineages that have speciated millions of years ago.Still, it may be informative if we consider whichgenes or gene ontology classes are repeatedly identifiedto be under positive selection, as these genes may alsobe involved in earlier stages of the splitting process. Acomplementary approach that can identify the spreadof beneficial mutations in single lineages consists ofcontrasting polymorphism to divergence data betweenspecies with McDonald–Kreitman (McDonald &Kreitman 1991) and Hudson–Kreitman–Aguade-type (Hudson et al. 1987) approaches (Begun et al.2007).

So far, past comparative genomic approaches havebeen limited to a small number of organisms wherewhole genome sequences have been available (Kosiolet al. 2008). Having entered the era of massively paral-lel sequencing, this will rapidly change and the firstlarge-scale examples of comparative genomic analyseson non-model organisms are being published (Kunst-ner et al. 2010).

5. A ROLE FOR GENE EXPRESSION INSPECIATION(a) Structural variation versus variation in

expression

Thirty-five years ago, King & Wilson (1975) expressedtheir amazement that homologous protein and DNAsequences appeared to be almost identical betweenhumans and chimpanzees. This influential papertouched upon an important concept whose basic pos-tulate is still valid. Functional polymorphism in genesrelevant to evolutionary change is not restricted tocoding variation, which ultimately alters amino acidcomposition and protein structure; it also includesregulatory variation modulating the expression of agene. Several lines of research have made clear thatchanges in gene expression are indeed relevant in spe-ciation (Tautz 2000; Wittkopp et al. 2008). Thisapplies to a broad variety of taxa and ranges fromcolour patches in the wings of flies (Gompel et al.2005) to beak size in Galapagos finches (Abzhanovet al. 2006). While the evolutionary implications ofstructural variation have been extensively explored inan evolutionary framework both in theory and prac-tice, scrutiny of the evolution of gene expressionremains a big challenge.

Analysis of the role of gene expression in speciationfaces many obstacles. Part of this relates to technologi-cal restrictions. For studying structural variation, theone-dimensional DNA sequence can nowadays beread with great ease and the amino acid compositioncan directly be derived from the genetic code. How-ever, it is technically more demanding to work withRNA and quantify gene expression. In contrast toDNA sequencing, where clear quality standards havebeen established that enable comparative resultsacross laboratories, quantification of transcript


abundance differs between technologies such as qRT-PCR and microarray studies. Furthermore, geneexpression studies often fail to reflect the (major)quantity of interest: protein abundance (Schrimpfet al. 2009). Nonetheless, the development of promis-ing new approaches (Wang et al. 2009) will facilitateinvestigations of the role of gene expression in specia-tion. Instead, biological complexity may pose a greaterchallenge. Numerous complex and interacting pro-cesses like transcription, transcript stability, splicing,regulatory RNAs and translational efficiency even-tually determine protein abundance in a cell and it isdifficult to make allowances for all. Another complicat-ing factor is the sometimes widely different expressionprofiles among tissues and developmental stages,which makes it hard to pick the right time and placeto study the evolution of expression differencesbetween lineages. Similarly, expression profiles arenotoriously plastic (Cheviron et al. 2008), whichlimits expression studies to species that can be bredunder common garden conditions with relative ease.

Despite the analytical difficulties associated withstudying gene expression, a body of literature has accu-mulated over the last years showing that regulatoryvariants are a primary substrate for the evolution ofspecies (Wray 2007). In the past, it has been customaryto focus on structural sequence variation and considereach gene as a separate unit of evolution in both popu-lation genetic theory and empirical practice. However,phenotypic traits are controlled by a large number ofdifferent genes and changes in their temporal and spatialcoordination have far-reaching consequences. Stern &Orgogozo (2009) posit that once we start consideringthe interactions of genes and transcripts, we may under-stand that not all genes are equal in the eyes of evolution,and that evolutionarily relevant changes may accumulatein certain hotspot genes located at specific positions inregulatory networks. Results of experimental evolutionstudies corroborate this claim (Cooper et al. 2003).Tapping the full potential of such a perspective canshed new light on evolutionary phenomena like parallelevolution in divergent lineages that are difficult to explainotherwise. For example, does parallel speciation com-monly involve parallel changes in expression patterns,following strong selection for particular beneficial alleles(Unckless & Orr 2009)? The integration of networkthinking into evolutionary genetics may constitute asimilar quantum leap as the integration of Mendeliangenetics into Darwin’s evolutionary framework(Koonin 2009). Without doubt, the burgeoning interestin the contribution of gene expression to speciesdivergence is part of this transition.

