Over the past thirty years there have been sporadic reports in the literature of pairing between the centromeres of both homologous and non-homologous chromosomes at two different stages of meiosis. First, studies in a variety of organisms (onions, wheat, budding yeast, mice) have revealed that early in meiosis, just after DNA replication, centromeres arrange themselves in pairs. This pairing is primarily between non-homologous centromeres. This non-homologous, early, meiotic centromere pairing dissolves as homologous chromosomes become aligned in later meiotic prophase. Second, centromeres can also actively pair at a later stage of meiosis. For example, studies with budding yeast and female Drosophila have shown that partner chromosomes that have failed to recombine (non-exchange chromosomes) pair at their centromeres (or pericentric heterochromatin) in late prophase, when homologous chromosomes are completely synapsed. This late meiotic centromere pairing between non-exchange partners promotes their disjunction at the first meiotic division. In budding yeast, both the early and late stages of centromere pairing depend upon the synaptonemal complex (SC) protein, Zip1. This project aims to characterize the two phases of centromere pairing in meiosis, test whether they are mechanistically related, or distinct, and determine how they impact the segregation of chromosomes in meiosis I. Because observations of meiotic centromere pairing have been gathered from such a diverse range of experimental organisms, the proposed experiments may reveal the details of a conserved, but largely unrecognized, aspect of meiotic chromosome behavior. The project is organized into five groups of experiments. The first group of experiments determines the region of Zip1 that is involved in association with the centromere in early meiosis and uses affinity purification methods to identify proteins that are involved in the early phase of centromere pairing. Little is known about the transition from early to later centromere pairing. A second group of experiments will explore this transition and shed light on the relationship of the two stages. What is the purpose of aligning non-homologous centromeres at the beginning of a process (meiosis I) that is ultimately intended to pair then separate homologous chromosomes? A third group of experiments tests the hypothesis that non-homologous centromere pairing blocks the formation of crossovers near to centromeres. Such crossovers are known to disrupt meiosis I chromosome segregation fidelity in many organisms. The final two groups of experiments will explore first, how Zip1 promotes the pairing of centromeres in later meiotic prophase, and second, will test the hypothesis that this late centromere pairing promotes the attachment of centromeres to opposite poles of the meiosis I spindle, and in doing so, contributing to meiosis I segregation fidelity in important ways.
Errors in the process of distributing chromosomes to the gametes is the major cause of birth defects. This project uses budding yeast to identify undiscovered ways in which a component of the chromosome, called the centromere, might help direct chromosomes movements, in doing so helping to prevent the errors that lead to birth defects.
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