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Darwin and the Origin of Interspecific Genetic Incompatibilities.
Author(s): Daven C. Presgraves
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Source: The American Naturalist, Vol. 176, No. S1, Darwinian Thinking: 150 Years after The
Origin A Symposium Organized by Douglas W. Schemske (December 2010), pp. S45-S60
Published by: The University of Chicago Press for The American Society of Naturalists
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vol. 176, supplement
the american naturalist
december 2010
Darwin and the Origin of Interspecific
Genetic Incompatibilities
Daven C. Presgraves*
Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts 02138
abstract: Darwin’s Origin of Species is often criticized for having
little to say about speciation. The complaint focuses in particular on
Darwin’s supposed failure to explain the evolution of the sterility
and inviability of interspecific hybrids. But in his chapter on hybridism, Darwin, working without genetics, got as close to the modern understanding of the evolution of hybrid sterility and inviability
as might reasonably be expected. In particular, after surveying what
was then known about interspecific crosses and the resulting hybrids,
he established two facts that, while now taken for granted, were at
the time radical. First, the sterility barriers between species are neither
specially endowed by a creator nor directly favored by natural selection but rather evolve as incidental by-products of interspecific
divergence. Second, the sterility of species hybrids results when their
development is “disturbed by two organizations having been compounded into one.” Bateson, Dobzhansky, and Muller later put Mendelian detail to Darwin’s inference that the species-specific factors
controlling development (i.e., genes) are sometimes incompatible. In
this article, I highlight the major developments in our understanding
of these interspecific genetic incompatibilities—from Darwin to Muller to modern theory—and review comparative, genetic, and molecular rules that characterize the evolution of hybrid sterility and
inviability.
Keywords: Darwin, speciation, hybrid incompatibility, postzygotic
isolation.
The importance of the fact that hybrids are very generally
sterile, has, I think been much underrated by some late writers.
On the theory of natural selection the case is especially important, inasmuch as the sterility of hybrids could not possibly
be of advantage to them, and therefore could not have been
acquired by the continued preservation of successive profitable
degrees of sterility. I hope, however, to be able to show that
sterility is not a specially acquired or endowed quality, but is
incidental on other acquired differences. (Darwin 1859, p. 245)
* Present address: Department of Biology, University of Rochester, Rochester,
New York 14627; e-mail: [email protected].
Am. Nat. 2010. Vol. 176, pp. S45–S60. 䉷 2010 by The University of Chicago.
0003-0147/2010/176S1-51450$15.00. All rights reserved.
DOI: 10.1086/657058
Introduction: A Strange Arrangement
Despite its title, Darwin’s (1859) great book never really
solved “that mystery of mysteries”—the origin of species.
Or so it is often said. Shortly after The Origin appeared,
none other than Darwin’s bulldog, T. H. Huxley (1894),
complained that it had failed, in particular, to adequately
explain the origins of hybrid sterility. Selective breeding
of domesticated varieties, Huxley noted, had replicated all
of the key evolutionary phenomena—mutation, heredity,
response to selection—but one: no breeder, starting from
a single progenitor, had ever produced varieties that when
crossed gave rise to sterile hybrids. For Huxley, this was
a serious problem. The worry was echoed 60 years later
by William Bateson (1922, p. 58), who confessed that “that
particular and essential bit of the theory of evolution which
is concerned with the origin and nature of species remains
utterly mysterious.”1 Neither Darwin, Huxley, nor Bateson
advocated a sterility test to determine species status because from “the ascertained facts on the intercrossing of
plants and animals, it may be concluded that some degree
of sterility, both in first crosses and in hybrids, is an extremely general result; but that it cannot, under our present state of knowledge, be considered as absolutely universal” (Darwin 1859, p. 254). But, as Huxley (1894)
argued, it hardly mattered that not all species pairs are
isolated by hybrid sterility—so long as even one species
pair is, any theory that fails to explain it must be considered incomplete. For Huxley and Bateson, then, the sterility of species hybrids stood as one of the great unsolved
problems in evolutionary biology. Indeed, until the prob1
In a provocatively titled address, “Evolutionary faith and modern doubts,”
made to the AAAS in 1921 (published in 1922), Bateson (1922, p. 61) offered
a frank assessment of what he regarded as the most pressing unsolved problems
facing evolutionary biologists. Recognizing the danger in this, he ended by
saying: “When such confessions are made the enemies of science see their
chance. … Let us then proclaim in precise and unmistakable language that
our faith in evolution is unshaken. … Our doubts are not as to the reality
or truth of evolution, but as to the origin of species, a technical, almost
domestic, problem. Any day that mystery will be solved.” William Jennings
Bryan and the prosecution in the Scopes trial would nevertheless use Bateson’s
remarks to question the value of a theory that could not, after all, explain
the origin of species (Weiss 2007).
S46 The American Naturalist
lem of hybrid sterility was solved, Bateson (1922, p. 59)
said, “we have no acceptable account of the origin of
‘species.’”
In the chapter on hybridism, Darwin’s (1859, p. 255)
chief objective was not to provide a full account of the
evolution of hybrid sterility but rather “to see whether or
not the rules [governing the sterility of first crosses and
their hybrids] indicate that species have specially been endowed with this quality, in order to prevent their crossing
and blending together in utter confusion.” (The sterility
of first crosses, unfortunately, conflates prezygotic and
postzygotic isolation: “The early death of the embryo is a
very frequent cause of sterility in first crosses” [Darwin
1859, p. 264].) From Darwin’s (1859) survey of crosses
between species, varieties, and their hybrids, several rules
emerged: among different crosses, the degree of sterility
graduates from zero to complete (p. 255); the fertility of
the first cross and of hybrids depends largely on systematic
affinity (p. 256); hybrid males are most liable to suffer
sterility (p. 265); species that are difficult to cross generally
produce sterile hybrids, but in some cases species that cross
easily produce sterile hybrids, whereas in others species
that cross rarely produce fertile hybrids (p. 256); and hybrids from reciprocal species crosses often differ in fertility
(p. 258). The last observation, in particular, was especially
problematic for creationist-naturalists of the day: if hybrid
sterility was endowed by the creator to maintain the integrity of closely related species, then why make hybrids
sterile in only one direction of the cross? Darwin’s (1859,
p. 260) conclusion was firm: “Now do these complex and
singular rules indicate that species have been endowed with
sterility simply to prevent their becoming confounded in
nature? I think not.” Indeed, why, Darwin asked, was the
production of hybrids permitted at all?
