Chromosomal speciation: a reply

Donald R. Forsdyke  

Journal of Theoretical Biology (2004) 230, 189-196

Copyright held by Else vier Ltd.


1. Introduction 

2. Non-Genic Factors are Sub-Microscopic

3. Areas of Agreement and Disagreement

4. Are GC% Differences Primary?

5. GC% Differences Suppress Intragenomic Recombination

6. "The Problem of Simple Underdominance in Forsdyke's Model"

7. GC% as an Agency of Group Selection

8. Quantitative Factors

9. Conclusions

End Note (Nov. 2004)

End Note (Mar 2006)

End Note (Feb 2007)

End Note (Mar 2008)

End Note (Dec 2008)

End Note (Nov 2009)

End Note (Sept 2010)

End_Note_(Jan_2013)_ Non-Genic_Post-Zygotic_Reproductive_Isolation_in_Mice



End_Note_(Oct_2014)_ RNA_Virus_Evolution_and_Speciation

End_Note_(Nov_2014)_ Spyglass_or_Magnifying_Glass_Perspectives

End_Note_(Nov_2018)_ Further_support_from_Greig's_yeast_studies



The "genic" and the "non-genic" (chromosomal) hypotheses for the predominant mechanism by which species diverge into two have long been in contention. In 1998 Coyne and Orr attacked certain formulations of the chromosomal hypothesis on the grounds that they required macromutations (structural changes in chromosomes). In 1999 I replied that numerous independent micromutations (single DNA base changes) should suffice (GC% hypothesis). Kliman et al., with the support of Coyne and Charlesworth, have presented various counterarguments, to which the present paper responds with evidence that GC% differences are primary to genic differences and would operate by changing the structure of stem-loops extruded from duplex DNAs. Chromosomes attempting to align by means of complementary loop-loop interactions would fail if GC% differences exceeded a critical threshold. This would disrupt meiosis (hybrid sterility) and the parents of organisms with failed meiosis would be reproductively isolated from each other. If they could find new mates with which they were GC-compatible, then new species could emerge. The model leads to predictions consistent with several lines of evidence. The GC% version of the chromosomal hypothesis has a sound basis and deserves at least as much attention as its genic rival.

Keywords: Base composition; Chromosomal hypothesis; Genic hypothesis; Gene homostabilizing propensity; Non-genic hypothesis; Recombination; Speciation; Stem-loops

1. Introduction

Biological evolution proceeds linearly within a species until there is a branch into two species, each of which may then continue to evolve in linear mode [see End Note 2008]. A major source of controversy has been the question whether linear and branching evolution can both be explained by Darwinian natural selection acting upon gene products, or whether branching evolution requires another process that is, in its fundamentals, independent of gene products and natural selection. Is species survival fundamentally different from species arrival?

        In the latter half of the twentieth century the controversy coalesced around two figures, Richard Dawkins (advocate of natural selection and genes) and Stephen Jay Gould (advocate of hierarchical levels of selection involving an agency other than natural selection). This gained wide public attention as is related in popular texts such as The Evolutionists (Morris, 2001) and Dawkins vs. Gould (Sterelny and Turney, 2001). In 2002, after a two decade struggle with cancer, Gould in his posthumous The Structure of Evolutionary Theory appeared to withdraw an earlier view that there might be "a new and general theory of evolution emerging" (Gould, 1980):

"I do not, in fact and retrospect -- regard this 1980 paper as among the -- most cogent -- that I have ever written. -- I then read the literature on speciation as beginning to favor sympatric alternatives to allopatric orthodoxies -- and predicted that views on this subject would change substantially, -- . I now believe that I was wrong in this prediction."

     In some quarters Gould's demise may be seen as marking the demise of the non-genic viewpoint (Kitcher, 2004). However, apparently unknown to Gould, in various laboratories including my own, bioinformatic analyses of the vast amounts of sequence information that emerged in the 1990s had yielded what seemed an independent affirmation. Some members of the genic community took notice and a "commentary" was provoked (Kliman, Rogers and Noor, 2001).

     The commentary by Kliman et al. in 2001 of "Forsdyke's chromosomal viewpoint" on the initiation of speciation (Forsdyke, 1996, 1999) would, I hoped, have been effectively dealt with by my book published later that year (Forsdyke, 2001). But a member of the Advisory Board of the
Journal of Theoretical Biology has recently reviewed the book, citing with approval the paper of Kliman et al. (Charlesworth, 2003). Accordingly, a reply to the commentary with an updating of references may now be in order.

2. Non-Genic Factors are Sub-Microscopic

      The non-genic "chromosomal" viewpoint on speciation has a long history that, to my reading of the literature, can best be considered as beginning with George Romanes (1886). Indeed, the classic dual between Alfred Wallace and Romanes in the 1880s covered much the same ground as that between Dawkins and Gould (Forsdyke, 2004a; Smith, 2004). The non-genic torch was borne through the twentieth century by some of the most able biologists of our times - William Bateson, Nicolai Kholodkovskii, Richard Goldschmidt, Cyril Darlington, Addison Gulick, Gregory Bateson, Michael White, Max King, and Stephan Jay Gould. Romanes and Bateson were both convinced of the importance of what we would now call "non-genic" factors, but were reluctant to specify a chromosomal location (Forsdyke, 2001). The role of the chromosomes was made explicit by Kholodkovskii and the Russian school (Krementsov, 1994), a view adopted by all who followed.

