Heterosis via non-additive genetic effects
Understanding and predicting the fitness outcomes of outcrossing has
been a core ambition in biology since at least the
19th century, motivated by agriculture and artificial
breeding reports of high yield of hybrid offspring (reviewed in Crow
1987). Specifically, when highly inbred lines derived from individuals
within single or weakly differentiated populations are crossed,
F1 offspring commonly show “hybrid vigour” or
“outbreeding enhancement”, where values of focal phenotypic traits
exceed the mean across the parental lines, or even exceed the maximum
parental value (Burke & Arnold 2001, Crow 1987, Lynch & Walsh 1998).
These early findings fueled extensive study on “heterosis”, describing
[positive or negative] deviations of offspring phenotypic value from
the mid-parental phenotype expected under additive genetic effects
(Burke & Arnold 2001, Lynch & Walsh 1998; Box 1, Fig. 3). This work
has subsequently generated theoretical and empirical insights with
consequences well beyond their applications to agriculture.
In wild populations, positive heterosis is commonly observed as the
result of outbreeding with conspecifics that arrive or are artificially
translocated to alleviate inbreeding depression in highly inbred
populations (termed ‘genetic rescue’; Fig. 2; Derry et al. 2019,
Frankham 2015, Hoffmann et al. 2021, Ingvarsson 2001, Whiteley et al.
2015). These beneficial effects have been shown to span multiple
generations (Derry et al. 2019, Frankham 2016), leading to increased
population growth (e.g. Åkesson et al 2016) and rapid fixation of
immigrant’s genetic variants (e.g. Adams et al 2011). Here, heterosis
primarily reflects genetic dominance (Box 1, Fig. 3A,C), via
heterozygosity masking the consequences of deleterious recessive alleles
or via overdominance (Charlesworth & Willi 2009, Crow 1948, Lamkey &
Edwards 1999).
Meanwhile, at the other end of the spectrum of parental divergence,
hybrid offspring of crosses between distantly related populations,
including inter-(sub)species crosses, often show decreased fitness
(termed negative heterosis or outbreeding depression; Lynch 1991, Rhymer
& Simberloff 1996, Tallmon et al. 2004, Waser & Price 1989; Fig. 2).
While hybrid inviability or sterility may imply reproductive isolation
between lineages, these crosses often show imperfect isolation in the
F1 offspring or fitness reductions that are only
apparent in later generations (e.g. F2 and backcrosses).
This may allow introgression of locally maladaptive variants that can
lead to genetic or population extinction (Allendorf et al. 2004, Rhymer
and Simberloff 1996). These consequences are often caused by negative
effects of epistasis due to incompatibilities between highly diverged
genomes (genetic, intrinsic or Dobzhansky-Muller incompatibility; Box 1,
Fig. 3A,D) or by loss of within-lineage coadapted epistatic interactions
(Demuth & Wade 2005, Dobzhansky 1950, Edmands & Deimler 2004, Orr
1995, Rundle & Whitlock 2001).
Despite such broad generalisations, it is now clear that fitness
outcomes of interbreeding are far more complex. Crossing inbred lines
can cause decreased fitness in hybrid offspring (Derry et al. 2019,
Edmands 2007, Lynch 1991). Conversely, interspecific crosses may
commonly generate beneficial effects, that even last to the
F2 generation (Brice 2021). Furthermore, such crosses
can result in novel or transgressive phenotypes (i.e. outside of the
limits of parental phenotypes, e.g. best-parent heterosis) for fitness
and fitness-related traits in F1 offspring (Atsumi et
al. 2021, Grant & Grant 2010, Rieseberg et al. 1999). In turn,
transgressive phenotypes have been linked to increased adaptive
potential (Edelman & Mallet 2021), and increased ability of hybrids to
colonize new environments (Pfennig et al. 2016, Rius & Darling 2014).
Therefore, contrary to traditional expectations, crosses between either
inbred lines or highly divergent lineages may result in either negative
or positive effects.
