Segregation distorters are selfish genetic elements that operate by over-representing themselves in the mature gamete pool, thus fundamentally violating Mendel?s law. The evolutionary arms races triggered between distorter genes and their suppressors have long been recognized as a powerful force that shapes the evolution of genomes, cells, and species. Despite the ubiquity and importance of segregation distorters, we understand very little about the genetic basis and molecular mechanisms of this class of selfish genetic elements. A key barrier in understanding the mechanisms of segregation distorters is that they are present in non-model systems that lack genetic tools, and are almost always associated with chromosomal inversions that thwart traditional genetic approaches to gene discovery. Without characterizing the underlying genetic basis and molecular mechanisms it remains impossible to directly connect the arms race initiated by selfish elements to broader phenomena in the evolution of meiosis and sex chromosome systems. Here, we develop two independent methods to side-step traditional barriers presented by chromosomal inversions to gene discovery, and dissect the genetic basis underlying this selfish behavior in closely related Drosophila species. In our first aim, we develop a mutagenesis approach to identify the genes causing Sex- Ratio distortion in D. pseudoobscura. Through a combination of sequencing, in silico complementation, bulked- segregant mapping, and CRISPR/ Cas9 based editing, we are poised to resolve the complex genetic architecture that underlies distortion and to identify the complete set of genes, including modifiers and enhancers, that drive the selfish behavior of the D. pseudoobscura Sex-Ratio chromosome. In our second aim, we uncover cryptic variation within species for suppressors of distortion. Here, we aim to understand the molecular arms races between distorters and their suppressors through the identification of the genes and mechanisms of suppression of segregation distortion, and suppressors of suppressors-of-distortion. In our third aim, we engineer a synthetic chromosomal inversion to allow recombination mapping of Sex-Ratio distortion in D. persimilis. This approach adapts the Flp/FRT site-specific recombination tools to generate a perfectly collinear non-driving chromosome to allow free recombination in the region containing all necessary and sufficient genes for SR distortion. Once candidate genes are mapped, validated, and organized into a functional pathway for D. persimilis, a comparative analysis of these two systems will test whether SR mechanisms are unique or shared. Together, this work will provide the most complete genetic architecture of sex-linked segregation distorters to date, open the door to understanding the molecular mechanisms of distortion in two Sex-Ratio systems, and for the first time explicitly test independent or shared origins and mechanisms of Sex-Ratio distortion in these closely related species.
Our goal is to understand the genetic and molecular basis of selfish chromosomes and speciation in animals, including humans. We are using a multidisciplinary approach and developing new techniques to identify genes and molecular pathways that evolve rapidly between species and cause defects in hybrids. Our studies will provide a unique perspective to fundamental cellular processes that are important in cancer biology and birth defects in humans.