      As first formulated, the chromosomal viewpoint was particularly vulnerable to criticism (Coyne and Orr, 1998) since it postulated that large, often microscopically visible, chromosomal differences ("macromutations") would be evident early in the speciation process. These would inhibit the meiotic pairing of homologous chromosomes so that recombination would be inhibited and the hybrid would produce fewer and/or maldeveloped gametes (hybrid sterility). Thus, the parents of the hybrid would be reproductively isolated form each other. In contrast, Goldschmidt (1940) postulated sub-microscopic changes ("micromutations") that we can now interpret at the level of individual bases. My bioinformatic analyses emphasized the role of differences in Chargaff's species-specific component of the base composition, GC% - an agency that earlier scholars could only refer to in abstract terms (Forsdyke, 2003).

3. Areas of Agreement and Disagreement

      Coyne and Orr (1998) considered "the question of whether postzygotic isolation in animals is based on chromosomal or genic differences" and listed five major criticisms of "chromosomal speciation," which I addressed in my 1999 paper. The paper of Kliman et al. (2001) that acknowledges the "helpful comments" of Coyne, and the review of Charlesworth (2003), seems to constitute the Drosophila community's latest response.

      We all agree that members of a species are so defined because they are reproductively isolated from members of other species. (When so inclined, even prokaryotes exchange nucleic acid best with their own kind; Radman and Wagner, 1993; Gratia and Thiry, 2003). We all agree that the question of the origin of species is essentially the question of the origin of reproductive isolation. We all agree that reproductive isolation can be achieved in a variety of ways, both genic and non-genic. However, we disagree on which of these ways is likely to have predominated over evolutionary time. This is an issue that cannot be settled by showing how reproductive isolation has been achieved in an individual, or even in several, case(s). The induction as to which form of reproductive isolation is the best candidate for having been the most usual origin of species must be made by looking at a large body of biological, genetical and biochemical evidence that relates to a variety of taxa.

      Related issues include the questions of the existence of hierarchical levels, and different units, of selection (Gould, 2002), and the question whether the mechanisms postulated for the type of group selection known as speciation are vulnerable to the same criticisms as are the mechanisms postulated for some other types of group selection (Wynne-Edwards, 1962; Maynard Smith, 1989). Not considered here is the question of the existence of some vital force not explicable by known laws of physics and chemistry (Driesch, 1914). Also not considered here is the argument that, despite disagreements, evolutionists should present a united front to the advocates of "creationism" and "intelligent design." Also not considered here is the argument that evolutionists should present a united front in order not to confuse other scientists who need to understand speciation although working in other fields. Sadly, these issues have been coloured by, sometimes ad hominem, attacks by members of the genic school on members of the non-genic school. Early targets were Romanes, Bateson and Goldschmidt (Forsdyke 2001, 2003). The most prominent modern target has been Gould (Morris, 2001; Sterelny and Turney, 2001; Forsdyke, 2004a).

4. Are GC% Differences Primary?

      For both Kliman et al. (2001) and Charlesworth (2003) a major stumbling block is that, between species that appear to have recently diverged, differences in GC% may seem neither substantial, nor primary. Is an observed GC% difference a cause (non-genic viewpoint) or consequence (genic viewpoint) of the initiation of divergence into distinct species? If a cause, how much difference is needed to initiate speciation, and what is the mechanism?
      The first evidence was provided by Sueoka's studies (
1961) in ciliates. He noted:

"DNA base composition is a reflection of phylogenetic relationship. Furthermore, it is evident that those strains which mate with one another (i.e. strains within the same 'variety') have similar base compositions. Thus strains of variety 1 --, which are freely intercrossed have similar mean GC content. -- If one compares the distribution of DNA molecules of Tetrahymena strains of different mean GC contents, it is clear that the difference in mean values is due to a rather uniform difference of GC content in individual molecules. In other words, assuming that strains of Tetrahymena have a common phylogenetic origin, when the GC content of DNA of a particular strain changes, all the molecules undergo increases or decreases of GC pairs in similar amounts."

Naboru Sueoka

    Recently diverged bacterial species also show early GC% differences, predominantly at third codon positions (i.e. at the codon position that, when changed, is least likely to change the encoded amino acid; Bellgard and Gojobori, 1999; Bellgard et al., 2001; Gupta and Ghosh, 2003). The case that such differences are primary has been strengthened by the demonstration of a plausible mechanism relating GC% differences to reproductive (i.e. recombinational) isolation. There is no one definitive model for recombination (Holliday, 1990).  But all models regard similarity between sequences as necessary for legitimate recombination, since a successful similarity search initiates the pairing of complementary strands of potentially recombining duplexes. Thus, all models associate sequence non-similarity with recombinational suppression. Among the various models there is one that implicates GC%. This model postulates that the similarity search is between stem-loop structures that must be extruded from classical Watson-Crick duplexes so that a mutual loop-loop "kissing" exploration, which precedes extensive strand pairing, can begin. A slight degree of negative supercoiling of DNA (the usual situation) would favour such extrusion. Small differences in stem-loop configurations should suffice to misalign loops and prevent pairing, so inhibiting recombination (Sobell, 1972; Wagner and Radman, 1975; Doyle, 1978).

