Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

Diverse mechanisms contribute to the evolution of reproductive barriers, a process that is critical in speciation. Amongst these are alterations in gene products and in gene dosage that affect development and reproductive success in hybrid offspring. Because of its strict parent-of-origin dependence, genomic imprinting is thought to contribute to the aberrant phenotypes observed in interspecies hybrids in mammals and flowering plants, when the abnormalities depend on the directionality of the cross. In different groups of mammals, hybrid incompatibility has indeed been linked to loss of imprinting. Aberrant expression levels have been reported as well, including imprinted genes involved in development and growth. Recent studies in humans emphasize that genetic diversity within a species can readily perturb imprinted gene expression and phenotype as well. Despite novel insights into the underlying mechanisms, the full extent of imprinted gene perturbation still remains to be determined in the different hybrid systems. Here we review imprinted gene expression in intra- and interspecies hybrids and examine the evolutionary scenarios under which imprinting could contribute to hybrid incompatibilities. We discuss effects on development and reproduction and possible evolutionary implications.In many plants and animals, interspecific hybridization events yield offspring that are phenotypically different from either of the parent species. Such hybrids typically display developmental abnormalities and, in animals, often have reduced fertility or complete sterility, particularly in males. Hybrid incompatibilities arise because, although the parental species may be genetically similar, the genomes are still too divergent to sustain normal development, physiology and reproduction when mixed in the hybrid offspring (Wu and Ting, 2004). Extensive research has been performed on genetic incompatibilities in plant and animal hybrids (Ishikawa and Kinoshita, 2009; Johnson, 2010). Key loci have been mapped and characterized in experimental model species, providing important insights into the aberrant phenotypes such as male hybrid sterility (Maheshwari and Barbash, 2011).Phenotypic abnormalities in interspecies hybrids often differ greatly between the reciprocal crosses. The classic example of such an asymmetry is seen in reciprocal crosses between donkeys and horses, where both directions of the cross produce sterile offspring, but the gross phenotype of the progeny (that is, ‘mule'' versus ‘hinny'') depends on the direction of the cross. Horses and donkeys have a different chromosome number, but this cannot explain the differential hybrid phenotypes that depend on the direction of the cross (as the reciprocal crosses have the same autosomal karyotype). More than 50 years ago serum concentrations of a placental hormone were reported to be markedly higher in mule than in hinny conceptuses, suggestive of parental genome-specific gene expression (Allen, 1969).The North-American genus Peromyscus (‘deer mice'') has been studied extensively to explore hybrid incompatibilities in mammals (see Vrana et al., 1998). Also in interspecies hybrids in Mus (house mouse), between the sympatric species M. musculus and M. spretus, morphological differences are apparent between reciprocal hybrids (Zechner et al., 2004). These hybrid effects were observed in crosses between a mixed M. musculus domesticus strain and lab stocks of M. spretus. To be definitive about where the incompatibilities lie between M. musculus and M. spretus (or M. m. castaneus, see below), reciprocal crosses between several different wild-derived stocks (or wild caught animals) of M. musculus and M. spretus populations would be needed.

Table 1

Terminology and abbreviations

Mules	Progeny of a male donkey and a female horse
Hinnies	Progeny of female donkeys and male horses
Peromyscus	North-American genus of mice (‘deer mice'')
P. maniculatis (‘M'')	A species with polygamous mating behaviour
P. polionotus (‘P'')	Species with apparent monogamous mating behaviour
P × M	Hybrid produced by a female P. maniculatis paired with male P. polionotus
M × P	Hybrid produced by a male P. maniculatis paired with female P. polionotus
Mus musculus (‘MU'')	Widely studied mouse species
M. spretus (‘S'')	Species related to M. musculus, in the Mediterranean, that diverged over one million years ago
(MU × S) F1	Hybrid produced by a male M. musculus paired with a female M. spretus
(S × MU) F1	Hybrid produced by a female M. musculus paired with a female M. spretus
C57Bl/6J (‘B'')	A mixed M. M. domesticus laboratory mouse inbred strain
CAST/EiJ (‘C'')	M. M. castaneus laboratory mouse strain
Arabidopsis	Genus of small flowering plants of the mustard family (Brassicaceae)
A. thaliana, A. arenosa	Related Arabidopsis species used in imprinting studies
DMR	‘Differentially methylated region'': here, a sequence element with allele-specific CpG methylation
ICRs	‘Imprinting control regions'': essential regulatory DMRs, which have germ line-derived, mono-allelic DNA methylation and mediate imprinted gene expression in cis.
D–M model	Dobzhansky–Muller model
AmAp	Alleles derived from the mother and father, respectively

Open in a separate windowBesides other candidate mechanisms—such as the maternal inheritance of mitochondrial DNA and its interactions with the nuclear genome, or possible maternal effects (Turelli and Moyle, 2007; Johnson, 2010)—the epigenetic phenomenon of genomic imprinting is thought to be one of the contributors to the phenotypic differences between reciprocal hybrids. Genomic imprinting evolved convergently in flowering plants and mammals (Feil and Berger, 2007) and mediates mono-allelic expression at selected genes, in a parent-of-origin-dependent manner. Imprinted genes contribute to diverse processes in development and growth, including that of nourishing the extra-embryonic tissues (placenta in mammals/endosperm in plants). In mammals, imprinted genes also have important roles in brain development and function (Wilkinson et al., 2007).In interspecies hybrids, differences between the parental species in the genetic control and patterns of imprinting may have different effects dependent on the orientation of the cross, including epigenetic perturbation of imprinting control leading to ‘loss of imprinting'' (biallelic expression). Studies in mammals have provided clear evidence for perturbed imprinting in inter- and intraspecies hybrids (reviewed below). However, as many imprinted genes have been discovered in these same interspecies hybrids, and polymorphisms are necessary to identify allele-specific expression differences, it is possible that hybridization itself could induce imprinting depending on the location of the polymorphism(s) between strains, for instance in cis-acting elements.Crosses between different Arabidopsis species have provided evidence that perturbed imprinted gene expression occurs also in plant hybrids (Josefsson et al., 2006; Jullien and Berger, 2010). Particularly, the imprinted expression of MEDEA (MEA) and PHERES (PHE) in endosperm is perturbed in hybrids between A. thaliana and A. arenosa and this could contribute to the endosperm overgrowth seen in these hybrids (Josefsson et al., 2006). As ploidy was often altered in these existing studies, the results have been somewhat difficult to interpret considering the mechanisms involved (Walia et al., 2009; Jullien and Berger, 2010).Here we focus on the animal systems, which have provided most insights into imprinting in hybrids. We also discuss the extent to which intraspecies polymorphisms may perturb imprinted gene expression and hence phenotype.