Genetic Conflict Shapes Centromeres and Heterochromatin

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Chromosome segregation is an essential process. The key chromosomal sites that ensure proper segregation of chromosomes are centromeres, which bind microtubules that pull chromosomes or chromatids apart during meiosis and mitosis. Centromere function is thus essential for chromosome segregation. Defective centromeres can lead to infertility, tumorigenesis and birth defects like Down's syndrome. Despite the conservation of the chromosome segregation process, centromeric DNA sequences evolve rapidly, both within and between closely related species. Moreover, essential centromeric proteins, which bind centromeric DNA to assemble microtubule-recruiting kinetochores, also evolve rapidly. This rapid evolution of both centromeric proteins and DNA is in sharp contrast to the expectation that they should be highly conserved to maintain essential function, whose basic mechanism has been conserved in all eukaryotes. We have proposed that this rapid evolution occurs due to 'centromere-drive', i.e., competition between chromosomes during female meiosis, in which only one of four meiotic products is chosen to be the egg pronucleus. Deleterious consequences of centromere-drive, especially in male meiosis, selects for the rapid evolution of centromeric and heterochromatin proteins, to quell drive or its deleterious effects. Using an approach that combines insights from evolutionary genetics and cell biology, we propose to test this model of genetic conflict in Drosophila species. We will further test the functional consequences of rapid evolution and genetic innovation in centromeric proteins, on the fundamental process of chromosome segregation.