To grant to species the special power of producing hybrids,
and then to stop their further propagation by different degrees
of sterility, not strictly related to the facility of the first union
between their parents, seems to be a strange arrangement.
(Darwin 1859, p. 260)
For Darwin, then, neither God’s design nor natural selection to maintain species boundaries explained the
messy, seemingly capricious rules of speciation. Instead,
the sterility barriers between species were not adaptive but
“incidental on other acquired differences” (Darwin 1859,
p. 245).
Developing a Genetic Theory for Hybrid
Sterility and Inviability
For it is scarcely possible that two organisations should be
compounded into one, without some disturbance occurring
in the development. (Darwin 1859, p. 266)
Darwin, of course, did not provide specifics on the genetic
basis of hybrid sterility and inviability. But he got as close
as one might, working as he did without Mendelian genetics. Hybrid sterility and inviability, he argued, result
from a hybrid’s “organization having been disrupted by
two organizations having been compounded into one”
(Darwin 1859, p. 266). While Darwin saw that natural
selection did not directly favor the evolution of hybrid
sterility, he saw no impediment to its incidental evolution
as a by-product of interspecific divergence. It was Bateson
(1909) who first realized that evolution at a single locus
could not result in hybrid sterility. Suppose two species
with genotypes aa and AA evolve from a common ancestor
with genotype aa, so that A arises and spreads in one
lineage (aa r Aa r AA) and no change occurs in the
other; their Aa hybrids cannot very well have been sterile
or else the A mutation, arising in a heterozygous state,
would never have spread in the first place. Bateson (1909)
immediately saw the solution to this conundrum but then,
it seems, promptly forgot or perhaps later doubted it (Orr
1996).
Some 30 years would pass before Dobzhansky (1934,
1937) and then Muller (1939, 1940, 1942), both apparently
unaware of Bateson’s forgotten solution (Orr 1996), would
arrive at the same model: hybrid sterility and inviability
result from incompatible epistatic interactions between
two or more complementary factors (fig. 1). Unlike the
single-locus case, incompatible interactions between loci
can evolve readily, unopposed by natural selection within
species (fig. 1). Just a few years earlier, Bonnier (1927)
had come close to proposing what is now known as the
Dobzhansky-Muller model, pointing out that aabb genotypes can evolve from AABB ones (AABB r aaBB r
aabb) unopposed by selection and then, when crossed with
AABB species, produce sterile AaBb hybrids due to an
incompatibility between A and b alleles. “But,” Bonnier
(1927, p. 140) wrote, “such intermediate genotypes [aaBB]
are not to be found in Nature among the kind of organisms
we are considering.” The lack of intermediate genotypes
led Bonnier (1927, p. 143) to dismiss the two-locus model
and “to assign the question as to the mode of occurrence
of new species to the sphere of quite unknown things.”
Hollingshead (1930) soon provided evidence for the missing intermediate genotypes in Crepis, showing that a hybrid inviability factor between Crepis tectorum and Crepis
capillaris was not only polymorphic but also mendelized:
some C. tectorum (LL) produced only lethal hybrids with
C. capillaris, some (ll) produced only viable hybrids, and
heterozygotes (Ll) produced one-half lethal and one-half
viable hybrids. In his Genetics and the Origin of Species,
Dobzhansky (1937, p. 255) cites Bonnier as one of those
“inclined to believe that the known genetic principles are
insufficient to account for [hybrid sterility and inviability]”
Darwin and Interspecific Incompatibilities S47
DMIs and concluded, among other things, the following:
DMIs accumulate gradually. Postzygotic isolation will
approach completeness as divergence between species, and
hence the number DMIs, increases (Muller 1942, p. 109).
To Muller, the open-ended accumulation of DMIs even
after reproductive isolation is complete proved that natural
selection did not directly favor postzygotic isolation, just
as Darwin (1859, p. 105) inferred. By formalizing the
Dobzhansky-Muller model and thus pioneering the modern theory of DMIs, Orr (1995) showed that the number
of DMIs not only increases but also accelerates as species
diverge. Between two species separated by K fixed differences, there are
()
K
2
Figure 1: The Dobzhansky-Muller model for the evolution of interspecific genetic incompatibilities. A, In Dobzhansky’s (1937) version, an
ancestral population with the two-locus genotype, aabb, splits into two
allopatric populations; a new mutation, A, arises and spreads to fixation
in one population (AAbb), and the B mutation does the same in the
second population (aaBB). The key to the model is that during their
entire evolutionary history, the derived A and derived B mutations have
never been combined in a single individual, and, consequently, their
genetic interaction has never been tested by natural selection. Thus, while
both mutations are individually neutral or beneficial on their own genetic
background, the A and B mutations may be incompatible when brought
together in a hybrid, causing sterility or inviability. In this case, the
incompatibility occurs between two derived alleles. B, In Muller’s (1942)
version, both substitutions occur in the same lineage so that in the case
shown, the B substitution occurs first in an aa genetic background, followed by the A substitution, which occurs in a BB genetic background.
Note that the derived A substitution has never been tested in combination
with the ancestral b substitution. In this case, the incompatibility occurs
between the derived A and ancestral b alleles.
before presenting his own version of the model with Crepis
as supporting evidence. It would appear that Dobzhansky
saw Bonnier’s misstep, how the Crepis work provided the
missing intermediate genotypes, and how the two-locus
model provided a feasible genetic basis for the evolution
of hybrid sterility and inviability.
While Dobzhansky (1934, 1937) first rediscovered and
popularized Bateson’s solution, it was Muller (1942) who
fully developed its implications in arguably the most important article ever written on the evolution and genetics
of interspecific incompatibilities (hereafter, DobzhanskyMuller incompatibilities, or DMIs). In the curiously titled
“Isolating mechanisms, evolution, and temperature,” Muller (1942) expanded on Darwin by surveying the comparative and genetic rules characterizing the evolution of
possible pairwise interactions, each with a probability p of
being incompatible. The expected number of incompatibilities, I, is thus
()
K p ≈ 1 K 2p.
2
2
(1)
The number of two-locus DMIs thus increases with the
square of, or snowballs with, the number of substitutions
fixed between species (Orr 1995; Orr and Turelli 2001).
