Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion

Abstract

The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by un-attached chromosomes, but that randomly-directed active forces applied to the telomeres speeds up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions.

Modeling meiotic chromosome pairing: increased fidelity from a tug of war between telomere forces and a pairing-based Brownian ratchet

“…Zippering is thought to account for the classic observation of Y-shaped chromosome arrangements during meiosis, in which homologs are paired starting at one end and continuing over part of their length, with the remainder of the homologs unpaired, a configuration known as "amphitene" (for review of this literature, see Wilson 1928). In our previously published simulations of meiotic pairing (Marshall and Fung, 2016) we found that even low-affinity pairing interactions, as reflected in a high probability of unpairing, led to processive pairing of the whole chromosome. The ability of low affinity interactions to drive processive pairing creates a potential problem for achieving high fidelity of pairing -if even poorly matched loci can drive processive zippering, how can correct interactions be distinguished from incorrect?…”

“…inside a spherical nuclear envelope by a repulsive force applied to any node moving outside the spherical shell in a direction normal to the surface with a spring constant k_nuc as previously described (Marshall and Fung, 2016). Telomeres are constrained to be located on the nuclear surface by calculating the radial distance from each telomeric node and then translating the telomere along the radius by this distance, so that after each step the telomere is always returned to a position on the nuclear surface (Marshall and Fung, 2016). Pairing is modeled on an individual node basis, such that node 1 on a chromosome is only allowed to pair with node 1 on the homolog, node 2 with node 2, and so on.…”

“…Thus, in our model, discrimination between correct and incorrect associations is reflected entirely by a difference in off-rates. Table 1 gives the parameter values used for the simulations presented here, following order of magnitude estimates previously described (Marshall and Fung, 2016). Our model is not intended to precisely represent the actual chromosomes of any particular species, but rather is designed to be an abstract model that captures essential features of meiotic chromosome pairing.…”

Optical trapping of nucleolus reveals viscoelastic properties of nucleoplasm inside mouse germinal vesicle oocytes

“…35 Forces, created by cytoskeleton and motor proteins during oocyte growth also contribute into chromatin dynamics through telomeres, attached by SUN/KASH complex on nuclear envelope. Well known, that active motion of telomeres or subtelomeric regions promotes pairing of homologs during early prophase, 36 but in pachytene telomeres motion is inhibited in mice. 37 It can be assumed, that for further segregation of chromosomes around the nucleolus (SN-stage) during diplotene/diakinesis, revival of telomeres movement is essential.…”

Reduced Telomerase Interaction with Telomeres Alters Meiotic Chromosome Motion and Gamete Viability

“…Individual loci can pair when they randomly move within some capture radius. The probability of such a pairing event depends on the random motion of the chromosomes(Marshall and Fung, 2016). Once paired, any locus has a probability p(unpair) of becoming unpaired at any given time in the simulation.…”