      Since the ability to recombine is a general property of DNA, this model predicts that (i) stem-loop potential should be widely dispersed in the DNA of all species, (ii) at least by virtue of the base pairing in stems, Chargaff's parity rule (%A = %T, %G = %C) should apply, to a close approximation, to single-strands of DNA of all species, and (iii) the quantity of the strongest bonding Watson-Crick base pair (G and C) should be a critical determinant of the configuration of extruded stem-loop structures. These predictions are fulfilled (
Forsdyke, 2001). In particular, the energetics of stem-loop formation is very sensitive to extremely small fluctuations in GC% (Forsdyke, 1998). This implies that such small fluctuations would suffice to change stem-loop configuration and so prevent recombination.

      Thus, the present non-genic case rests on the facts that (i) GC% differences have been observed early in the speciation process, and (ii) there is a plausible mechanism by which small GC% differences inhibit recombination. Furthermore, although contested by Kliman et al. (2001), a variety of biological phenomena ("empirical data") lend themselves to interpretation in such terms ("post hoc evaluations of published data"). These include (i) large differences in the GC% of viruses that have a common host cell (Forsdyke, 1996, 1999), (ii) the cure of hybrid sterility by polyploidization (Winge, 1917; Goldschmidt, 1940), and (iii) Haldane's rule (Forsdyke, 2000, 2001).

      Of course, GC% differences can affect gene function, but this would be largely by affecting first and second codon positions. The non-genic hypothesis attaches most importance to changes in genomic regions that do not necessarily affect gene function (i.e. third codon positions, introns, extragenic DNA). Thirteen years before the discovery of DNA structure, this point was elegantly made by Goldschmidt (1940):

"Within the species the internal chromosomal pattern may slowly change in a series of steps without any visible effect on the genotype and without any accumulation of so-called gene mutations, small or large!"

Richard Goldschmidt. Photograph from the collection of Dr. Alan Cock.

Thus, stem-loop potential should be best developed in introns and extragenic DNA as, indeed, the evidence suggests (Forsdyke, 1995; Barrette et al., 2001; Bultrini et al., 2003). To regard "G+C differences in --flanking DNA" as producing "the reproductive isolation effect via Forsdyke's compositional model," is not to be shrugged off as a "special pleading" (Kliman et al., 2001).

5. GC% Differences Suppress Intragenomic Recombination

      Charlesworth (2003) notes:

"Studies of codon usage show that the mean GC contents of synonymous sites are often indistinguishable between related species (Kliman et al., 2001). This difficulty is recognized by Forsdyke, who suggests that GC content first diverges and the converges, thereby rendering his theory untestable."

Actually, there are many ways of testing based on a sound theory of why GC content might change during linear, non-divergent, evolution, so leading to the possibility of convergence of the GC% values of two species.

If GC% differences can suppress intergenomic recombination, then they should also be able to suppress intragenomic recombination (and vice versa). This has a long history, beginning with William's (
1966) definition of what we would now call a "selfish gene," not as a unit of function, but as a segment of DNA that "segregates and recombines with appreciable frequency."  The discovery of intragenomic differentiation of regions by virtue of differences in GC% led Wada and Suyama (1985) to conclude that each gene has a "homostabilizing propensity" so that "every base in a codon seems to work cooperatively towards realizing the gene's characteristic value of (G+C) content." Thus, for both prokaryotes and eukaryotes, each gene maintains a distinctive GC% that distinguishes it from other genes in the same genome (
Skalka, Burgi and Hershey, 1968; Wada et al. 1976; Vizard and Ansevin, 1976; Suyama and Wada, 1983; Bibb, Findlay and Johnson, 1984; Wada and Suyama, 1985, 1986; Wada, Suyama and Hanai, 1991). The temptation to link the ability of individual genes to resist recombination with other genes in the same genome, to their distinctive GC% values, was inescapable.

George C. Williams

Akiyoshi Wada. Photograph by Dennis Normile

George C. Williams Akiyoshi Wada

      Skalka et al. (1968) suggested that if base "composition and function are indeed related," then segments of relative GC% uniformity [i.e. segments demarkated from other segments by their characteristic GC%. DRF 2009] would appear "not to encourage recombination" between functional units. Wada et al. (1976) found it "hard, if not impossible, to believe" that the homostabilizing regions reflected a fundamental characteristic of the genetic code itself. Rather, the regions must play "an important part somewhere in the biological process within which the DNA is closely related -- recombination might be one possible process." The fact that duplicating genes often showed an early differences in third codon position GC%, rather than first and second codon position GC%, led Matsuo et al. (1994) to propose that GC% differences were an important "line of defence" against recombination between an original gene and its duplicate copy.

      On this basis it would be predicted that successful transposition of a gene of distinctive GC% to a region of a genome of different, but relatively uniform, GC%, would require that the gene accept mutations converting its GC% to that of the new host region. This is supported by recent studies of gene transposition from a non-recombining part of a sex chromosome to the pseudoautosomal region (Montoya-Burgos, Boursot and Galtier, 2003; Iwase et al., 2003). Overall, it is becoming clear that GC% is responsive to both intragenomic (genic), and intergenomic (species), demands. Indeed, we have found that in genomes of extreme GC% (high or low) there is a conflict, which is settled in favour of the genome (i.e. in favour of the species) rather than of the gene (Forsdyke, 2004b; S.-J. Lee, J. R. Mortimer and D. R. Forsdyke, unpublished work).

