Reenacting a mouse genetic evolutionary arms race in yeast reveals SLXL1/SLX compete with SLY1/2 for binding to Spindlins.

The house mouse X and Y chromosomes have recently acquired high copy number, rapidly evolving gene families representing an evolutionary arms race. This arms race between proteins encoded by X-linked Slxl1/Slx and Y-linked Sly gene families can distort male offspring sex ratio, but how these proteins compete remains unknown. Here, we report how Slxl1/Slx and Sly encoded proteins compete in a protein family-specific and dose-dependent manner using yeast. Specifically, SLXL1 competes with SLY1 and SLY2 for binding to the Spindlin SPIN1. Similarly, SLX competes with SLY2 for binding the Spindlin SSTY2. These competitions are driven by the N-termini of SLXL1, SLX, SLY1, and SLY2 binding to the third Tudor domains of SPIN1 and SSTY2. SLY1 and SLY2 form homo- and heterodimers, suggesting the competition is between complex multimers. Residues under positive selection mapping to the interaction domains and rapid exon gain/loss are consistent with competition between the X- and Y-linked gene families. Our findings support a model in which dose-dependent competition of these X- and Y-linked encoded proteins to bind Spindlins occurs in haploid X- and Y-spermatids to influence X-versus Y-sperm fitness and thus sex ratio. Significance StatementIn house mouse, an evolutionary arms race between proteins encoded by the X-linked Slxl1/Slx and Y-linked Sly gene families during spermatogenesis can distort male offspring sex ratio, but how these proteins compete remains unknown. We report how SLXL1/SLX competes with SLY1/SLY2 by demonstrating their dose-dependent competitive binding to Spindlins, the key protein domains and rapidly evolving residues and exons that drive the competition, and how the competition is likely between complex multimers. Our findings have broad implications for the mechanics of evolutionary arms and how competition between sex chromosomes influences X-versus Y-sperm fitness and sex ratio.