Modeling identifies chromosome number, size, and non-homologous repulsion as novel determinants of meiotic pairing

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. Author summary Pairing of homologous chromosomes is a key process during meiosis and is shared among all sexually reproducing eukaryotes. Mechanistic determinants of homology-specific chromosome alignment are presently unknown. We have developed an agent-based model where contributions of the entire chromosome set to the pairing process is taken into account, comprising both homologous and non-homologous chromosomal encounters. Chromosome number and size as well as movement velocity and repulsive forces are identified as key factors in the kinetics and efficiency of homologous pairing. Predictions from the model are readily compared to experimental data from budding yeast, parameters can be adjusted to other cellular systems and predictions from the model can be tested via experimental manipulation of the relevant chromosomal features.