Derived and ancestral alleles can contribute to DMIs. A
two-locus DMI can occur between two derived alleles (fig.
1A, A and B) or, as Muller (1942) noted, between a derived
allele and an ancestral allele (fig. 1B, A and b). Derived
ancestral DMIs evolve when both the A and the B substitutions are fixed in a single lineage, as in figure 1B;
Muller (1942, pp. 87–88) further saw that for these cases,
the causative substitutions must occur in a particular order
(in fig. 1B, the A substitution is permissible only after the
B substitution has occurred). Derived ancestral DMIs
might be expected if the A and B substitutions result from
coevolution among interacting loci (Cattani and Presgraves 2009). An A substitution, for instance, could increase the probability of a B substitution at an interacting
locus (Schlosser and Wagner 2008).
DMIs tend to be recessive. Muller (1942, p. 89) was the
first to suggest that Haldane’s (1922) rule—the preferential
sterility and inviability of interspecific F1 hybrids of the
XY (or ZW) sex—will result when recessive X-linked DMI
alleles are expressed in hemizygous (XY or ZW) hybrids
but masked in their heterozygous (XX or ZZ) hybrid siblings. Indeed, Haldane’s rule, along with the crude genetic
data available at the time, convinced Muller (1942, p. 99)
of “a large class of recessive complementary incapacitating
S48 The American Naturalist
genes, a class much larger than the dominants, which usually escapes observation, however, except where the gene
is in a sex chromosome, because of the indetectability of
(their) effects in the F1 generation.” Turelli and Orr (1995,
2000) have formalized what is now known as the dominance theory. Muller was careful to note that the dominance of deleterious DMI effects in hybrids says nothing
about the dominance of any possibly favorable effects of
the substitutions within species—the preponderance of recessive DMIs does not imply that adaptation involves recessive beneficial mutations.
DMIs can be complex. Muller (1942, p. 93) noted that
DMIs are often complex, so that “more than two genes
interact to produce the harmful result.” Cabot et al. (1994)
and, more formally, Orr (1995) argue that complex DMIs
should be common, as there are more viable and fertile
intermediate steps among the genotypic paths to the evolution of complex DMIs versus simple ones.
Large-effect DMIs cause asymmetric isolation. Muller realized that the asymmetric sterility or inviability of hybrids
from reciprocal crosses (termed “Darwin’s corollary” to
Haldane’s rule; Turelli and Moyle 2007) implicates asymmetrically transmitted DMI factors, like those on sex chromosomes or in the cytoplasm (Sturtevant 1920; Turelli and
Moyle 2007). He further realized, and Turelli and Moyle
(2007) have confirmed, that Darwin’s corollary implies
that species are often separated by a small number of largeeffect DMIs: “The difference in results of reciprocal crosses
must therefore be an expression of the high statistical error
to which the sampling of small numbers is subject. That
is, the effects in question were in the main dependent on
only a very few loci each which had considerable influence
on viability or fertility” (Muller 1942, p. 101).
DMIs can result from gene transposition. “By some types
of transfers in the position of genes, effects similar to those
of complementary genes can be produced in hybrid recombinants that come to contain the given gene in neither
position” (Muller 1942, p. 88). One way gene functions
can change position involves gene duplication, followed
by the neutral degeneration (or functional divergence) of
alternative, redundant duplicate gene copies (Werth and
Windham 1991; Lynch and Force 2000).
DMIs cause permanent reproductive isolation. Muller
(1942, p. 83) argued that geographic or ecological isolation
was important in facilitating divergence but often temporary: “Remove the outer source of discontinuity—bring
together again forms that have been separated by physical
barriers, or provide ecological bridges for those kept apart
only by their mode of life—and a reversal can often set
in if the isolation has not proceeded so far as to include
more deepseated bars to crossing.” Of the different kinds
of barriers between species, then—geographic or biological—intrinsic postzygotic barriers, while “very seldom a
primary step in isolation” (p. 84), are the ones that “effect
permanent genetic isolation in general” (p. 83). Once multiple DMIs have become established, causing complete
postzygotic isolation between species, there is no going
back.
What evolutionary forces cause DMIs to evolve? Like Darwin, Muller (1942) avoided speculating about the specific
forces driving the accumulation of DMIs, saying only that
they arise “as an automatic consequence of evolution in
general” (p. 103), with the causative substitutions coming
about “either through selection … or through mere accidental multiplication [drift]” (p. 102). Dobzhansky
(1937, p. 258) went further, calling our ignorance about
the properties of DMI genes within species “the weakest
point of the whole theory.”
Muller’s (1942) treatise marks a major turning point in
the development of a detailed genetic model of DMIs
(Johnson 2002), inspiring much of modern theory (Orr
1993b; Turelli and Orr 1995, 2000; Orr and Turelli 2001;
Turelli et al. 2001; Gavrilets 2003, 2004; Welch 2004; Turelli
and Moyle 2007). In the sections that follow, I will review
the comparative patterns, genetics, and molecular basis of
hybrid sterility and inviability in the light of three major
developments: Darwin’s chapter on hybridism, Muller’s
1942 article, and the new mathematical theory of DMIs.
I will conclude that Darwin got more right than he is often
credited with; that since Muller (1942), little has changed
in our thinking about the genetics of hybrid sterility and
inviability; and that emerging fine-scale and molecular genetic rules, while largely confirming Darwin and Muller,
have nevertheless revealed surprises that neither anticipated. In particular, the comparative, genetic, and molecular patterns characterizing the evolution of hybrid sterility
and inviability are best explained as by-products of recurrent genetic conflicts.
Comparative Rules
Postzygotic Isolation Accumulates Gradually
Now the fertility of the first crosses between species, and of
the hybrid produced from them, is largely governed by their
systematic affinity. (Darwin 1859, pp. 256–257)
The evolution of intrinsic postzygotic barriers between
species follows several comparative rules. First, confirming
Darwin’s inference, the strength of intrinsic postzygotic
isolation affecting F1 hybrids increases gradually, from zero
to complete, as species diverge from one another (fig. 2).
