Modeling cell biological features of meiotic chromosome pairing to study interlock resolution

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.

Agent-based modeling of nuclear chromosome ensemble identifies determinants of homolog pairing during meiosis

“…1; here ℓ r 1 = 50 nm). Using a purely repulsive force derived from an energy potential to enforce an excluded volume constraint was also successfully used recently to study chromosome pairing in [24]. Accordingly, interactions between homologs are determined by their distance: namely, attractive with increasing strength as distance decreases from 400 to 50 nm, and repulsive at or below 50 nm.…”

“…Little is known about the molecular mechanism(s) of homolog pairing. Several mathematical models have been put forward examining potential contributions of molecular processes to homolog pairing, including telomere attachment to the nuclear envelope, chromosome bending stiffness or polymer chains exhibiting an excluded volume repulsive potential [19,[21][22][23][24]. Moreover, a cellular automaton model was developed that examines random searching via chromosome shuffling [25].…”

Kinetic analysis of synaptonemal complex dynamics during meiosis of yeast Saccharomyces cerevisiae reveals biphasic growth and abortive disassembly

“…Meiotic chromosomes undergo rapid, large-scale motions whose function is important in attaining proper and timely homologous alignment ( Conrad et al, 2008 ; Koszul et al, 2008 ; Navarro et al, 2022 ). In C. elegans , the disruption of this motion in a Sun mutant leads to perturbed pairing and synapsis elongation ( Sato et al, 2009 ; Rog and Dernburg, 2015 ).…”

“…An intriguing possibility for the observed biphasic growth rate is that the slower rate may be due to chromosome interlocks. Since in yeast, all chromosome ends are embedded in the nuclear membrane, as chromosomes pair, other chromosomes may become trapped and obstruct pairing or alignment in advance of SC formation ( Navarro et al, 2022 ). This would in turn impede synapsis and thereby attenuate the rate of SC assembly in the region of the interlock.…”

“…This would in turn impede synapsis and thereby attenuate the rate of SC assembly in the region of the interlock. It was proposed that entanglements can be resolved by motion of the entrapped chromosome to the telomeric end where the chromosome can escape ( Navarro et al, 2022 ). The delay caused by clearing the entanglement might account for the slower rate of Zip1 assembly.…”