This complexity in outcomes derives from two main facts. First, fitness
consequences depend on more than just the degree of genetic divergence
between parental lineages, but also on an axis of variation pertaining
to the degree of ecological (i.e. adaptive) divergence between the
parental lineages (Fig. 2). Here, fitness decreases with greater
divergence between the parental environments as a consequence of
genotype-environment mismatches, leading to extrinsic or ecologically
dependent incompatibility even at the lower end of the spectrum of
genetic divergence (Derry et al. 2019, Edmands & Deimler 2004, Rundle
& Whitlock 2001, Thompson et al. 2022a,b). Second, both positive or
negative heterosis can result from combinations of various genetic
effects, including dominance, under/overdominance and epistasis, as
outlined by traditional line-cross theory (Box 1; Boeven et al. 2020, Fu
et al. 2015, Guo et al. 2014, Kusterer et al. 2007, Lynch 1991, Lynch
and Walsh 1998, Mather & Jinks 1982, Shapira et al. 2014). Fitness
outcomes, therefore, may depend not on one of the genetic effects alone,
but on a balance between the relative magnitude of them, resulting in
outcomes that can be unique to individual crosses and contexts (e.g.
Armbruster et al. 1997).
In fact, fitness outcomes vary across traits that differ in underlying
genetic architecture, and change across filial generations, because of
changes in the magnitude of the different genetic effects (Burke &
Arnold 2001, Brice et al. 2021, Fox et al. 2004, Lamkey & Edwards 1999,
Lynch 1991, Roff & Emerson 2006, Rundle & Whitlock 2001, Rius &
Darling 2014, Zhang et al. 2021). For instance, fitness components are
often more affected by outcrossing than other traits (Whitlock et al.
2013), in line with findings that dominance and epistasis are more
common in life history than in morphological traits (Roff & Emerson
2006). In turn, fitness gains in F1 offspring can be
partially or entirely wiped out, or even reversed, in the
F2 or subsequent generations, due to reduced dominance
and increased epistatic interactions across filial generations (Box 1,
Fig. 3D). Similarly, gene-by-environment interactions may change the
relative magnitudes of genetic effects across rearing environments
experienced by the hybrid offspring (e.g. Fox et al. 2004). Finally,
loss of beneficial epistatic interactions that commonly arise from
adaptive ecological differentiation (e.g. Carroll et al. 2003) can
outweigh benefits of increased heterozygosity even for highly inbred
populations in an environment-dependent manner (Edmands 2007, Frankham
et al. 2011; Fig. 2). Outcomes of outbreeding, therefore, are affected
by current environmental conditions experienced by the hybrid offspring,
and also by how the genetic architecture of traits have been shaped by
past evolutionary responses of the parental lineages.
A recent model of speciation (Dagilis et al. 2019) further emphasizes
the complexity in fitness outcomes of outbreeding and how the balance
between positive and negative effects connects the extremes of the
genetic and ecological divergence continuum. Specifically, in addition
to negative epistatic interactions arising in hybrid offspring (i.e.
Dobzhansky-Muller incompatibilities), and loss of positive epistatic
interaction within lineages (i.e. breakdown of coadapted gene
complexes), Dagilis et al. (2019) allowed outcrosses to result in
positive epistasis and loss of negative epistasis. Under these
conditions, the same genetic effects can explain both positive and
negative heterosis along a continuum of genetic and ecological
divergence, as the balance between positive and negative epistatic
effects (i.e. the fitness of the hybrid offspring) changes across the
divergence continuum. Interestingly, the net balance between effects is
extremely variable in the early stages of lineage divergence, due to the
relative influence of drift and selection on focal loci (Dagilis et al.
2019). This is exactly the parameter space that demes within fragmented
wild populations typically occupy, highlighting the potential for
genetic effects to generate complex and dynamic forms of both positive
and negative heterosis following natural dispersal and outcrossing in
metapopulation systems.
