Functional constraints ofwtfkiller meiotic drivers
Authors: Nidamangala Srinivasa Ananya , Campbell Samuel , Venkatesan Shriram , Nuckolls Nicole L. , Lange Jeffrey J. , Halfmann Randal , Zanders Sarah E. 
Published: August 2024

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.Author SummaryDiploid organisms, such as humans, have two copies of most genes. Only one copy, however, is transmitted through gametes (e.g., sperm and egg) to any given offspring. Alternate copies of the same gene are expected to be equally represented in the gametes, resulting in random transmission to the next generation. However, some genes can "cheat" to be transmitted to more than half of the gametes, often at a cost to the host organism. Killer meiotic drivers are one such class of cheater genes that act by eliminating gametes lacking the driver. In this work, we studied thewtffamily of killer meiotic drivers found in fission yeasts. Eachwtfdriver encodes a poison and an antidote protein to specifically kill gametes that do not inherit the driver.Through analyzing a large suite of diverse natural and engineered mutantwtfgenes, we identified multiple properties—such as poison self-assembly and poison-antidote co-assembly—that can constrain poison toxicity and antidote rescue. These constraints could influence the evolution ofwtfgenes. Additionally, we discovered several incompatiblewtfpoison-antidote pairs, demonstrating expanded potential for self-killingwtfalleles. Such alleles could potentially arise spontaneously in populations cause infertility.