Assessment and disease comparisons of hybrid developmental defects

Abstract

Rodents of the genus Peromyscus are among the most common North American mammals. Crosses between natural populations of two of these species, P. maniculatus (BW) and P. polionotus (PO), produce parent-of-origin effects on growth and development. BW females mated to PO males produce growth-retarded offspring. In contrast, PO females mated to BW males produce overgrown but dysmorphic conceptuses. Variation in imprinted loci and control of genomic imprinting appear to underlie the hybrid effects. Prior morphological and genetic analyses have focused on placental and post-natal growth. Here, we assess the frequency and scope of embryonic defects. The most frequent outcome of the PO x BW cross is death prior to embryonic day 13. Conceptuses lacking an embryo proper are also observed as in gestational trophoblast disease. Among the common embryonic phenotypes described and tabulated are edema, blood vessel enlargement/hemorrhaging, macroglossia, retention of nucleated erythrocytes, placentomegaly. We investigate expression of loci known to be mis-regulated in human growth/placental disorders and/or mouse knockouts with similar phenotypes. These loci are Igf2, Cdkn1c, Grb10, Gpc3, Phlda2 and Rb1. All exhibited significant differences in either placental or embryonic expression levels at one or more of the three timepoints examined. The data underscore the importance of placental gene expression on embryonic defects. We suggest that the hybrid defects offer a novel system to understand how natural allelic combinations interact to produce disease phenotypes. We propose that such interactions and their resulting epimutations may similarly underlie the phenotypic and causal heterogeneity seen in many human diseases.

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

“…Also in Peromyscus hybrids, expression levels are abnormally high at the growth-related Igf2, Grb10, Cdkn1c and Phlda2 genes (Duselis and Vrana, 2007). In humans, perturbed expression of IGF2 is involved in the fetal growth syndromes such as Beckwith-Wiedemann syndrome and SilverRussell syndrome (Hirasawa and Feil, 2010), and reduced expression of PHLDA2 is associated with increased birth weight (Ishida et al, 2012).…”

Adaptive genetic variation, stress and glucose regulation

“…Testing the effects of the reciprocal combination, a BW Y chromosome on a PO genetic background, is problematic. The difficulty in producing this genetic combination lies in the non-viability of offspring produced by PO females mated to BW males (Duselis and Vrana, 2007).…”

Aberrant Growth and Pattern Formation in Peromyscus Hybrid Placental Development1

“…Roughly half of all female PO 3 male BW breedings end in complete death of the litter by the time gestation is two-thirds complete [14,15]. Female PO 3 male BW hybrids that survive to late gestation display numerous developmental defects, many reminiscent of human syndromes [14].…”

“…Roughly half of all female PO 3 male BW breedings end in complete death of the litter by the time gestation is two-thirds complete [14,15]. Female PO 3 male BW hybrids that survive to late gestation display numerous developmental defects, many reminiscent of human syndromes [14]. Rare female PO 3 male BW litters that reach parturition typically result in maternal death because of an inability to pass the hybrid offspring through the birth canal [13].…”

“…The female bw 3 male po placentas average half the weight of those from the parental strains, while those of the female PO 3 male BW cross weigh about three times that of the parental strains. An additional portion (;10%) of female PO 3 male BW conceptuses lack any obvious embryonic structures [14]. These conceptuses typically resemble placental tissue and thus may be analogous to hydatidiform moles.…”