Table 1 summarizes comparative studies from plants,
fungi, insects, and vertebrates that show a positive relationship between the severity of hybrid fitness problems
and the genetic distance between parent species. The
Darwin and Interspecific Incompatibilities S49
Haldane’s Rule for Sterility versus Inviability
When in the F1 offspring of two different animal races one
sex is absent, rare, or sterile, that sex is the heterozygous sex.
(Haldane 1922, p. 101)
Figure 2: Postzygotic isolation speciation clock in Drosophila (Coyne and
Orr 1989a, 1997). The strength of postzygotic isolation increases with
genetic distance between species (each triangle represents a phylogenetically independent species pair). Similar relationships exist in fungi,
plants, vertebrates, and other insects (table 1).
roughly linear, clocklike accumulation of postzygotic isolation is consistent with any theory in which speciation
results from gradual genetic divergence between species.
As Coyne and Orr (1989a) conclude in their classic study
of patterns of speciation in Drosophila, the only theories
not consistent with these data are those predicting frequent
instantaneous speciation—and special creation.
While the generally linear accumulation of postzygotic
isolation might appear inconsistent with predictions of the
snowball theory, there are many reasons why comparative
data do not allow an appropriate test (Sasa et al. 1998;
Mendelson et al. 2004; Johnson 2006). The simplest and
most trivial reason is that the data are, in most cases, very
crude. Hybrid fitness data are typically gathered from literature spanning many labs and decades and then distilled
down to simple isolation indices. Second, once a species
pair is completely isolated, the continued accumulation of
DMIs post-speciation goes unregistered in comparative
data. Of several other reasons, the most important is that
the snowball theory predicts how the number of DMIs,
not the total strength of postzygotic isolation, increases
over time. Strength will reflect number only under the
unsafe assumption that DMIs tend to make individually
small contributions to the cumulative strength of isolation.
But comparative data suggest and genetic data show that
complete F1 hybrid sterility or inviability can often result
from one or a few strong DMIs. Consequently, there need
not be a strong correlation between the number of DMIs
and the strength of postzygotic isolation. Testing the snowball theory will therefore be difficult, as the relevant data
are genetic, not comparative.
As table 2 shows, Haldane’s rule is one of the strongest
patterns characterizing the evolution of intrinsic postzygotic isolation (Coyne and Orr 1989b, 2004; Coyne 1992;
Wu and Davis 1993; Turelli and Orr 1995, 2000; Wu et
al. 1996; Laurie 1997; Orr 1997; Gérard and Presgraves
2009). Comparative analyses show that Haldane’s rule for
sterility is an obligate, intermediate phase in the evolution
of complete postzygotic isolation in both male and female
heterogametic taxa: species pairs with intermediate genetic
distances and levels of postzygotic isolation are almost
always cases in which XY (or ZW) hybrids are sterile
(Coyne and Orr 1989a, 1997; Presgraves 2002; Price and
Bouvier 2002). The ubiquity of Haldane’s rule suggests
that common evolutionary or genetic causes may characterize the evolution of postzygotic isolation in a wide
range of taxa (Coyne 1992). The most general explanation
is the dominance theory: Haldane’s rule will result so long
as the alleles causing hybrid sterility and inviability are,
on average, partially recessive (Turelli and Orr 1995, 2000).
The power of the dominance theory is that it can explain
Haldane’s rule for sterility and inviability in both maleand female-heterogametic taxa. The limits of the dominance theory, however, become evident when hybrid sterility and hybrid inviability are contrasted. As table 2
shows, Haldane’s rule for sterility is much stronger than
that for inviability, especially in male-heterogametic taxa,
and evolves earlier during the time course of speciation
than does hybrid inviability. The evolutionary or genetic
factors contributing to hybrid sterility and hybrid inviability must therefore differ.
For starters, DMIs causing hybrid inviability, like lossof-function mutations within species, tend to affect both
sexes, whereas those causing hybrid sterility tend to be
sex-specific (Coyne 1985; Orr 1993a; Wu and Davis 1993).
But since many fewer loci are mutable to sex-specific sterility than to lethality within species, the faster evolution
of hybrid sterility requires one of two things: either
fertility-related genes diverge between species faster than
viability-essential ones or gametogenesis is more easily disrupted than viability in hybrids. Two models predict faster
divergence of fertility-related genes. First, the faster-male
theory posits that sexual selection drives the especially
rapid divergence of male-specific fertility-essential genes
between species (Coyne 1985; Orr 1993a; Wu and Davis
1993; Wu et al. 1996). Second, the drive theory posits that
recurrent genetic conflicts over transmission of the sex
chromosomes leads to arms races between selfish meiotic
S50 The American Naturalist
Table 1: Intrinsic postzygotic isolation increases with divergence between species
Taxa
Insects:
Drosophila
Lepidoptera
Stalk-eyed flies
Vertebrates:
Teleost fishes
Centrarchid fishes
Frogs
Toads
Birds
Birds
Pigeons and doves
Mammals
Fungi:
Microbotryum
Plants:
Glycine
Silene
Streptanthus
Orchids
Hybridizations
Postzygotic
isolation
increases
with
divergence?
Hybrid sterility
evolves before
hybrid inviability?
References
Sterility ⫹ inviability
Sterility ⫹ inviability
Sterility ⫹ inviability
171
212
8
Yes
Yes
Yes
Yes
Yes
Yes
Coyne and Orr 1989a, 1997
Presgraves 2002
Christianson et al. 2005
Sterility ⫹ inviability
Inviability
Sterility ⫹ inviability
37
130
116
Yes
Yes
Yes
Yes
NA
Yes
Sterility ⫹ inviability
Inviability
Sterility ⫹ inviability
Inviability
Inviability
680
36
254
21
31
Yes
Yes
Yes
Yes
Yes
NA
NA
Yes
NA
NA
Russell 2003
Bolnick and Near 2005
Sasa et al. 1998; see also
Wilson et al. 1974
Malone and Fontenot 2008
Prager and Wilson 1975
Price and Bouvier 2002
Lijtmaer et al. 2003
Wilson et al. 1974; Fitzpatrick 2004
Yes
NA
de Vienne et al. 2009
Yes
Yes
No
Yes
NA
NA
NA
No
Moyle et al. 2004
Moyle et al. 2004
Moyle et al. 2004
Scopece et al. 2008
Hybrid fitness problem
Inviability
Sterility
Sterility
Sterility
Sterility ⫹ inviability
20
29
61
136
Note: NA p no statistical test for selection available.
drive elements and their suppressors (Hall 2004) that, in
turn, cause perpetual divergence of genes affecting gametogenesis (Frank 1991; Hurst and Pomiankowski 1991a;
Henikoff et al. 2001; Tao et al. 2001; Presgraves 2008a).
