Meiotic Sex Chromosome Inactivation Is Disrupted in Sterile Hybrid Male House Mice

Abstract

In male mammals, the X and Y chromosomes are transcriptionally silenced in primary spermatocytes by meiotic sex chromosome inactivation (MSCI) and remain repressed for the duration of spermatogenesis. Here, we test the longstanding hypothesis that disrupted MSCI might contribute to the preferential sterility of heterogametic hybrid males. We studied a cross between wildderived inbred strains of Mus musculus musculus and M. m. domesticus in which sterility is asymmetric: F 1 males with a M. m. musculus mother are sterile or nearly so while F 1 males with a M. m. domesticus mother are normal. In previous work, we discovered widespread overexpression of X-linked genes in the testes of sterile but not fertile F 1 males. Here, we ask whether this overexpression is specifically a result of disrupted MSCI. To do this, we isolated cells from different stages of spermatogenesis and measured the expression of several genes using quantitative PCR. We found that X overexpression in sterile F 1 primary spermatocytes is coincident with the onset of MSCI and persists in postmeiotic spermatids. Using a series of recombinant X genotypes, we then asked whether X overexpression in hybrids is controlled by cis-acting loci across the X chromosome. We found that it is not. Instead, one large interval in the proximal portion of the M. m. musculus X chromosome is associated with both overexpression and the severity of sterility phenotypes in hybrids. These results demonstrate a strong association between X-linked hybrid male sterility and disruption of MSCI and suggest that transacting loci on the X are important for the transcriptional regulation of the X chromosome during spermatogenesis. FORTY years ago, Lifschytz and Lindsley (1972) proposed the provocative hypothesis that the X chromosome is inactivated during male meiosis and that disruption of this process could lead to sterility. The idea that failure of meiotic sex chromosome inactivation (MSCI) might cause sterility is significant in speciation genetics since it provides a possible explanation for the widespread observation that in crosses between species, sterility typically appears first in the heterogametic sex (Haldane 1922;Forejt 1996;Presgraves 2008).Whether MSCI takes place in Drosophila has been debated for several decades (Kremer et al. 1986;McKee and Handel 1993;Hense et al. 2007;Vibranovski et al. 2009). Current evidence suggests that expression on the X chromosome is suppressed relative to the autosomes during spermatogenesis but that this suppression precedes meiosis and thus does not reflect MSCI (Meiklejohn et al. 2011; but see Vibranovski et al. 2012). Likewise, the sex chromosomes are not differentially silenced in chicken oocytes (Guioli et al. 2012). Therefore, failed MSCI cannot explain hybrid sterility in all female-heterogametic taxa. In therian mammals, however, MSCI is well established (Solari 1974;McKee and Handel 1993;Namekawa et al. 2007). Although no MSCI-essential loci have been found on the sex chromosomes, many of the autosomal genes t...

The great escape

“…Recent studies using mice have revealed that hybrid sterility, the phenomenon by which offspring of an inter-species cross become sterile (thereby keeping both species distinct), is associated with disruption of MSCI. 28,29 These studies further confirm the strong link between successful MSCI and fertility.…”

The Pace of Hybrid Incompatibility Evolution in House Mice

“…One explanation for this result is that the X chromosome contains more shared incompatibilities than the autosomes, and the PhyloQTL approach offers higher power than the heuristic method to detect these loci. The X chromosome confers hybrid male sterility between domesticus and musculus through complex regulatory mechanisms that remain unclear (Storchová et al 2004;Good et al 2008bGood et al , 2010Oka et al 2010;Campbell et al 2013;Turner et al 2014;Bhattacharyya et al 2014;Oka and Shiroishi 2014). It is possible that incompatibilities involving the X chromosome differ from purely autosomal interactions in some way that affects the snowball prediction.…”

Interspecific hybrids of dwarf hamsters and Phasianidae birds as animal models for studying the genetic and developmental basis of hybrid incompatibility

“…Spermatocytes of the Mus hybrids display improper gene expression due to MSCI failure (Good et al, 2010;Bhattacharyya et al, 2013;Campbell et al, 2013). Several genetic loci, including Hst1 (Prdm9), which is involved in determining recombination hotspot locations, are associated with this hybrid male sterility; however, the molecular mechanisms have not yet been fully elucidated (Forejt, 1996;Mihola et al, 2009;Davies et al, 2016).…”

“…In addition, MSUC-induced postmeiotic transcriptional repression, due to MSCI failure-induced disrupted postmeiotic sex chromatin repression, is an alternative cause of the malformation and reduction of sperm (Burgoyne et al, 2009;Campbell et al, 2013). A reduction in the number of postmeiotic cells due to the arrest of meiosis I may cause a reduction in sperm, leading to reduced fertility.…”