Pairing of homologous chromosomes is a key biological phenomenon that underlies Mendelian inheritance but also occurs outside of meiosis in diverse contexts including DNA repair, transvection, and X- chromosome inactivation. But while many of the molecules have been identified that mediate homolog recognition, the fact that homolog pairing requires the chromosomes to physically align with each other poses a challenge from a polymer dynamics perspective. How can individual chromosomes locate and pair with their homologs in the densely packed interior of a nucleus? Cytoskeletal motors attach to telomeres via nuclear envelope spanning proteins, thus dragging chromosomes around in the nucleus by their ends, but this motion appears to be randomly directed, and does not serve to pull homologs directly together. We hypothesize that these random active forces serve to increase chromosome mobility, causing chromosomes to undergo anomalous superdiffusion, a type of motion predicted to facilitate search and capture. We have developed a Brownian dynamics simulation of meiotic chromosome pairing that predicts super-diffusion and zippering, a processive association driven by successive pairing of neighboring loci. Our model predicts that active forces can have a large effect on pairing rates even in comparison with non-random chromosome positioning effects such as nuclear envelope attachment or meiotic bouquet formation. We propose to test the predictions of this model using live cell imaging and quantitative image analysis, combined with yeast genetics to alter key elements of the process including force generation, nuclear envelope attachment, pairing site density, and nonrandom chromosome organization. Our results should impact not only the understanding of meiotic homolog pairing as a physical process, but also the physical biology of chromosome motion in general.
Project Relevance/Narrative Chromosome missegregation during meiosis is directly tied to human infertility and is also the leading known genetic cause for mental retardation and developmental disabilities. This work investigates the mechanisms in place to ensure faithful chromosome pairing during meiosis since in order for chromosomes to segregate faithfully, they must first find their homologous partner. Such research may lead to new ideas for treatment of infertility or to development of diagnostic tests to detect potential problems of chromosome segregation early on before expensive medical and surgical treatments are attempted.
| Arter, Meret; Hurtado-Nieves, Vanesa; Oke, Ashwini et al. (2018) Regulated Crossing-Over Requires Inactivation of Yen1/GEN1 Resolvase during Meiotic Prophase I. Dev Cell 45:785-800.e6 |
| Pollard, Michael G; Fung, Jennifer C (2017) In Vivo Imaging of Budding Yeast Meiosis. Methods Mol Biol 1471:175-186 |