There is a critical difference between the two models.
Faster-male evolution should contribute to Haldane’s rule
for sterility in male-heterogametic taxa but hinder it in
female-heterogametic ones. The comparative data, however, show that Haldane’s rule for sterility not only is
strong in female-heterogametic taxa but also, at least in
Lepidoptera, evolves as fast as in male-heterogametic ones
(Presgraves 2002; Price and Bouvier 2002). The drive theory, on the other hand, predicts faster evolution of fertilityrelated genes in male- and female-heterogametic taxa and
thus contributes to Haldane’s rule for sterility in both
(Hurst and Pomiankowski 1991a; Laurie 1997; Tao and
Hartl 2003). This is the first hint that evolutionary conflict
involving selfish genes may play an important role in the
evolution of intrinsic postzygotic isolation. The implication of the drive theory of Haldane’s rule, if true, is that
genetic conflict generally, and meiotic drive specifically, is
a more pervasive force than previously imagined.
Darwin’s Corollary
It is also a remarkable fact, that hybrids raised from reciprocal
crosses, though of course compounded of the very same two
species … generally differ in fertility in a small, and occasionally in a high degree. (Darwin 1859, p. 258)
Table 3 updates and quantifies Darwin’s corollary, the observation that reciprocal hybrids often differ in their degree
of sterility or inviability. The simplest explanation for this
asymmetry is that reciprocal hybrids are not genotypically
identical. Reciprocal hybrids can differ for any number of
uniparentally inherited factors, such as sex chromosomes,
maternal factors, and cytoplasmic organelles. Perhaps the
best-characterized example involving sex chromosomes is
the hybridization between Drosophila melanogaster and
Drosophila simulans: hybrid females from D. melanogaster
mothers are viable, but those from D. simulans mothers
are killed by a dominant factor on the D. melanogaster X
chromosome that is incompatible with a D. simulans maternal factor(s) (Sturtevant 1920; Sawamura et al. 1993a,
1993b). In addition to these common asymmetrically inherited factors, angiosperm embryos also rely on a nutri-
Darwin and Interspecific Incompatibilities S51
Table 2: Haldane’s rule
Taxa, sex determination,
and sterility/inviability
Drosophila:
XY/XX:
Sterility
Inviability
Mammals:
XY/XX:
Sterility
Inviability
Anopheles:
XY/XX:
Sterility
Inviability
Aedes:
XX/XX:
Sterility
Inviability
Lepidoptera:
ZW/ZZ:
Sterility
Inviability
Birds:
ZW/ZZ:
Sterility
Inviability
Haldane’s rule
(XY or ZW
sex afflicted)
Exceptions
(XX or ZZ
sex afflicted)
Proportion
obeying
Haldane’s rule
199
14
3
9
.99
.61
Wu and Davis 1993
Wu and Davis 1993
25
0
0
1
1.00
.00
Wu and Davis 1993
Wu and Davis 1993
56
21
0
3
1.00
.88
Presgraves and Orr 1998
Presgraves and Orr 1998
11
1
0
1
1.00
.50
Presgraves and Orr 1998
Presgraves and Orr 1998
29
56
1
1
.97
.98
Presgraves 2002
Presgraves 2002
72
21
3
2
.96
.91
Price and Bouvier 2002
Laurie 1997
tive triploid (3N) endosperm during development that
arises from the union of a paternally transmitted haploid
genome (1N) and a maternally transmitted diploid one
(2N). As DMIs that disrupt endosperm development in
hybrids can cause inviability of hybrid seeds, this additional layer of potential DMIs may explain why asymmetry
appears to be more common in plants than in animals
(table 3). The very existence of Darwin’s corollary, along
with direct evidence for large-effect DMIs from genetic
analyses, substantiates the concern that comparative data
on the strength of postzygotic isolation in F1 hybrids are
inappropriate for tests of the snowball theory.
Genetic Rules
We know virtually nothing about the genetic changes that
occur in species formation. (Lewontin 1974, p. 159)
Speciation is an old but still unsolved problem. (Nei 1987, p.
430)
The sad truth is that we know almost nothing about the genetics of species formation. (Hartl and Clark 1989, p. 587)
Until the mid-1980s, genetic analyses of intrinsic postzygotic isolation languished. Since then, however, there has
References
been an explosion of work on hybrid sterility and inviability, with the Dobzhansky-Muller model forming the basis of virtually all genetic analyses. In this section, I review
genetic estimates of the numbers and kinds of DMIs between species, their dominance, their distribution in the
genome, and the potential forces driving their evolution.
How Many DMIs?
Direct estimates of the number of DMIs separating two
species, and hence the rate at which DMIs accumulate,
remain scarce, as few fine-scale genome-wide analyses exist. The most high-resolution genome-wide screens for
DMIs come from two sets of hybridizations in Drosophila.
The first set involves crosses between Drosophila melanogaster and Drosophila simulans (Sturtevant 1920; Sawamura et al. 1993a, 1993b), which split from one another
∼3 million years ago. Although F1 hybrids from this species
cross are normally sterile or dead, hybrid rescue mutations
(Watanabe 1979; Hutter and Ashburner 1987) and the
genetic tools of D. melanogaster have allowed a thorough
dissection of lethal DMIs. These analyses suggest that ∼190
hybrid-lethal DMIs separate D. melanogaster and D. simulans (Coyne et al. 1998; Presgraves 2003). The second
set of genetic analyses involves the three species of the D.
