Large-scale regulation of meiotic chromosome dynamics

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Chromosome segregation during sexual reproduction places one chromosome, either the maternal or paternal copy, in each gamete. Accurate meiotic chromosome segregation requires that the parental chromosomes interact with one another and exchange genetic information through the formation of crossovers. Mis-regulated chromosomal interactions could lead to karyotype rearrangement and chromosomal mis-segregation, and consequently to infertility and congenital birth defects. Indeed, crossover formation is tightly regulated on both local and chromosome-wide scales. The research proposed here addresses the mechanisms regulating chromosomal interactions by using nematodes and budding yeast, and by developing new experimental approaches suited to study chromosomal processes that are regulated on large scales. This proposal probes two aspects of chromosome organization and dynamics. The first part addresses the role of the synaptonemal complex, a conserved interface that assembles between the parental chromosomes and regulates the distribution of crossovers. This work builds on the recent understanding that the synaptonemal complex, despite its ordered appearance when visualized by electron microscopy, is a liquid-like compartment. By applying genetic approaches, evolutionary analysis, single-molecule tracking and cutting-edge microscopy, the research aims to understand how the ultrastructure and liquid properties of the synaptonemal complex allow it to assemble onto the parental chromosomes and regulate crossovers on a large scale. Specifically, how do protein-protein interactions and the conserved coiled-coil domains in synaptonemal complex proteins generate an ordered, 3-dimensional structure that nonetheless has liquid properties such as constant subunit exchange? And, what is the molecular mechanism that regulates loading of a liquid-crystalline synaptonemal complex onto meiotic chromosomes, aligning all of them from end to end? The second part addresses the organization of the parental chromosomes and the sister chromatids during sexual reproduction. These large bundles of chromatin form distinct cytological entities that can nonetheless undergo precise exchange of information – a necessary step to successfully pass genomes from one generation to the next. An approach developed in the lab to label only one of the two identical sister chromatids will allow probing of the differentiation of the sisters from one another. This is important, since formation of crossovers – which exchange information between the parental chromosomes – involves regulated avoidance the sister chromatid. The lab is also developing a novel approach to obtain a single-molecule, high-resolution description of chromosome conformation and dynamics by utilizing an emerging technology to sequence very long molecules of DNA. Applying this approach to chromosomes during sexual reproduction – when chromosomes are organized as an array of chromatin loops – will shed light on the mechanisms that align the parental chromosomes, keeping them in register and allowing them to accurately exchange information.