Genetic conflict shapes centromeres and heterochromatin

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DESCRIPTION (provided by applicant): Defects in chromosome segregation can lead to infertility, to birth defects and to cancer. Centromeres serve as attachment points of mitotic and meiotic spindles to DMA, and mediate the faithful segregation of all eukaryotic chromosomes. Centromeric DMA evolves rapidly, and can range in size and complexity over several orders of magnitude. Traditional attempts at studying centromeres have left unexplained the causes underlying this complexity and rapid evolution. Our approach is to study the proteins that epigenetically determine centromere identity, instead of directly studying centromeric DNA sequence. We have discovered that the Drosophila centromeric histone (CenH3), Cid, has constantly evolved under positive selection, suggesting its involvement in recurrent genetic conflict. Our hypothesis is that 'centromere-drive' is the source of this conflict. Under this model, centromeres compete via microtubule attachments for preferential transmission in female meiosis in animals and plants, since only 1 of 4 meiotic products becomes the egg. This competition confers a selfish advantage to chromosomes that can make more microtubule attachments, and can result in runaway expansions of centromeric satellites. While beneficial to the 'driving' chromosome, these expansions can have deleterious effects on the fitness of an organism and of the species. For instance, in human populations, Robertsonian fusions (chromosome fusions at centromeres found in 0.12% of the population) are preferentially transmitted through females but male carriers of Robertsonian fusions can be partially or completely sterile. We propose that CenH3s as well as other heterochromatin proteins may be under positive selection to suppress the deleterious consequences of 'centromere-drive' and to restore meiotic parity. We plan to test our hypothesis with the following specific aims: (1) We will test whether recent satellite expansions in D. melanogaster have a transmission advantage in female meiosis, (2) We will examine the effects of the positive selection of Cid and other heterochromatin proteins in Drosophila by replacing 'adapted' endogenous genes with 'unadapted' versions from closely related species or hypothetical ancestors, and (3) We will assay the effects of asymmetric female meiosis on centromere evolution, in yeast and Tetrahymena that lack female and male meiosis, and bdelloid rotifers that lack meiosis altogether.