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

Abstract

Pairing of homologous chromosomes (homologs) is a key feature of multiple cellular processes including gene expression control, chromosome break repair, and chromosome segregation. During meiosis, homolog pairing ensures formation of haploid gametes from diploid precursor cells, a prerequisite for sexual reproduction. Pairing during meiotic prophase I facilitates crossover recombination and homolog segregation during the ensuing reductional cell division. The timing of homolog pairing relative to meiotic recombination and chromosome movements has been determined in several organisms. Yet, mechanisms by which homologs become stably aligned in the presence of an excess of non-homologous chromosomes have remained elusive. Apart from homolog attraction, provided by early intermediates of homologous recombination, disruption of non-homologous associations also appears to contribute to homolog pairing, as suggested by the detection of stable non-homologous chromosome associations in pairing-defective mutants. Here, we have developed an agent-based model for homolog pairing derived from the dynamics of a naturally occurring chromosome ensemble. The model simulates unidirectional chromosome movements, as well as collision dynamics determined by both attractive and repulsive forces. Incorporating natural chromosome lengths, the model accurately recapitulates efficiency and kinetics of homolog pairing observed for wild-type and mutant meiosis in budding yeast. Identification of thresholds for chromosome movement velocity, number, and repulsive forces suggests that collisions between non-homologous chromosomes may contribute to pairing by crowding homologs into a limited nuclear area thereby creating preconditions essential for close-range homolog pairing.

Homologous chromosome pairing: The linchpin of accurate segregation in meiosis

“…Researchers developed an agent-based model to simulate homologous chromosome pairing, derived from the dynamics of naturally occurring chromosome ensembles. This model accurately reproduces the efficiency and kinetics of homologous chromosome pairing observed in wild-type and mutant budding yeast during meiosis (Chriss et al, 2023). The study supports that nuclear crowding and nonhomologous chromosome collisions promote homologous chromosome pairing.…”

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

“…For example, when chromosome centers of mass are separated by three effective length radii, forces decrease by an order of magnitude from their maxima. Thus, all computed forces represent short-range interactions that do not affect the motion of either homologous or nonhomologous chromosomes beyond one effective radius scale, as further evident from the Supplemental Movies [45] of representative simulation runs (see Fig 2; below).…”

“…The numerical approach was designed in MATLAB [51]. A base code for the wild-type dynamics is available at [52] and corresponding Supplemental Movies are available at [45]. Importantly, the simulation allows concurrent tracking of all 16 homolog pairs and comparing their pairing dynamics to appropriately matched non-homologous partners within the same nucleus.…”

“…As before, distances between homologous chromosomes were plotted as a function of time, but results were sorted by increasing chromosome lengths rather than by initial chromosome distance (Fig 5A). For one of the realizations of the entire homology search of size-adjusted homolog pairs, see [45] (or https://zenodo.org/records/10246589). Again, initial chromosome PLOS COMPUTATIONAL BIOLOGY distances are on average 3μm for all chromosomes, independent of length, corresponding to half of the diameter of the cell nucleus.…”

“…Several additional features of the model are evident from inspection of the Supplemental Movie Files [45]: Both attractive and repulsive forces affect the path of other chromosomes only at short distances, as the path of a given chromosome is only altered when their effective radii overlap. Moreover, even when homologous chromosomes approach each other, they may remain closely aligned for extended periods, but fail to complete pairing at that time and separate again, e.g., due to repulsive interaction with a non-homologous chromosome.…”