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    Battle of the Sex Chromosomes: Competition between X and Y Chromosome-Encoded Proteins Drives Gene Expression and Evolution

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    Team Daniel Vaiman

    Battle of the Sex Chromosomes: Competition between X and Y Chromosome-Encoded Proteins Drives Gene Expression and Evolution

     

    A study directed by Julie Cocquet in the team "Genomics, Epigenetics & Physiopathology of Reproduction" has been published in the journal Molecular Biology & Evolution.  This work presents the mechanism by which two multicopy genes, called Slx and Sly, respectively encoded by the mouse X and Y chromosomes, compete with each other in male germ cells and have opposite effect on gene expression. 

    These genes are transmission distorters, or “selfish” genes, engaged in a genomic conflict, as each favours its own transmission to the detriment of the other. Since they are located on the sex chromosomes, they can alter the sex ratio of the progeny. In their article, Moretti and colleagues describe the molecular role of Slx and Sly-encoded proteins, via studying their genomic location and protein partners; they show that their competition at the protein level has impacted on the expression and evolution of their target genes in some Muroids.

     

    The rodents of the Muroid family account for ~30% of the diversity of mammalian species, evolving 25 million years ago from a common ancestor. The tendency to rapid speciation of this superfamily makes it a fascinating model to study evolutionary biology and is visible in all aspects of genome dynamics, in particular, in the establishment of 'genomic conflicts'. Among the species belonging to this superfamily, the house mouse is a great model: its physiology, especially its reproductive physiology, as well as the organization of its genome are very well characterized; the ability to produce genetic mutants is also beneficial. The study of this model unravelled a genomic conflict between Slx and Sly genes which are carried by the sex chromosomes.

    Slx and Sly are, in fact, "selfish" genes (also called TD for transmission distorter) each promoting its own transmission to the detriment of the other (with a higher frequency than expected from the classic Mendelian pattern of inheritance). They are specifically expressed in male gametes after meiosis, in haploid cells called spermatids which later differentiate into spermatozoa. This step of spermatogenesis is a stage at which TDs can promote the transmission of gametes carrying them and/or prevent/destroy gametes that do not carry them.

    Slx and Sly genes are present dozens of times on the X chromosome for Slx, and on the Y for Sly, respectively. Their number of copies is not the same depending on the species and it appears that their number of copies has co-evolved. Slx and Sly are engaged in a genomic conflict which results in a genetic arms race in which the amplification of the number of copies of one is counterbalanced by the amplification of the other. An imbalance in the number of copies of one versus the other (obtained by genetic mutants inducing a "knock-down" of Slx or Sly) leads to a skewed sex ratio of the progeny associated with hypofertility up to infertility, if copy number ratio is severely imbalanced. The effect of these two genes compensates each other regardless of their level of expression since the double "knockdown" of Slx and Sly improves the phenotype of the simple "knockdown" of one or the other.

    This imbalance and its consequences can be found naturally in the case of interspecific crosses which thus lead to hypofertility/infertility and to the extinction of the resulting hybrid lines. This phenomenon therefore contributes to speciation.

     

    From a molecular point of view, the mechanism by which Slx and Sly compete remained unclear until recently. This is the question that the group led by Julie Cocquet sought to answer. In the article that have just been published in MBE, they show that SLX and SLY proteins are present at the promoter of thousands of spermatid genes, and that the knockdown of Sly increases the presence of SLX these promoters. Competition at the promoter level is mediated via SSTY protein, with which SLX or SLY (but not the 2 together) interacts. Interestingly, SSTY belongs to a family of proteins, SPINDLIN, which recognizes the chromatin mark H3K4me3, characteristic of the promoter of active (expressed) genes. When SLY predominates, the genes with which it is associated are under-expressed, conversely when SLX predominates these genes are over-expressed.

    To complete the elucidation of the molecular mechanism, the authors show that SLY, but not SLX, interacts with proteins of the SMRT/N-Cor complex that repress transcription; in case of Sly knockdown, this complex is less recruited at the promoters of SLX/SLY target genes resulting in upregulation. This result explains, at least in part, the fact that SLY acts as a repressor and SLX, as an activator.

     

     Working model: competition between SLX (here named SLX/SLXL1) and SLY for partner interaction and chromatin occupancy drives multi-copy gene expression in mouse spermatids. 

    SSTY proteins bind to H3K4me3-enriched promoters of expressed (active) genes in spermatids. In WT spermatids (left panel), SLX/SLXL1 and SLY proteins compete for interaction with SSTY in the cytoplasm and in the nucleus. With SLX/SLXL1 being predominantly cytoplasmic, SLY occupies most of SSTY-bound promoters. SLY recruits SMRT/N-Cor repressive transcriptional complex which restrains (but does not switch off) the expression of multicopy genes. When Sly is knocked-down (right panel), Slx/Slxl1 genes are upregulated and SLX/SLXL1 protein level in the nuclei is higher. SLX/SLXL1 proteins are now the main partners of SSTY and, most of SSTY-bound promoters are devoid of SLY and occupied by SLX/SLXL1 proteins. Since SMRT/N-Cor protein complex preferentially interacts with SLY but not with SLX/SLXL1, SMRT/N-Cor recruitment at these promoters is diminished, which leads to upregulation of target genes.

     

    From an evolutionary point of view, it is important to note that Ssty gene is itself multicopy and carried by the Y chromosome. Among the target genes of SLX, SLY and SSTY, the authors observed a high proportion of multicopy genes that were amplified along with Slx, Sly and Ssty during Muroid evolution, particularly Speer/Takusan genes amplified >150 times on chromosome 14.

    In conclusion, this work is an important step towards elucidating the molecular mechanism behind the competition between X and Y genes - a genomic conflict that has influenced the organization of the genome and the evolution of some rodents. This type of phenomenon is predicted to be quite widespread in evolution but is rarely described because their identification requires interspecific crosses or the occurrence/production of mutants.

     

    Reference

     

    Charlotte Moretti, Mélina Blanco, Côme Ialy-Radio, Maria-Elisabetta Serrentino, Clara Gobé, Robin Friedman, Christophe Battail, Marjorie Leduc, Monika A Ward, Daniel Vaiman, Frederic Tores, Julie Cocquet. Battle of the sex chromosomes: competition between X- and Y-chromosome encoded proteins for partner interaction and chromatin occupancy drives multi-copy gene expression and evolution in muroid rodents, Molecular Biology and Evolution, msaa175

    https://doi.org/10.1093/molbev/msaa175

     

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