      Therefore it is quite plausible that intergenomic (non-genic) demands first dominate GC% as species diverge. This establishes post-zygotic reproductive isolation by virtue of hybrid sterility. Next, other post-zygotic, and prezygotic, isolating mechanisms (genic) come into effect, so that GC% becomes free to respond to intragenomic pressures. Finally these intragenomic pressures cause the GC% values of the diverged species to vary in a way that can, in some cases, lead to convergence. However, by this time the other post-zygotic mechanisms (hybrid inviability) and prezygotic mechanisms (e.g. mating incompatibilities) have made GC% differences between the two species irrelevant to their sustaining reproductive isolation.

6. "The Problem of Simple Underdominance in Forsdyke's Model"

      By "underdominance" (sometimes called "negative heterosis"; King, 1993) is meant that heterozygotes are less fit than parental homozygotes (e.g. hybrid sterility). If gene A were incompatible with its allele a, then heterozygotes Aa would be underdominant (decreased fitness relative to their parents). Accordingly, homozygous forms AA could not productively cross with homozygous forms aa. The forms would be reproductively isolated by this "speciation gene," and so could further develop into distinct species. However, a single initial mutation in a member of a healthy homozygote population (say AA) to Aa would be lost, so that a could not begin to become established in the population and aa homozygotes would not arise.

      A solution of this underdominance problem (Coyne and Orr, 1998) is to invoke multiple non-allelic incompatibilities, the simplest case being that with two "speciation genes" a and b that are incompatible. A healthy homozygous form might be AABB.  In one individual there might be a mutation to AaBB. In another individual there might be a mutation to AABb. Both heterozygous forms would be viable and further crossing could lead to forms AAbb and aaBB. However, hybrids between these forms would be incompatible.

      From this it is seen that a single genic change (e.g. a single base change in a first or second codon position) constitutes a problem for the genic hypothesis that is surmounted by postulating polygenic changes (involving at least two base changes in non-allelic genes). This argument leaves the genic speciation hypotheses in contention (i.e. on the table, for serious consideration). The same argument is less necessary for the non-genic GC% hypothesis, since GC% begins by supposing that one base change, although it would slightly affect GC%, would probably be insufficient to impair a similarity search between chromosomes. Again, in complete ignorance of GC%, Goldschmidt (1940) may have been close to the mark:

"The classical theory of the gene and its mutations did not leave room for any other method of evolution. Certainly a pattern change within the serial structure of the chromosome, unaccompanied by gene mutation or loss, could have no effect whatsoever upon the hereditary type and therefore could have no significance for evolution. But now pattern changes are facts of such widespread and, as it seems, typical occurrence that we must take a definite stand regarding their significance. -- The pattern changes are in themselves effective in changing the genotype without any change of individual genes. -- Point mutations have never been known to change the point-to-point attractions between the homologous chromosomes in the heterozygote. -- A repatterning of a chromosome may have exactly the same effect as an accumulation of mutations. -- The change from species to species is not a change involving more and more additional atomistic changes, but a complete change in primary pattern or reaction system into a new one, which afterwards may again produce intraspecific variation by micromutation."

 Thus, it can be supposed that two forms will progressively deviate in their respective GC% values (repattern their chromosomes) until some threshold is reached at which chromosomal mispairing is sufficient to activate "check-points" and disrupt meiosis (Page and Orr-Weaver, 1996).

      Kliman et al. (2001) recognize that "the general concept of underdominance can be applied to any unit of heredity in a diploid system," meaning genic or non-genic. Thus, it is stated that my "model may suffer from the same problems inherent in other models that require underdominance." They argue that the problem of "hybrid fitness reduction -- addressed at great length by population geneticists" is also a problem for my non-genic GC% model for hybrid fitness reduction. "The major theoretical problem" with my model is that it "requires deleterious mutations to rise in frequency in at least one of the incipient species." Thus, "the G+C model -- cannot easily get around the problem of underdominance. For there to be G+C divergence between species there must first be deleterious G+C variation within species."

      Without defining what they mean by "neutral," and seeming to imply that they are going some way towards solving the alleged underdominance problem of my model, they state that "heterozygozity within species could be nearly or effectively neutral as long as an arbitrary threshold of G+C divergence - which would be exceeded in interspecies heterozygotes - was not reached." It is not clear from this whether Kliman et al. are clearly distinguishing the conventional phenotype and the genome phenotype. They would not be alone if they are not. Agreeing with Romanes (1886), Ernst Mayr when referring in 1963 to what he called "the biological species concept" postulated that: "The most indispensable step in speciation is the acquisition of isolating mechanisms." However, Mayr continued: "Isolating mechanisms have no selective value as such until they are reasonably efficient and can prevent the breaking up of gene complexes. They are ad hoc mechanisms.

         Here, Mayr seems to have been thinking only of natural selection acting on the conventional phenotype.  But it is the genome phenotype that is primarily affected by the postulated differences in GC%, and there may be no accompanying change in the conventional phenotype (i.e. no deleterious conventional mutations). At the "threshold of G+C divergence" there would be deleterious mutations affecting the genome phenotype (e.g. changed stem-loop architecture) to an extent sufficient to suppress recombination. To this extent the mutations would not be "neutral" (Forsdyke, 2002). The hybrid would immediately be selected against in that gametogenesis would be impaired. Accordingly, the parents of that hybrid could immediately be recognized as being partially or completely reproductively isolated from each other.