(b) A role for selection on gene expression?

Under the assumption that most characters are con-trolled by a large number of interacting genes, we canexpect that the underlying genetic network may be lar-gely resilient to slightly deleterious changes in one of itselements. Likewise, advantageous mutations may notbe manifested significantly in a genetic pathway withmany developmental ramifications (Wagner 2000).Many features of transcriptional networks may indeedbe described by non-adaptive processes and a non-




negligible number of regulatory changes may thus beexpected to evolve approximately in a neutral fashion(Lynch 2007). Khaitovich et al. (2005) have laid outthe theoretical basis for a neutral evolutionary model ofgene expression which predicts an approximately linearaccumulation of expression differences with time aswell as a correlation of expression variance within aspecies and expression differences between species. Sev-eral studies explicitly addressing this question are in linewith a predominantly neutral scenario (Khaitovich et al.2004; Staubach et al. 2010). If divergence in geneexpression progresses simply as a function of time in alargely neutral fashion, we may expect regulatory incom-patibilities to arise analogous to the BDM model forstructural variation. Indeed, experimental evidencesuggests that divergence in gene regulation is a majorcontributor to BDM incompatibilities between severalspecies of Drosophila (Haerty & Singh 2006), whichmay be a more widespread phenomenon as hybrid mis-expression between taxa is not restricted to drosophilids(Cowles et al. 2002; Tirosh et al. 2009). Still, it may bepremature to argue that regulatory incompatibilities gen-erally arise analogous to genetic incompatibilities sensuthe BDM model. Alternative scenarios such as compen-satory changes among interacting gene products or geneproducts and regulatory elements need to be taken intoconsideration (Landry et al. 2007).

(c) Cis or trans?

The study of hybrid mis-expression has also proven toyield valuable insights on the relative role of trans andcis factors in the evolution of novel phenotypes.Changes in cis-acting sites occur on the regulatorysequences of the gene itself. This way, their effect isrestricted to the sequences of their own DNA (orRNA) molecule. Trans factors (such as transcriptionfactors) on the other hand are separate molecules (pro-teins or RNAs) that can influence the activity of abroad variety of targets. Studies in several modelspecies suggest that expression divergence is predomi-nantly owing to changes in cis factors (Wray 2007;Wittkopp et al. 2008). A broad study in yeast (Tiroshet al. 2009) further suggests that upstream com-ponents involved in transduction of environmental orinternal signals to direct regulatory elements (sensorytrans factors) seem to be more often involved thandirect transcription and chromatin regulators (regulat-ory trans factors). Taken together, these results suggestthat not all divergence processes are strictly neutral.Reviewing the empirical evidence to date, Fay &Wittkopp (2008) conclude that adaptation oftenoccurs by changes in gene regulation and that cis-regulatory sequences appear to play a special rolein adaptive divergence.

What is the evolutionary relevance of cis-regulatorychanges and how can they affect the speciation process?It is often proposed that natural selection can operatemore efficiently on cis-regulatory mutations. First,alleles in diploid organisms are largely transcribed inde-pendently suggesting that—in contrast to structuralmutations that are mostly recessive—mutations in cis-regulatory sequences are often co-dominant andthereby directly accessible to selection (see Wray 2007


and references therein). Second, modular organizationand tissue-specific expression governed by enhancerelements reduce the degree of negative pleiotropy.Wray (2007) and Prud’homme et al. (2007) provide abroad array of empirical examples that nicely illustratethe vast creative potential of cis-regulatory evolution.In sticklebacks, for instance, cis-regulatory changes inthe Pitx1 gene seem to be associated with differencesin pelvic skeleton structure between marine and fresh-water forms (Shapiro et al. 2004; Chan et al. 2010).The repeated evolution of pelvic reduction in freshwaterpopulations is not limited to populations of the three-spined sticklebacks, but can also be observed in the dis-tantly related lineage of nine-spined sticklebacks(Pingitius pungitius; Shapiro et al. 2006). This obser-vation of repeated habitat-associated changes in theregulatory region of Ptx1 is not only suggestive of arole in cis-elements in parallel evolution, but it alsounderlines the importance of studying the geneticbasis of speciation in combination with ecologicalresearch. It will be of crucial importance to our under-standing of regulatory divergence processes to applygenomic tools to non-model species that have beenextensively studied on morphological, ecological andbehavioural grounds.

