Discovering principles of chromosome organisation directing segregation in mitosis and meiosis

An abnormal chromosome number, called aneuploidy, is associated with cancer and causes birth defects and infertility. Aneuploidy arises from errors in chromosome segregation during mitosis or meiosis. Mitosis segregates duplicated sister chromatids to opposite poles to produce genetically identical daughter cells. Meiosis sequentially segregates homologs in meiosis-I and sister chromatids in meiosis-II to sort half the genome into gametes. How chromosome segregation is customised to ensure distinct outcomes in mitosis and meiosis is a fundamental question in biology. Central players are kinetochores, the protein assemblies at centromeres, which attach to the spindle with different orientations in mitosis and meiosis. We discovered crucial roles of pericentromeres, discrete chromosomal domains flanking centromeres, in directing kinetochore orientation. Here, I propose to address how pericentromere organisation and kinetochore specialisation direct chromosome segregation in mitosis and meiosis. Pericentromeres are functionally conserved, but sequence diverse. Therefore, to define key concepts, we will take a multi-species, inter-disciplinary approach. We will uncover molecular mechanisms using budding yeast with simple pericentromeres, reveal conserved principles using fission yeast with repetitive heterochromatic pericentromeres and establish relevance to mammalian fertility using mouse gametes. Overall, we will discover fundamental, conserved mechanisms that distinctly sort chromosomes into somatic cells and gametes to prevent aneuploidy.