Functional constraints of killer meiotic drivers.

Killer meiotic drivers are selfish DNA loci that sabotage the gametes that do not inherit them from a driver+/driver- heterozygote. These drivers often employ toxic proteins that target essential cellular functions to cause the destruction of driver- gametes. Identifying the mechanisms of drivers can expand our understanding of infertility and reveal novel insights about the cellular functions targeted by drivers. In this work, we explore the molecular mechanisms underlying the family of killer meiotic drivers found in fission yeasts. Each killer acts using a toxic Wtf protein that can be neutralized by a corresponding Wtf protein. The genes are rapidly evolving and extremely diverse. Here we found that self-assembly of Wtf proteins is broadly conserved and associated with toxicity across the gene family, despite minimal amino acid conservation. In addition, we found the toxicity of Wtf assemblies can be modulated by protein tags designed to increase or decrease the extent of the Wtf assembly, implicating assembly size in toxicity. We also identified a conserved, critical role for the specific co-assembly of the Wtf and Wtf proteins in promoting effective neutralization of Wtf toxicity. Finally, we engineered alleles that encode toxic Wtf proteins that are not effectively neutralized by their corresponding Wtf proteins. The possibility of such self-destructive alleles reveals functional constraints on evolution and suggests similar alleles could be cryptic contributors to infertility in fission yeast populations. As rapidly evolving killer meiotic drivers are widespread in eukaryotes, analogous self-killing drive alleles could contribute to sporadic infertility in many lineages.