     So achieving underdominance is a problem neither with the genic model, nor with my model - less so with my model. Perhaps Kliman et al. (2001) have the same problem as Darwin (1875):

"Take the case of any two species which, when crossed, produce few and sterile offspring; now what is there which could favour the survival of those individuals which happened to be endowed in a slightly higher degree with mutual infertility, and which thus approached by one small step towards absolute sterility? Yet an advance of this kind, if the theory of natural selection be brought to bear, must have incessantly occurred with many species, for a multitude are mutually quite barren."

This is sometimes called the paradox of negative heterosis. Of course, Darwin recognized that absolutely sterile individuals themselves survive. He was writing about hybrid sterility, not hybrid inviability. He meant that "the survival" of the lineage of a pair of individuals endowed "with mutual infertility" would not be favoured since they produce offspring that are themselves unable to produce offspring. The line could not continue. Thus, the healthy fertile parents of a healthy, but sterile, individual are reproductively isolated from each other. Kliman et al. (2001) seem to regard those mutations most likely to cause reproductive isolation as least likely to fix in populations. Here the concept of hierarchical levels of selection, that Gould (2002) struggled so valiantly to communicate, may help.

7. GC% as an Agency of Group Selection

      In the usual situation, when the speciation process begins Darwin's "two species" are a main species with many members and an incipient species with a few variant members. The healthy hybrid offspring formed when a member of the main species crosses with a member of an incipient species are usually discarded from the point of view of maintaining either lineage. Although phenotypically healthy, the offspring are genetically unfit (genotypically unhealthy) by virtue of their partial or absolute sterility. Their discardment reflects the fact that they belong neither to the main species, nor to the incipient species. There is then nothing that "could favour the survival of individuals" (i.e. the survival of individual lineages corresponding to a potentially incipient species) that have undergone changes in GC% leading towards "absolute sterility" (when crossed with members of the main species), save finding a GC%-compatible mate (i.e. another member of the same incipient species lineage that has undergone similar changes in GC%).

      Because the hybrids are sterile, the main species can be viewed as constituting a "reproductive environment" that moulds the genome phenotype by negatively selecting (by denying reproductive success to) variant organisms that attempt (by mating and producing healthy, fertile, offspring) to recross the emerging interspecies boundary. Thus, a species can positively select itself by negatively selecting variants (i.e. sterile hybrids are discarded). Should these variants find compatible mates, then they might accumulate as a new species that, in turn, would positively select itself by negatively selecting further variants. This would be "species selection," a form of group selection that many biologists have found hard to imagine. Indeed, Dawkins (1986), having scorned the "argument from personal incredulity," was obliged to resort to it when confronted with the possibility of species selection: "It is hard to think of reasons why species survivability should be decoupled from the sum of the survivabilities of the individual members of the species."

        When the latter sentence is parsed its logic seems impeccable. Yet, "the species" is the established main species, members of which imperil themselves only marginally, if at all, by mating with (denying reproductive success to) members of a small potentially incipient species. Thus, in reproductive interactions between a main and an incipient species, survivability of the main species, as a species, is coupled negatively to the sum of the survivabilities of individual members of the incipient species much more than it is coupled positively to the survivabilities of individual members of the main species. In this sense, main species survivability is coupled to the former survivabilities and decoupled from the latter survivabilities. Again, by individual survivabilities is meant, not just mere survival, but survival permitting unimpeded production of fertile offspring. Survival of members of an incipient species occurs not only when classical Darwinian phenotypic interactions are favourable (e.g. escape from a tiger), but also when reproductive interactions are favourable (e.g. no attempted reproduction with members of the main species). Tigers are a phenotypic threat. Members of the main species are a "reprotypic" threat (Forsdyke, 2001). 

      There is no dispute that the differential survival of groups of individuals (species), or of genes within individuals, operate through the differential survival of individuals. The dispute is over how, in the general case, groups of individuals survive to form a new species. The non-genic viewpoint is that individual members of a main species, which are involved (when there is an attempted crossing) in the denial of reproductive success to individual members of potential incipient species (that differ significantly in GC%), are like individual stones in the walls of a species fortress against which the reproductive arrows of potential incipient species become blunted and fall to the ground. Alternatively, the main species can be viewed as a Gulliver who barely notices the individual Lilliputian incipients brushed off or trampled in his evolutionary path. 
     Just as individual cells acting in collective phenotypic harmony constitute a Gulliver, so individual members of a species acting in collective "reprotypic" harmony constitute a species. That harmony is threatened, not by its own members, but by deviants that, by definition, are no longer members of the main species (since a species is defined as consisting of individuals between which there is no reproductive isolation). These deviants, differing in GC%, constitute potential incipient species that might one day pose phenotypic threats to the main species.

      It is true that a member of a main species that becomes irretrievably pair-bonded with a member of an incipient species (e.g. pigeons) will leave fewer offspring, so that both members will suffer the same fate (have decreased survivability in terms of number of fertile offspring). But, in the general case, one such infertile reproductive encounter with a member of an incipient species will be followed by many fertile reproductive encounters with fellow members of the main species. Much more rarely, a member of an incipient species may encounter a fellow incipient species member with which it can successfully reproduce (i.e. they have similar deviations in GC%). This is an essential precondition for species divergence.

