Haldane's rule in the placenta: Sex‐biased misregulation of the Kcnq1 imprinting cluster in hybrid mice

Abstract

Hybrid phenotypes that contribute to postzygotic reproductive isolation often exhibit pronounced asymmetry, both between reciprocal crosses and between the sexes in accordance with Haldane's rule. Inviability in mammalian hybrids is associated with parent‐of‐origin placental growth abnormalities for which misregulation of imprinted gene (IGs) is the leading candidate mechanism. However, direct evidence for the involvement of IGs in hybrid growth dysplasia is limited. We used transcriptome and reduced representation bisulfite sequencing to conduct the first genome‐scale assessment of the contribution of IGs to parent‐of‐origin placental growth dysplasia in the cross between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus). IGs with transgressive expression and methylation were concentrated in the Kcnq1 cluster, which contains causal genes for prenatal growth abnormalities in mice and humans. Hypermethylation of the cluster's imprinting control region, and consequent misexpression of the genes Phlda2 and Ascl2, is a strong candidate mechanism for transgressive placental undergrowth. Transgressive placental and gene regulatory phenotypes, including expression and methylation in the Kcnq1 cluster, were more extreme in hybrid males. Although consistent with Haldane's rule, male‐biased defects are unexpected in rodent placenta because the X‐chromosome is effectively hemizygous in both sexes. In search of an explanation, we found evidence of leaky imprinted (paternal) X‐chromosome inactivation in hybrid female placenta, an epigenetic disturbance that may buffer females from the effects of X‐linked incompatibilities to which males are fully exposed. Sex differences in chromatin structure on the X and sex‐biased maternal effects are nonmutually exclusive alternative explanations for adherence to Haldane's rule in hybrid placenta. The results of this study contribute to understanding the genetic basis of hybrid inviability in mammals, and the role of IGs in speciation.

Bidirectional Introgression between Mus musculus domesticus and Mus spretus

“…F1 male sterility is due to lack of spermatozoa ( Pelz and Niethammer 1978 ). Placentas of female F1s are hyperplasic when backcrossed with M. musculus and hypoplasic when backcrossed with M. spretus ( Zechner et al 1997 ), resulting in a moderate reduction in the viability of hybrid conceptuses ( Arévalo et al 2021 ). In light of these barriers to gene flow, the observation of low levels of introgression across the genome serves as a reminder that even good “biological species” may have semipermeable genomes.…”

The genomic consequences of hybridization

“…One well-established example is the observation that introgression is reduced on the sex chromosomes, presumably because DMIs are overrepresented on the sex chromosomes, due to factors such as faster X evolution, meiotic drive, and the importance of X chromosome genes in male fertility ( Trier et al, 2014 ; Presgraves, 2008 ; Maheshwari and Barbash, 2011 ; Qvarnström and Bailey, 2009 ; Storchová et al, 2010 ). Beyond sex chromosomes, certain genes appear to be repeatedly involved in hybrid incompatibilities ( Figure 1 ; Trier et al, 2014 ; Atanasov et al, 2018 ; Barr and Fishman, 2010 ; Chase, 2007 ; Schartl, 2008 ; Arévalo, 2020 ; Smagulova et al, 2016 ; Davies et al, 2016 ). While some of this overrepresentation may reflect sampling biases ( Chase, 2007 ), as DMIs are characterized across more species it will become increasingly possible to test the hypothesis that certain genes act as ‘hotspots’ for the formation of hybrid incompatibilities.…”

Indirect effects of parental conflict on conspecific offspring development

“…While a growing body of evidence has highlighted the role of parental conflict in the origins of reproductive isolation (namely HSI, and early-onset hybrid inviability in mammalian systems; (Vrana et al 1998, 2000; Brekke and Good 2014; Brekke et al 2016, 2021; Oneal et al 2016; Lafon-Placette et al 2018; Roth et al 2018 a ; Coughlan et al 2020 b ; Sandstedt et al 2020; Arévalo et al 2021)), the work presented here highlights a secondary role of parental conflict in speciation: hybridization between species that vary in their histories of parental conflict may result in indirect effects to intraspecific offspring development, in the event that intraspecific offspring develop alongside hybrids. In this system, M. guttatus co-occurs with both Northern and Southern M. decorus for large portions of their range (JMC personal obs; (Coughlan et al 2020 a )), and are thought to routinely hybridize and introgress (JMC unpublished data; (Puzey et al 2017)).…”