S52 The American Naturalist
Table 3: Incidence of asymmetric postzygotic isolation
Taxon and hybrid
phenotype
Drosophila:
Hybrid male sterility
Hybrid female inviability
Anopheles:
Hybrid male sterility
Hybrid female inviability
Lepidoptera:
Hybrid female inviability
Centrarchid fishes:
Hybrid viability
Angiosperms:
F1 seed viability
Hybrid male sterility
Asymmetric
(%)
References
15
25
Coyne and Orr 1989a, 1997; Turelli and Orr 1995
Coyne and Orr 1989a, 1997; Turelli and Orr 1995
16
27
Presgraves and Orr 1998
Presgraves and Orr 1998
60
Presgraves 2002
6
45
35
Bolnick et al. 2008
Tiffin et al. 2001
Tiffin et al. 2001
Note: All data, except those for centrarchids, were compiled by Turelli and Moyle (2007).
simulans clade—D. simulans, Drosophila sechellia, and Drosophila mauritiana—which split from one another
∼250,000 years ago (Kliman et al. 2000; McDermott and
Kliman 2008). All pairwise crosses between these species
produce sterile hybrid sons but fertile hybrid daughters
(Lachaise et al. 1986). Introgression analyses (True et al.
1996; Tao and Hartl 2003; Tao et al. 2003a, 2003b; Masly
and Presgraves 2007) show that ∼15 different D. mauritiana regions cause complete hybrid male sterility (HMS)
when made homozygous in the genomes of its sister species, few (D. simulans) or no (D. sechellia) regions cause
hybrid female sterility, and few cause hybrid inviability
(Cattani and Presgraves 2009). Genetic analyses in plants
are also consistent with the faster accumulation of DMIs
that reduce hybrid male (pollen) fertility versus other aspects of hybrid fitness (Moyle and Graham 2005; Moyle
and Nakazato 2008).
The Dominance of DMIs
The same genetic analyses allow tests of the dominance
theory. For two-locus DMIs, there are three kinds of incompatible interactions: those in which the incompatible
effects of both alleles are dominant (denoted H0, following
Turelli and Orr 2000), those in which one is dominant
and the other recessive (H1), and those in which both are
recessive (H2). Between D. melanogaster and D. simulans,
there are no H0 DMIs (but see Barbash et al. 2000), ∼22
H1 DMIs (H1), and ∼169 H2 DMIs (Presgraves 2003).
These results confirm Muller’s (1942, p. 99) inference that
there must be “a large class of recessive complementary
incapacitating genes, a class much larger than the dominants, which usually escapes observation.” The genetic
analyses of D. mauritiana and its sister species provide
similar support for the dominance theory: there is not one
case of a fully dominant HMS factor (Tao and Hartl 2003).
But, while confirming the relative abundance of recessive
DMIs, these findings raise a new question. If Haldane’s
rule results from incompatibilities between recessive Xlinked factors and dominant autosomal ones, then why
are the dominant autosomal HMS factors missing from
introgression analyses? Chang and Noor (2009) may provide the answer: individually recessive autosomal HMS
factors can become partially dominant when co-introgressed into hybrids—that is, epistasis modifies the dominance of HMS factors.
Complexity of DMIs
Complex epistasis—in which a DMI involves three or
more loci—has been the rule for HMS for some time (Wu
et al. 1993; Wu and Hollocher 1998; Tao et al. 2003b). The
D. mauritiana allele of Odysseus (Odsmau), for instance,
causes complete HMS only when co-introgressed into D.
simulans with another D. mauritiana factor (Perez and Wu
1995). It is becoming increasingly clear, however, that
complex epistasis is the rule for hybrid lethality as well
(see below). In F1 hybrid males from D. melanogaster
mothers and D. simulans fathers, the wild-type D. simulans
allele of Lethal hybrid rescue (Lhrsim) causes lethality (Watanabe 1979), but expressing a Lhrsim transgene in a pure
D. melanogaster genetic background does not (Brideau et
al. 2006). These findings imply that additional factors are
required from D. simulans for Lhrsim to produce its lethal
effect. Why complex epistasis is the rule for DMIs is unclear (but see Cabot et al. 1994; Orr 1995).
Darwin and Interspecific Incompatibilities S53
Figure 3: The large X-effect for hybrid male sterility in Drosophila. Backcross hybrid male genotypes with chromosomes X, Y, 2, 3, and 4 are shown
(the small dot for 5 is not shown; white p Drosophila pseudoobscura chromosomes, black p Drosophila persimilis chromosomes; Orr 1987). The
percent of hybrid males with motile sperm is shown on the X-axis. Introduction of a foreign (D. persimilis) X chromosome reduces fertility far
more than does introduction of foreign autosomes.
The Large X-Effect
Dobzhansky’s (1936) groundbreaking backcross analysis
of DMIs in Drosophila—the first to show that HMS factors
localize to chromosomal regions—showed that the X chromosome has a disproportionately large effect on the fertility of hybrid males (Orr 1987). This large X-effect has
since been replicated in backcross analyses of hybrid sterility in other male-heterogametic taxa (e.g., Good et al.
2008) and in female-heterogametic taxa (reviewed in
Coyne and Orr 1989b; Coyne 1992; Presgraves 2008b).
While the large X-effect could imply that there is something special about the X chromosome during speciation,
its meaning and significance have been disputed. The reason is that in backcross analyses, the hemizygous effects
of a foreign X chromosome are usually contrasted with
the heterozygous effects of foreign autosomes (fig. 3). If
DMIs are generally recessive, then the effects of autosomal
ones will be mostly hidden and those on the X fully expressed (Wu and Davis 1993; Turelli and Orr 2000). Several
genetic analyses have nevertheless hinted at a higher density of HMS factors on the X (Naveira and Fontdevila
1986; True et al. 1996; Tao et al. 2003a), a finding now
confirmed by recent fine-scale genetic analyses that control
for introgression size: the density of HMS factors is approximately three or four times higher on the X than on
the autosomes (Masly and Presgraves 2007).
The high density of HMS factors, coupled with dominance, provides a proximate explanation for the large Xeffect, but why the X is a hot spot for hybrid sterility
remains unclear (Presgraves 2008b). The drive theory of-
S54 The American Naturalist
fers one (but not the only) explanation (Tao et al. 2003a;
Presgraves 2008b; Meiklejohn and Tao 2010). If X-linked
meiotic drive elements arise and spread to fixation more
readily than do autosomal ones, then species will tend to
accumulate functional divergence (and hence DMIs) at Xlinked loci affecting gametogenesis (Frank 1991; Hurst and
Pomiankowski 1991a; Tao and Hartl 2003). While the first
tests of the drive theory failed to turn up evidence of drive
in hybrid genotypes (Coyne 1986; Johnson and Wu 1992;
Coyne and Orr 1993), there are now several examples of
cryptic drive systems, suppressed within species but unleashed in species hybrids (Tao et al. 2007a, 2007b; Presgraves 2008a). Two of these show a clear association with
HMS. First, the D. mauritiana allele of Tmy, when homozygous in a D. simulans background, contributes to
HMS and exposes otherwise cryptic X chromosome drive
(Tao et al. 2001). Second, the genetic factors causing HMS
in F1 hybrid males from Drosophila pseudoobscura bogotana
mothers and D. p. pseudoobscura fathers also cause hybrid
meiotic drive (Orr and Irving 2005; Phadnis and Orr
2009). The rapid accumulation of HMS factors, their concentration on the X chromosome, and their occasional
association with meiotic drive phenotypes further implicate evolutionary conflict as a force in speciation.