8. Quantitative Factors

Kliman et al. (2001) correctly state that "the essence" of my hypothesis "is that subtle differences in G+C content of genetically similar individuals have a role in the hybrid sterility leading to speciation." We currently have no quantitative information allowing us to state what "subtle" means in terms of a GC% difference sufficient to activate meiotic checkpoints and cause a partial or complete impairment of gametogenesis. Thus, the quantitative studies of Kliman et al. (2001) of crosses between various Drosophila species which, as they note, have already begun to differentiate prezygotically ("it would be improper to call them incipient"), are of questionable relevance.

     Needed are more detailed in vitro biochemical studies of the enzymes of recombination, of their interactions with DNAs from different sources, and of meiotic checkpoint mechanisms (Page and Orr-Weaver, 1996). There should also be more introgression studies as described by Naviera and Maside (1998). The latter found their results "unexpected" and suggested that "a new paradigm is emerging, which will force us -- to revise many conclusions of past studies" (Forsdyke, 2001).

9. Conclusions

While asserting that the "genic model -- is far from a theory in crisis," Kliman et al. (2001) dismiss my non-genic model (Forsdyke, 1996, 1999) as mere "conjecture" that provides "a misleading account of the state of the field," and does not further "our understanding of the genetics of post-zygotic isolation." Calling for "quantitative analysis" and conceding only that the "G+C model cannot be explicitly ruled out," they imply that a chromosomal model based on GC% differences does not deserve a prominent place at the table of evolutionary discourse. 

      On the contrary, I have argued that the model, with a history spanning over a century, has been greatly strengthened by recent bioinformatic studies (Forsdyke, 2001). It is time for Coyne and Charlesworth to call off their "bulldogs" and concede that, however elegant, mathematical modelling without a sufficient appreciation of the number of variables, and their underlying chemistry, may not be productive. The GC% model should be taken seriously. Researchers, both old and new, should be encouraged to study it.


Queen's University hosts my web-pages, where full text versions of some of the cited references may be found.


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Bellgard, M. I., Gojobori, T., 1999. Inferring the direction of evolutionary changes of genomic base composition. Trends Genet. 15, 254-256.

Bellgard, M., Schibeci, D., Trifonov, E., Gojobori, T., 2001. Early detection of G + C differences in bacterial species inferred from the comparative analysis of the two completely sequenced Helicobacter pylori strains. J. Mol. Evol. 53, 465-468.

Bibb, M. J., Findlay, P. R., Johnson, M. W., 1984. The relationship between base composition and codon usage in bacterial genes and its use for the simple and reliable identification of protein-coding sequences.
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Dawkins, R., 1986.
The Blind Watchmaker. Longman Scientific, Harlow, pp. 38, 267.

Driesch, H. A. E., 1914.
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Doyle, G. G., 1978. A general theory of chromosome pairing based on the palindromic DNA model of Sobell with modifications and amplification.
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End Note (Nov. 2004)
In error, the title of section 5 of the published paper has "intragenic", not "intragenomic", as in this (correct) web-page copy of the paper. 
End Note (Mar 2006)
Growing evidence for speciation occurring in one geographical location ("sympatric speciation") adds indirect support to chromosomal models (see E. Pennisi in Science 311, 1372-3). Yet, most still seem to be seeking genic or hybrid (polyploid) explanations: 

Axel Meyer: "Sympatric events can now be detected with unprecedented certainty."

Michael Turelli: "It's less obvious that it's all allopatry all the time."

Giacomo Bernardi: "Evolutionary biologists are at last essentially agreeing that sympatric speciation is possible."


End Note (Feb 2007)  

Duncan Greig, summarizing over a decade's work by the Borts laboratory, concluded that "speciation genes do not play a major role in yeast speciation." Rather "simple sequence divergence is the major cause of sterility in F1 hybrids formed between S. cerevisiae and S. paradoxus." (PLOS Genetics 3, 281-286).

"In an earlier experiment we found that making diploid hybrids into allotetraploids completely restored the viability of their gametes, showing that sterilizing [genic] incompatibilities were absent. We therefore concluded that dominant genetic incompatibilities are not the cause of F1 gamete inviability."

      Greig's new paper showed "that recessive Dobzhansky-Muller speciation genes are unlikely to be responsible" for the defective gametes. This left open non-genic "chromosomal" hypotheses. Having excluded chromosomal rearrangements ("macromutations") Greig was left with "simple sequence divergence" (i.e. "micromutations" such as base substitutions). Since Greig believed that genic hypotheses were still "widely accepted," he found this result "surprising."


End Note (Mar 2008)  

In my opening sentence (Introduction) the phrase "within a species" incorrectly implies that linear evolution within a species (without branching) cannot also give rise to a new species. Actually, there can be a linear evolution from species to species, such that members of a new species B that had derived from species A would be unable to reproduce with members of species A were they still around. Since they are not still around there has been no branching. This is explained, hopefully more clearly, in our new Bateson biography (Click Here).


End Note (Dec 2008)

Having continued studies on the S. cerevisiae x S. paradoxus hybrids, Duncan Greig reviewed reproductive isolation in yeast in Heredity and remains surprised:
"The major cause of hybrid sterility is antirecombination - the inability of diverged chromosomes to form crossovers during F1 hybrid meiosis. Surprisingly, incompatibility between the genes expressed from different species genomes is not a major cause of F1 hybrid sterility, although it may contribute to reproductive isolation at other stages of the yeast life cycle."