Indeed, manifestation of heterosis does not require crosses between
highly diverged or inbred lines or demes, but can arise from crosses
among demes that show genetic structuring (i.e. population level
inbreeding) due to adaptive (i.e. ecological) divergence or independent
random fixation of alleles via genetic drift fostered by restricted
dispersal (Barton 2001, Chevin et al. 2014, Crow 1948, Fenster et al.
1997, Lamkey & Edwards 1999, Simon et al. 2018, Whitlock et al. 2000).
This scenario likely comprises most wild populations, since local
adaptation is common across natural systems (Hereford 2009, Leimu &
Fischer 2008) and genetic structure not only occurs in populations with
geographical separation, but also along clines or center-edge continuum
of distribution ranges (García-Ramos & Kirkpatrick 1997, Koski et al.
2019, Kottler et al. 2021). These empirical and theoretical developments
suggest that heterosis could be widespread or even ubiquitous in wild
systems, raising key questions of what fitness outcomes can - and
generally do - arise following crosses between populations with
intermediate degrees of genetic differentiation (Fig. 2).
Given that the same genetic effects shape the fitness of outcrossed
offspring across the biological spectrum of genetic divergence,
predictions regarding observed fitness outcomes of outcrossed offspring
resulting from natural immigration can be formulated. For example,
fitness consequences depend on the specific genetic architecture of a
trait within a population and between the pair of populations, and can
vary across life stages, sexes, and environments. Outcomes should
consequently not be universal across traits, across life stages, or
between sexes, and should vary among different pairwise combinations of
populations of the same species, or even when the same pairwise
combination experiences different environments. Yet, dominance effects
should be more pronounced as non-adaptive genetic divergence between
demes increases, generating a positive relationship between hybrid
fitness in the F1 generation and pairwise genetic
distance or divergence time between parental populations (Whitlock et
al. 2000).
However, interactions with the environment may affect predicted
outcomes. For instance, if dominance effects are environment-dependent,
relative fitness for F1 and F2 offspring
should vary across parental environments. If, instead, epistatic
interactions are environment-dependent, F1 and
F2 fitness should be similar across parental
environments, but environment-dependent effects should emerge in
reciprocal backcrosses (Dagilis et al. 2019, Rundle & Whitlock 2001).
In the context of natural dispersal between spatially structured
populations, backcrosses resulting from matings between
F1 and residents (i.e. B1 or
B2) will most likely live in the environment of the
parental population that composes most of their genome (i.e.
P1 or P2, respectively). Therefore, the
fitness of these backcrosses should be higher than that of the
F2 in these respective environments, due to effects of
both dominance and epistasis (Edmands & Deimler 2004, Rundle &
Whitlock 2001).
Finally, since coadapted gene complexes may play a big role in local
adaptation, epistasis may be stronger than dominance in cases of
ecologically driven divergence. For instance, populations may adaptively
evolve within-lineage positive epistatic effects that, if broken during
outbreeding, reduce the fitness of the hybrid offspring. Consequently a
negative relationship between hybrid fitness and genetic distance
between parental populations. Under such genetic architecture, fitness
gains via dominance in F1 offspring may be outweighed by
the loss of positive epistatic effects at larger genetic distances,
leading to an optimal intermediate crossing distance between lineages
(Lynch 1991, Price & Waser 1979; see also Fenster 1991). As beneficial
dominance effects decrease, and negative between-lineage epistatic
effects appear due to recombination, fitness declines for hybrids along
the divergence continuum may become particularly severe for the
F2 offspring and further recombinant generations. These
conclusions mirror those of simulations using line-cross theory, whereby
fitness of F1 and F2 offspring in
respect to the mid-parent value decline as epistasis becomes stronger
than dominance (Lynch 1991).
Overall, these theoretical developments reveal the degree to which
complex multigenerational fitness effects resulting from natural
immigration could arise, and provide tractable routes to predicting and
rationalising observed variation.