Molecular Rules
Direct molecular evolutionary data now support one of the
central tenets of the neoDarwinian view of speciation—that
reproductive isolation results from natural selection within
species. This may well represent the most important finding
to emerge from the last decade of work on the genetics of
speciation. (Coyne and Orr 2004, p. 319)
Determining the molecular genetic basis of hybrid sterility
and inviability provides information on the functions of
DMI genes within species (and hence the development of
postzygotic isolation), as well as the forces driving their
divergence between species. Twelve speciation genes that
cause sterility or inviability in species hybrids have now
been identified (table 4). From this small but rapidly growing sample, tentative molecular genetic rules that characterize the evolution of DMIs are beginning to emerge.
First, 11 of 12 genes are protein-coding genes, with a scattershot of functions, from cell signaling to DNA binding
and modification. Second, of the eight genes for which
population genetic or molecular evolutionary analyses
have been performed, all show patterns of substitution
consistent with recurrent positive selection. These episodes
of positive selection occurred in one species’ lineage in
some cases (e.g., Ods, Ovd) but in both lineages in other
cases (e.g., Hmr, Lhr, Nup96, Nup160).
Why should two species living in different locations
often experience, at the same time during their short histories, recurrent bouts of adaptation at the same loci?
These patterns of substitution seem most consistent with
evolutionary conflicts that might be expected from antagonistic interactions of a host genome with its pathogens
and selfish genes. In Drosophila, the functions of some
DMI genes further suggest a role for conflicts involving,
specifically, the regulation of heterochromatin, viruses and
retrotransposons, and meiotic drive elements (Sawamura
and Yamamoto 1997; Brideau et al. 2006; Presgraves 2007;
Presgraves and Stephan 2007; Phadnis and Orr 2009; Bayes
and Malik 2009; Ferree and Barbash 2009; Tang and Presgraves 2009). In the clearest case, evolution at Ovd, a gene
causing hybrid sterility in F1 males between Drosophila
pseudoobscura bogatana and D. p. pseudoobscura, involved
the fixation of selfish substitutions that cause segregation
distortion (Phadnis and Orr 2009). The mouse HMS gene
Prdm9 appears to disrupt meiotic sex chromosome inactivation (MSCI)—the transcriptional silencing of the X (or
Z) chromosome in the germline of the XY (or ZW) sex
(Mihola et al. 2009). MSCI is thought to be a generalized
system for suppressing selfish elements on the sex chromosomes (Hurst and Pomiankowski 1991b; Tao et al.
2007b; Meiklejohn and Tao 2010). Thus, in Drosophila,
and possibly mouse, genetic conflict is emerging as an
important evolutionary force in the molecular evolution
of DMIs (table 5). Similar molecular arms races between
plants and their pathogens may drive the evolution of
incompatibilities among genes with immune functions
(Bomblies and Weigel 2007; Bomblies et al. 2007).
Not all DMIs are necessarily by-products of evolutionary conflict. As Muller (1939; 1942, pp. 88–89) pointed
out, DMIs can also result from the transposition of gene
function from one genomic address to another in different
lineages so that “the original and the transferred loci (or
rather, their ‘absences’) operate as complementary factors”; as in the Dobzhansky-Muller model, gene transposition “occurs in two steps, each individually innocuous
or nearly so: first, the addition of the gene or block of
genes in the new position … and second, the loss of one
or more of the genes in the old position [by gene mutation
or deficiency].” Lynch and Force (2000) developed population genetic theory for this plausibly neutral evolution
of DMIs via gene transposition, and in at least one case,
gene transposition has given rise to an interspecific DMI:
the Drosophila male fertility-essential gene JYalpha, located
on chromosome 4 in Drosophila melanogaster, has moved
to chromosome 3 in the Drosophila simulans clade species.
As a result, recombinant hybrid males homozygous for the
D. melanogaster third chromosome and D. simulans fourth
chromosome are sterile because they completely lack JYalpha (Masly et al. 2006). Similar gene transpositions appear
to contribute to lethal gene combinations segregating
JYalpha
Overdrive
Zygotic hybrid rescue
Hybrid male rescue
Lethal hybrid rescue
Nucleoporin96
Nucleoporin160
Ovd
Zhr
Hmr
Lhr
Nup96
Nup160
PR domain containing 9
kinase 2
M. m. domesticus
Mus musculus musculus/
Xiphophorus helleri
X. maculatus receptor tyrosine Xiphophorus maculatus/
S. cerevisiae/S. bayanus
S. bayanus/S. cerevisiae
D. simulans/D. melanogaster
D. simulans/D. melanogaster
D. simulans/D. melanogaster
D. melanogaster/D. simulans
D. melanogaster/D. simulans
D. p. pseudoobscura
D. pseudoobscura bogatana/
D. simulans/D. melanogaster
D. mauritiana/D. simulans
Species
Hybrid phenotype
F1 hybrid males
F2 hybrids
F2 hybrids
F2 hybrids
F2-like hybrids
F2-like hybrids
F1 hybrids
F1 hybrids
F1 hybrids
Hybrid sterility
Hybrid inviability
Hybrid sterility
Hybrid sterility
Hybrid inviability
Hybrid inviability
Hybrid inviability
Hybrid inviability
Hybrid inviability
17
X
Mito.
13
2
3
2
X
X
X
F1 hybrid males
Hybrid male sterility
4
X
Chrom.
Introgression hybrid males Hybrid male sterility
Introgression hybrid males Hybrid male sterility
Affected hybrids
Note: Chrom. p chromosome; mito. p mitochondrion; NA p no statistical test for selection available.