The term "antirecombination" had been used decades earlier by Radman and his colleagues, and applied to phenomena in yeast by Borts et al. (2000). Greig asks:

"Is antirecombination important in other species barriers, or is yeast a special case?"

But he is careful not to go beyond his yeast data. On the other hand, studies of
S. cerevisiae x S. bayanus hybrids in Jun-Yi Leu's laboratory make a case for genic incompatibilities (Cell 135, 1065-1073).

End Note (Nov 2009)

When genomic GC% begins to differ from that of other members of a species it will affect certain genes before others. Since third codon positions respond most to GC-pressure, it is likely that codon-anticodon interactions will need "wobble" reading and/or that alternative isoacceptor tRNAs will increasingly be used. In the case of genes where rate of translation is not rate-limiting this will not matter. But eventually a gene (the rate of expression of which under some circumstance can be rate-limiting; e.g. "emergency" heat-shock proteins) will adapt to GC-pressure. There will be a selective pressure for increased expression of the alternative isoacceptor tRNAs, so changing the tRNA pool. Over time, other genes will then "come into line" by accepting mutations that create codons corresponding to the alternative tRNAs. Thus, GC-pressure will be assisted by "translation pressure," and the switch to a different genomic GC% will accelerate in the case of protein-coding genes. Perhaps reflective of this, from studies of codon choice in bacteria Hershberg and Petrov (2009) note that "identity of favored codons tracks the GC content of the genomes," and consider that selection "appears to be consistently acting in the same direction as the nucleotide substitution bias of genomes."

Hershberg R. & Petrov D. A. (2009) General rules for optimal codon choice. PLOS Genetics 5 (7) e1000556.

End Note (Sept 2010)  

Within a species GC base pairs in a duplex can mutate to AT base pairs and vice versa. If there is some intrinsic bias favouring, say, AT base pairs, so be it. Two groups report such a bias in bacteria. But the fact that between species there are wide differences in GC% means that some other factor is in play. Hershberg and Petrov (2010) invoke "natural selection and/or a natural selection-like process." Hildebrand et al (2010) conclude that "many, if not all, sites may be subject to natural selection in many bacteria," but are agnostic as to the cause. Reviewing these papers, Rocha and Feil (2010) suggest "we are facing a seismic shift of paradigm in molecular evolution" and admit the possibility (among many) of a role of GC% differences in speciation (citing Forsdyke 1996). However they argue opaquely that the latter "speciation and self recognition" hypothesis "does not explain why there are traces of pervasive selection only for GC." No further elaboration is offered.

Hershberg R. & Petrov D. A. (2010) Evidence that mutation is universally biased toward AT in bacteria. PLOS Genetics 6 (9) e1001115

Hildebrand F., Meyer A & Eyre-Walker A (2010) Evidence of selection on genomic GC-content in bacteria. PLOS Genetics 6 (9) e1001107.

Rocha EPC & Feil EJ (2010) Mutational patterns cannot explain genome composition: are there any neutral sites in the genomes of bacteria. PLOS Genetics 6 (9) e1001104.


End Note (Jan 2013)  Non-Genic Post-Zygotic Reproductive Isolation in Mice

A paper supporting a non-genic basis (involving non-coding DNA) for the hybrid sterility that separates two closely allied (recently diverged) mouse 'species,' comes from Forejt's Mouse Molecular Genetics Group, in Prague (Bhatacharyya et al. 2013). They conclude:

"We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis [failure of chromosome pairing] in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifest as pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit."

It is further proposed that the "sex-specific manifestation of asynapsis can explain the mechanism of Haldane's rule."

Bhattacharyya T,  Gregorova S, Mihola O, Anger M, Sebestova J, Denny P, Simecek P, Forejt J. (2013) Mechanistic basis of infertility of mouse intersubspecific hybrids. Proc. Nat. Acad. Sci. USA 

End Note (Feb 2013) Yeast Hybrid Incompatibility due to Sterility and Inviability  

Meibo Xu and Xionglei He (2011) carried out similar experiments as Greig (2007; see above).  They studied growth rate as a measure of hybrid viability, and sporulation as a measure of hybrid fertility. Yeast species (Sc and Sp) whose genomes had diverged about 15% were able to cross to produce functioning zygotes, but their incompatibilities then became apparent (thus they are defined as post-zygotically isolated independent species). Xu and He began by noting:

"In addition to genetic [genic] incompatibility, some confounding factors such as chromosomal translocation and sequence divergence may also reduce F1 hybrid fertility by disturbing meiosis. -- We are fully aware that, given the significant sequence divergence, any specific [genic] incompatibility identified from the two yeasts is more likely to be the aftermath, rather than the cause, of speciation."

To eliminate "confounding factors" such as sequence divergence, instead of F1 hybrids they studied F2 generation crosses (diploids resulting from the selfing of F1 gametes). These could have retained non-lethal genic incompatibilities, while carrying essentially identical homologous chromosomes (no sequence divergence). Thus, (as expected given 15% sequence divergence), since the initial divergence between the Sc and Sp lines, genic incompatibilities affecting meiosis had arisen, while genic incompatibilities affecting vegetative growth were still minor (i.e. "much stronger defects in sporulation than in clonal growth."). This result, interpreted as due to defects in meiosis-specific genes, did not exclude the possibility that differences in the DNA of the chromosomes that underwent meiosis in the F1 generation were the initiating cause of the speciation process.

