Battle of the Sex Chromosomes: Competition between X and Y Chromosome-Encoded Proteins for Partner Interaction and Chromatin Occupancy Drives Multicopy Gene Expression and Evolution in Muroid Rodents

Abstract

Transmission distorters (TDs) are genetic elements that favor their own transmission to the detriments of others. Slx/Slxl1 (Sycp3-like-X-linked and Slx-like1) and Sly (Sycp3-like-Y-linked) are TDs which have been co-amplified on the X and Y chromosomes of Mus species. They are involved in an intragenomic conflict in which each favors its own transmission, resulting in sex ratio distortion of the progeny when Slx/Slxl1 vs. Sly copy number is unbalanced. They are specifically expressed in male postmeiotic gametes (spermatids) and have opposite effects on gene expression: Sly knockdown leads to the upregulation of hundreds of spermatid-expressed genes, while Slx/Slxl1-deficiency downregulates them. When both Slx/Slxl1 and Sly are knocked-down, sex ratio distortion and gene deregulation are corrected. Slx/Slxl1 and Sly are, therefore, in competition but the molecular mechanism remains unknown. By comparing their chromatin binding profiles and protein partners, we show that SLX/SLXL1 and SLY proteins compete for interaction with H3K4me3-reader SSTY1 (Spermiogenesis-specific-transcript-on-the-Y1) at the promoter of thousands of genes to drive their expression, and that the opposite effect they have on gene expression is mediated by different abilities to recruit SMRT/N-Cor transcriptional complex. Their target genes are predominantly spermatid-specific multicopy genes encoded by the sex chromosomes and the autosomal Speer/Takusan. Many of them have co-amplified with Slx/Slxl1/Sly but also Ssty during muroid rodent evolution. Overall, we identify Ssty as a key element of the X vs. Y intragenomic conflict, which may have influenced gene content and hybrid sterility beyond Mus lineage since Ssty amplification on the Y pre-dated that of Slx/Slxl1/Sly.

Deficiency of SYCP3-related XLR3 disrupts the initiation of meiotic sex chromosome inactivation in mouse spermatogenesis

“…The two sub-species differ significantly in copy number of the Slx/Sly genes; in hybrid males, the presence of a higher Slx copy number compared to Sly leads to the up-regulation of sex-linked genes, which is consistent with the induced Slx/Sly imbalance and PMSC failure in the knockdown model [25]. Recently, it was shown that SLX/SLXL1 compete with SLY in binding to the H3K4me3-reader, SSTY1, in spermatid nuclei, mediating their respective activities as transcriptional up-or down-regulators [26].…”

“…At least some members of the Xlr family seem to have evolved under the influence of sexual antagonism as suggested by functional studies of the Slx/Slxl1 and Sly genes [22, 25, 26, 44]. Slx/Slxl1 and Sly , X-linked and Y-linked respectively, are multicopy genes found in certain species of Mus that are expressed predominantly in post-meiotic spermatids [42, 45].…”

“…Slx/Slxl1 knockdown males are also subfertile, but with the opposite effect observed in the Sly knockdown: PMSC repression is enhanced when Slx/Slxl1 expression is reduced, leading to inappropriate silencing of several otherwise active X-linked genes and an offspring sex ratio skewed toward males. Curiously, full fertility is restored in double knockdown males expressing both anti- Slx/Slxl1 and anti- Sly shRNAs [25], indicating that Y-linked copies are acting in conflict with X-linked copies [26]. Good and coworkers demonstrated that sterility in F1 hybrid males from the mating of two sub-species of Mus musculus is associated with a breakdown in PMSC, showing broad up-regulation of sex-linked genes [46].…”

“…The amplicons comprise the mammalian X-linked Lymphocyte Regulated (Xlr) superfamily [20] which includes: SYCP3-like X-linked (Slx) and SYCP3-like Y-linked (Sly) genes found in certain species of Mus; the Xlr3, 4 and 5 triad found in a variety of Rodentia, and the FAM9A, B and C genes in primates [21][22][23][24]. The function of most Xlr members is unknown, however Cocquet and co-workers have shown that Slx/Slxl1 and Sly are expressed in post-meiotic spermatids where they play antagonistic roles in the maintenance of PMSC [22,25,26]. Moreover, copy number variation of Slx/Slxl1 and Sly between species of Mus is thought to underlie male sterility in inter-subspecific hybrids underscoring the importance of the Xlr family members in spermatogenesis [27].…”

Sequence analysis in Bos taurus reveals pervasiveness of X–Y arms races in mammalian lineages

“…Moreover, targeted deletion and duplication of the Slx/Slx1 gene family skews sex ratios toward males and females, respectively (Kruger et al 2019). Progress toward a mechanistic understanding of this X-Y competition has come from a recent study demonstrating that the proteins encoded by Slx and Sly compete to interact with the product of another amplified gene family (Ssty) at the promoters of thousands of genes (Moretti et al 2020). Although no comparable functional studies exist for cattle, our examination of more than 200 bull genomes revealed that the longarm amplicon varies considerably in size within and between breeds (Supplemental Fig.…”