X chromosome-dependent disruption of placental regulatory networks in hybrid dwarf hamsters

Abstract

Disruption of placental gene expression contributes to several congenital developmental disorders in humans, and may play an important role in the evolution of reproductive barriers between species. The placenta is also highly enriched for interacting genes showing parent-of-origin or imprinted expression, which is thought to have evolved to mitigate parental conflict within this extra-embryonic tissue. However, relatively little is known about the broader organization, functional integration, and evolution of placental gene expression networks across species. Here we used a systems genetics approach to examine the genetic and regulatory underpinnings of placental overgrowth in hybrids between two species of dwarf hamsters (Phodopus sungorus and P. campbelli). Using quantitative genetic mapping and mitochondrial substitution lines, we show that the X chromosome is the major maternal factor explaining massive parent-of-origin dependent placental overgrowth in hybrids. Mitochondrial interactions did not contribute to abnormal hybrid placental development, and there was only weak correspondence between placental disruption and early embryonic growth phenotypes. In parallel, genome-wide analyses of placental transcriptomes from the parental species and first and second-generation hybrids revealed a central group of co-expressed X-linked and autosomal genes that were highly enriched for maternally-biased expression. Expression of this core placental regulatory network was strongly correlated with placental growth and showed widespread misexpression dependent on epistatic interactions with X-linked hybrid incompatibilities. Silencing of the paternal X chromosome and most candidate paternally imprinted autosomal genes appeared unperturbed in the same genetic crosses. Collectively, our results indicate that the X chromosome plays a prominent role in the evolution of placental gene expression and the rapid accumulation of hybrid developmental barriers between mammalian species.

The evolution of widespread recombination suppression on the Dwarf Hamster (Phodopus) X chromosome

“…Nine of the large scaffolds corresponded to single linkage groups, likely representing eight of the 13 autosomes and the X chromosome. Four autosomes were recovered in two large scaffolds, while chromosome 5 was more fragmented with six assembled scaffolds (Table S2; numbering based on de novo genetic map lengths from (33). Finally, we used available mouse protein data, Phodopus transcriptome data sampled from 10 tissues, and ab initio predictions to generate and refine gene models.…”

“…Widespread suppression of X-linked recombination on the Xp arm. Our previous mapping experiment indicated map compression on one end of the X chromosome (33). To quantify per chromosome recombination rates and the magnitude of X-linked compression, we compared the number of base pairs anchored on each chromosome to its genetic length on the linkage map.…”

“…It can be difficult to disentangle whether the accumulation of smaller inversions are cause or consequence of recombination suppression (11); however, the enrichment we find for small inversions between species on Xp likely results from the suppression, as there are also small inversions on Xq without such effect (albeit fewer). Although our recombination map was generated with interspecies hybrids (33), the lack of support for an inversion model is unsurprising in this instance. The Xp usually appears to be highly condensed within Phodopus species, with clear evidence for suppression of female recombination on the presumed Xp arm within both P. sungorus and P. campbelli based on immunolocalization of the MLH1 mismatch repair protein (32).…”

“…Sites in which the called base in the assembly does not match one of the two alleles in the most likely genotype are inferred as errors and can be corrected by inserting one of the alleles from that genotype. We generated a reference-guided genetic map using data from our previously published Phodopus genetic map based on high-throughput genotypes (ddRAD tags) from 189 backcross individuals [F1 female (P. campbelli female x. P. sungorus male) x P. campbelli male; (33)]. Processed RAD tags were aligned to the reference genome using BWA (Li and Durban 2009), and variants were called using HaplotypeCaller (gatk, v4; (91)).…”

“…Hybrid inviability in the reciprocal hybrid cross (P. sungorus x P. campbelli) is due to extreme placental overgrowth and developmental disruption, which is caused by a large-effect QTL near the Xq-Xp boundary (Fig. S9) that leads to the disruption of a network of autosomal genes expressed in the placenta (33). Understanding if and how the evolution of widespread recombination suppression is related to speciation awaits a more detailed dissection of the genetic and mechanistic bases of these hybrid incompatibilities.…”