Xu M, He X (2011) Genetic incompatibility dampens hybrid fertility more than hybrid viability: yeast as a case study. PLOS One 6, e18341.

End Note (June 2013) High Conservations of Synonymous Mutations  

In a burst of papers, several mathematical geneticists, having broken with the consensus view among geneticists that synonymous sites are under only weak selective constraint, have interpreted their results as indicating conservation of structure at the RNA level. Of course, structure conservation at the RNA level means that conservation is also at the DNA level of the corresponding genes. Which is primary and which is secondary? Since, as shown in these web-pages, DNA structure is well developed in non-genic regions and introns, it seems likely that conservation pressure rises primarily at the DNA level. This supports the view advanced in the above paper. Opting for "deep insights into the regulation of gene expression", Lawrie et al. (2013) hold that "a strong possibility remains that the function underlying the strong constaint at synonymous sites is related to mRNA structure":

"The strong constraint at synonymous sites in D. melanogaster -- represents a powerful force. -- This strength of selection is as strong or stronger as has been measured via population genetic techniques at any class of sites, including non-synonymous [amino acid changing] sites. -- While detectable within a population, these mutations are effectively lethal over evolutionary time."

"The underlying biological function disrupted by these [synonymous] mutations is unknown, but it is not related to the forces generally believed to be the principal actors shaping the evolution of synonymous sites."

Their observations are supported by Lind and Andersson (2013), who conclude that "the deleterious effects of synonymous mutations are not generally due to codon usage effects, but that mRNA secondary structure, is a major fitness constraint." 

Lawrie DS, Messer PW, Hershberg R, Petrov DA (2013) Strong purifying selection at synonymous sites in D. melanogaster. PLOS Genetics 9, e1003527.

Lind PA, Andersson DI (2013) Fitness costs of synonymous mutations in the rpsT gene can be compensated by restoring mRNA base pairing. PLOS One 8, e63373.

End Note (Oct 2014)  RNA Virus Evolution and Speciation

For more on recombination, speciation and questioning of neutral theory:  (Click Here)

End Note (Nov 2014)  Spyglass or Magnifying Glass Perspectives

Prejudice in analyzing different speciation models, especially by those favouring allopatric speciation, was noted by Johannesson (2010), who cited the distinction (Via 2009) between Spyglass and Magnifying Glass perspectives.

"As allopatric speciation is usually inferred from events distant in the past, and presumably under conditions that cannot be deduced from observing the resulting species in their current context, we may have to accept a poor resolution of the mechanisms that initiated separation into later independent evolutionary lineages (The Spyglass perspective). In contrast, sympatric speciation must be investigated at an incipient stage (the Magnifying Glass perspective), or soon thereafter, as the accumulation of genetic differences after the completion of sympatric speciation will efficiently hide the footprints of the mechanisms involved in isolation (with the exception of speciation through polyploidy)."

Both authors, being focused on speciation among complex organisms, failed to see the possibility that the "footprint" of speciation events might remain in simpler organisms that have not accumulated sufficient genomic differences to hide such footprints. In the papers in these webpages, the case is made that initially small GC% differences would be sufficient to prevent recombination between genomes. In today's retroviruses we may be seeing dramatic magnifications of these putative initiating differences.

Johannesson K (2010) Are we analyzing speciation without prejudice? Ann. N. Y. Acad. Sci. 1206, 143-149.

Via S (2009) Natural selection in action during speciation. Proc. Natl. Acad. Sci. USA 106, 9939-46. For video of Via's presentation at a Sackler Symposium celebrating the Darwin Centeniary Click Here

End Note (Nov 2018)  Further support from Greig's yeast studies

"Chromosomal mechanisms of speciation (including both rearrangements and sequence divergence) are often dismissed as unimportant because they generate underdominance [53]. Mutations that result in nondisjunction in heterozygotes (or hybrids) will be initially deleterious since rare mutants will predominantly mate with wild types. Consequently, these mutants should not rise to the frequency necessary to establish a new breeding population in which correct segregation occurs.

      We agree that underdominance reduces the likelihood of chromosomal mechanisms of speciation acting in obligately sexual organisms, which includes virtually all animals. However, underdominance is not necessarily a problem in facultatively sexual organisms, like yeast, in which a single mutant can rapidly establish a highly inbred population by clonal propagation. Although most speciation research is focused on obligate sexuality, facultative sexuality should not be ignored; many plants, most fungi, and nearly all unicellular eukaryotes are facultatively sexual, and this mode of reproduction is considered the ancestral state of all eukaryotes [54]. 

      Clearly, many mechanisms can contribute to postzygotic reproductive isolation, and how these mechanisms interact to drive speciation in yeast remains an open question [55,56]. Nevertheless, the importance - to speciation in facultatively sexual organisms, at least - of small amounts of sequence divergence should not be overlooked."

Rogers DW, McConnell E, Ono J, Greig D (2018) Spore-autonomous fluorescent protein expression identifies meiotic chromosome missegregation as the principal cause of hybrid sterility in yeast. PLoS Biol 16: e2005066.


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This page was established in June 2004 and last edited 13 Nov 2020 by Donald Forsdyke