(d) Expression studies in non-model organisms

A few years ago genomic studies of gene expressionin non-model organisms were out of reach. Today, theycertainly still constitute a technological challenge, asgenomic resources are, with the exception of a few spe-ciation models like Anopheles (Cassone et al. 2008),usually unavailable. Interspecific microarrays have beensuccessfully applied (Cheviron et al. 2008; Renaut et al.2009), but will always remain a compromise. We canexpect, however, that digital measures of expression onthe basis of next generation sequencing (RNAseq) willbe a major breakthrough (Gilad et al. 2009; Wang et al.2009). As sequence and expression data are simul-taneously generated, this approach has the advantagethat structural and expression divergence can be directlycompared. It further enables a much more detailed viewon expression, e.g. by considering allele-specificexpression patterns (Fontanillas et al. 2010) or by charac-terizing splicing variants (Harr & Turner 2010), whichare not tractable by interspecific microarrays. Firststudies exploring the potential of RNAseq in non-model organisms which rely on distant genomicresources are promising (Buggs et al. 2010; Goetz et al.2010; Wolf et al. 2010) and document the dawning ofan era where high-resolution transcript-profiling innon-model organisms will become commonplace(Gilad et al. 2009).

6. CONCLUSIONSince the conception of evolutionary biology, interestin speciation has gone through periods of intense dis-cussion and times of relative stasis. Over the last twodecades speciation research has gained enoughmomentum to address the genetics of the splitting pro-cess in earnest. This advancement has primarily beendriven by an interest in the genetics of intrinsic postzy-gotic isolation with particular reference to genic




incompatibilities. Despite considerable achievements,this field undoubtedly awaits further insights. Exper-imental studies will continue to contribute to theunderstanding of divergent selection in the accumu-lation of genic incompatibilities and the fastdevelopment in massive parallel sequencing technol-ogies now makes it affordable to monitor theevolutionary process across entire genomes.

Technological and analytical developments and anewfound interest in the role of ecology in promotingdifferentiation have recently encouraged speciationgenetic research to broaden its perspective. Frombeing confined to the study of genic incompatibilitiesin hybrid crosses, speciation genetics now extends toresearch on the forces involved in the initial phase ofthe speciation process and the role played by diversify-ing selection. This development enhances the chanceto establish the link between phenotypes and geno-types and to bring the study of speciation into thewild. Population genomic analyses and studies on therole of expression and copy number variation willsoon be common practice also in non-model organ-isms. A burgeoning field of great potential herein isthe genomics of hybrid zones where generations ofhybrid and backcross individuals lay the foundationfor genome scans, taking advantage of differences inwithin- and between-population levels of linkage dis-equilibrium. Similarly, long studied ecologicalmodels with well-established pedigree informationand knowledge on traits involved in reproductive iso-lation will remain highly valuable resources. Inparticular, wild species that can be kept under con-trolled conditions bear the potential to reveal theunderlying genetic causes of speciation. Finally andunquestionably, unravelling the mechanistic foun-dations underlying the ‘mystery of mysteries’ willever more benefit from combining the expertise frommany fields.

This review results from a symposium on speciation entitled‘Origin of Species–150 Years Later’, held at the Sven LovenCenter for Marine Sciences in Fiskebackskil, Sweden.We would like to thank the organizers Hans Ellegren,Staffan Ulfstrand and Michael Thorndyke along with theWenner-Gren Foundation and the Royal Swedish Academyof Sciences who made this meeting possible. We are alsograteful to Richard Bailey and one anonymous referee forhelpful comments and also thank Elizabeth Gold forhelping to improve the English throughout the manuscript.We further acknowledge post-doctoral research fundingfrom the Volkswagen Foundation (grant: I/83496 toJ.B.W.W.), the Swedish Research Council FORMAS(grant: 2008-1840 to J.L.) and the Swedish ResearchCouncil (grant: 2009-693 to N.B.), respectively.

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Speciation genetics: current status and evolving approaches

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