Functional and evolutionary constraints ofwtfkiller meiotic drivers

Abstract

AbstractKiller 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 thewtffamily of killer meiotic drivers found in fission yeasts. Eachwtfkiller acts using a toxic Wtfpoisonprotein that can be neutralized by a corresponding Wtfantidoteprotein. Thewtfgenes are rapidly evolving and extremely diverse. Here we found that self-assembly of Wtfpoisonproteins is broadly conserved and associated with toxicity across the gene family, despite minimal amino acid conservation. In addition, we found the toxicity of Wtfpoisonassemblies can be modulated by protein tags designed to increase or decrease the extent of the Wtfpoisonassembly, implicating assembly size in toxicity. We also identified a conserved, critical role for the specific co-assembly of the Wtfpoisonand Wtfantidoteproteins in promoting effective neutralization of Wtfpoisontoxicity. Finally, we engineeredwtfalleles that encode toxic Wtfpoisonproteins that are not effectively neutralized by their corresponding Wtfantidoteproteins. The possibility of such self-destructive alleles reveals functional constraints onwtfevolution 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.