Modeling Cell Biological Features of Meiotic Chromosome Pairing

Abstract

During meiosis, homologous chromosomes become associated side by side in a process known as homologous chromosome pairing. Pairing requires long range chromosome motion through a nucleus that is full of other chromosomes. It remains unclear how the cell manages to align each pair of chromosomes quickly while mitigating and resolving interlocks. Here, we use a coarse-grained molecular dynamics model to investigate how specific features of meiosis, including motor-driven telomere motion, nuclear envelope interactions, and increased nuclear size, affect the rate of pairing and the mitigation/resolution of interlocks. By creating in silico versions of three yeast strains and comparing the results of our model to experimental data, we find that a more distributed placement of pairing sites along the chromosome is necessary to replicate experimental findings. Active motion of the telomeric ends speeds up pairing only if binding sites are spread along the chromosome length. Adding a meiotic bouquet significantly speeds up pairing but does not significantly change the number of interlocks. An increase in nuclear size slows down pairing while greatly reducing the number of interlocks. Interestingly, active forces increase the number of interlocks, which raises the question: How do these interlocks resolve? Our model gives us detailed movies of interlock resolution events which we then analyze to build a step-by-step recipe for interlock resolution. In our model, interlocks must first translocate to the ends, where they are held in a quasi-stable state by a large number of paired sites on one side. To completely resolve an interlock, the telomeres of the involved chromosomes must come in close proximity so that the cooperativity of pairing coupled with random motion causes the telomeres to unwind. Together our results indicate that computational modeling of homolog pairing provides insight into the specific cell biological changes that occur during meiosis. Author SummaryEarly in meiosis, homologous chromosomes must find each other within the crowded nuclear space and become aligned along their entire length in a process known as homologous chromosome pairing. It remains unclear how the cell manages to align each pair of chromosomes quickly while mitigating and resolving interlocks. Here, we study this process by using a computational model. Our model attempts to capture the large-scale cell biological picture of meiotic pairing including the random initial 3D search, active motion of the chromosome ends, and meiosis specific constraints such as telomere attachment to the nuclear envelope. We use our model to study how these different features of meiosis affect the rate of pairing and the mitigation/resolution of interlocks. Importantly, our model gives us detailed movies of interlock resolution events, which we then analyze to build a step-by-step recipe for interlock resolution. We believe computational modeling of homolog pairing provides valuable insight into this complex biological process.