Prdm9
Xmrk2
Vertebrates:
ATPase ExPression
OLIgomycin resistance
AEP2
OLI1
Yeast (Saccharomyces):
Odysseus
JYalpha
Gene name
Ods
Drosophila:
Locus
Table 4: Hybrid incompatibility genes
positive
trimethyltransferase
Histone 3 lysine 4
Receptor tyrosine kinase
F0-ATP synthase subunit
Nuclear pore protein
Nuclear pore protein
DNA-binding
DNA-binding
Repetitive DNA
DNA-binding
activity
NA
Yes
NA
NA
Yes
Yes
Yes
Yes
NA
Yes
Yes
NA
DNA-binding
selection?
Na⫹/K⫹-exchanging ATPase
Molecular function
Evidence for
Mihola et al. 2009
Wittbrodt et al. 1989
Lee et al. 2008
Lee et al. 2008
Tang and Presgraves 2009
Presgraves et al. 2003
Brideau et al. 2006
Barbash et al. 2003
1997
Sawamura and Yamamoto
Phadnis and Orr 2009
Masly et al. 2006
Ting et al. 1998
References
S56 The American Naturalist
Table 5: Emerging molecular rules for DMIs in Drosophila
Gene
Hybrid
phenotype
Ods
JYAlpha
Ovd
Hmr
Lhr
Nup96
Nup160
Zhr
HMS
HMS
HMS
HI
HI
HI
HI
HI
Protein
coding
Complex
DMI
Positive
selection
Genetic
conflict
References
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Het
Yes
No
Yes
Yes
Yes
Yes
Yes
?
Yes
GTr
Yes
Yes
Yes
Yes
Yes
?
?
No
Yes
Yes
Yes
Yes
Yes
Yes
Ting et al. 1998; Bayes and Malik 2009
Masly et al. 2006
Phadnis and Orr 2009
Barbash et al. 2003
Brideau et al. 2006
Presgraves et al. 2003
Tang and Presgraves 2009
Sawamura and Yamamoto 1997; Ferree and Barbash 2009
Note: HMS p hybrid male sterility. HI p hybrid inviability. GTr p gene transposition. Het p heterochromatin.
within Arabidopsis (Bikard et al. 2009) and may have contributed to a burst of speciation in yeast (Scannell et al.
2006).
Conclusions
Darwin’s chapter on hybridism was a first attempt to synthesize the information available on the fitness of interspecific hybrids in plants and animals so that the rules
governing the sterility of hybrids might be inferred. From
Darwin’s survey, two general rules emerged. First, he recognized that the sterility of hybrids results from “two organizations having been compounded into one” (Darwin
1859, p. 266). Dobzhansky, and especially Muller, added
the Mendelian genetic details to Darwin’s intuition, and
modern genetic analyses confirm that hybrid sterility and
inviability are caused, by and large, by incompatible epistatic interactions. More than that, genetic analyses show
that DMIs tend to be complex, that the alleles involved
tend to be partially recessive, and that DMIs causing HMS
preferentially accumulate on the X chromosome. Second,
Darwin (1859) saw “that some degree of sterility, both in
first crosses and in hybrids, is an extremely general result”
(p. 254) and that interspecific sterility barriers must be
“incidental on other acquired differences” (p. 245). Darwin thus believed that speciation—at least when it involves
postzygotic isolation—occurs as a by-product of interspecific divergence. He might well have been satisfied by the
molecular genetic data, which show that hybrid sterility
and inviability evolve as by-products of recurrent positive
selection. But Darwin, Dobzhansky, and Muller might have
been surprised at the causes of selection. There is an
emerging consensus that the comparative, genetic, and
molecular rules characterizing the evolution of hybrid sterility and inviability are most consistent with pervasive,
recurrent conflicts between host genomes and their selfish
genes.
Two questions seem especially important as work on
hybrid sterility and inviability moves forward. First, the
case for conflict, while clear-cut for particular examples
(e.g., Ovd, Tmy), is far from certain. To further test the
veracity and generality of the conflict hypothesis, detailed
molecular characterization of more speciation genes from
a wider range of taxa—especially ZW ones—is needed.
Establishing the reasons why selection caused particular
DMI genes to diverge between species will, however, often
prove difficult. The reason is that selfish genetic elements
may frequently arise and run their course, spreading to
fixation or coming under the control of suppressors, and
ultimately leave no phenotype behind except sterility or
inviability in hybrids (Presgraves 2010). Second, the direct
evidence for natural hybridization (Grant and Grant 1992;
Presgraves 2002), the existence of hundreds of hybrid
zones (Barton and Hewitt 1985; Harrison 1993; Price
2008), and molecular population genetics analyses (Hey
2006) together suggest that gene flow between partially
reproductively isolated species may be common. Recent
whole-genome sequence analyses from multiple closely related species further suggest that speciation often may be
complex, involving hybridization and gene flow, and that
DMIs affect which regions of the genome can pass between
species and which cannot (Noor et al. 2001; Rieseberg
2001; Wu 2001; Wu and Ting 2004). The sex chromosomes
(Tucker et al. 1992; Llopart et al. 2005; Bachtrog et al.
2006; Putnam et al. 2007; Geraldes et al. 2008; Storchova
et al. 2009) and regions of the genome with low rates of
recombination (Turner et al. 2005; Noor et al. 2007; Carneiro et al. 2008), for instance, show especially reduced
propensity for gene flow between species. These patterns
are consistent with the higher density of (and hemizygous
selection against) DMIs on sex chromosomes and the
greater likelihood of linkage to DMIs for low-recombination regions (Noor et al. 2001; Rieseberg 2001). Going
forward, whole-genome studies that combine high-resolution mapping of DMIs with complementary population
genomics analyses of the history of speciation will be enormously valuable. The integration of fine-scale genomewide
mapping and population genomics data will put historical
inferences about the impact of DMIs on the cessation of
gene flow, and hence speciation, on solid footing.
Darwin and Interspecific Incompatibilities S57
Acknowledgments
D. Schemske and two anonymous reviewers provided valuable comments on an earlier draft of this article. This
work was supported by funds from the Radcliffe Institute
for Advanced Study at Harvard University, the David and
Lucile Packard Foundation, the Alfred P. Sloan Foundation, the University of Rochester, and the National Institutes of Health (GM79543).
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Symposium Editor: Douglas W. Schemske