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bioRxiv · 10.1101/2021.04.23.440859

Homologous locus pairing is a transient, diffusion-mediated process in meiotic prophase

Newman, T. A.·Beltran, B.·McGehee, J. M.·Elnatan, D.·Cahoon, C. K.·Paddy, M.·Chu, D. B.·Spakowitz, A. J.·Burgess, S. M.
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Abstract

The pairing of homologous chromosomes (homologs) in meiosis is essential for distributing the correct numbers of chromosomes into haploid gametes. In budding yeast, pairing depends on the formation of 150-200 Spo11-mediated double-strand breaks (DSBs) that are distributed among 16 homolog pairs, but it is not known if all, or only a subset of these DSBs, contribute to the close juxtaposition of homologs. Having established a system to measure the position of fluorescently tagged chromosomal loci in 3D space over time, we analyzed locus trajectories to determine how frequently, and how long, loci spend colocalized or apart. Continuous imaging revealed highly heterogeneous cell-to-cell behavior of foci, with the majority of cells exhibiting a "mixed" phenotype where foci move into and out of proximity, even at late stages of prophase, suggesting that the axial structures of the synaptonemal complex may be more dynamic than anticipated. The observed plateaus of the mean-squared change in distance (MSCD) between foci informed the development of a biophysical model of two diffusing polymers that captures the loss of centromere linkages as cells enter meiosis, nuclear confinement, and the formation of Spo11-dependent linkages. The predicted number of linkages per chromosome in our theoretical model closely approximates the small number (~2-4) of estimated synapsis-initiation sites, suggesting that excess DSBs have negligible effects on the overall juxtaposition of homologs. These insights into the dynamic in-terchromosomal behavior displayed during homolog pairing demonstrate the power of combining time-resolved in vivo analysis with modeling at the granular level. Significance StatementEssential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process is the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent "pairing" of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study is the first to provide observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.

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Newman, T. A., Beltran, B., McGehee, J. M., Elnatan, D., Cahoon, C. K., Paddy, M., Chu, D. B., Spakowitz, A. J., Burgess, S. M.. 2021-04-24. Homologous locus pairing is a transient, diffusion-mediated process in meiotic prophase. https://doi.org/10.1101/2021.04.23.440859

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