Abstract
Meiotic homolog pairing involves associations between homologous DNA regions scattered along the length of a chromosome. When homologs associate, they tend to do so by a processive zippering process, which apparently results from avidity effects. Using a computational model, we show that this avidity-driven processive zippering reduces the selectivity of pairing. When active random forces are applied to telomeres, this drop in selectivity is eliminated in a force-dependent manner. Further simulations suggest that active telomere forces are engaged in a tug-of-war against zippering, which can be interpreted as a Brownian ratchet with a stall force that depends on the dissociation constant of pairing. When perfectly homologous regions of high affinity compete with homeologous regions of lower affinity, the affinity difference can be amplified through this tug of war effect provided the telomere force acts in a range that is strong enough to oppose zippering of homeologs while still permitting zippering of correct homologs. The degree of unzippering depends on the radius of the nucleus, such that complete unzippering of homeologous regions can only take place if the nucleus is large enough to pull the two chromosomes completely apart. A picture of meiotic pairing thus emerges that is fundamentally mechanical in nature, possibly explaining the purpose of active telomere forces, increased nuclear diameter, and the presence of ‘Maverick’ chromosomes in meiosis.
Highlights
The pairing of homologous chromosomes in meiosis underlies all of Mendelian genetics, and yet its biophysical basis is poorly understood
The processivity of homolog pairing speeds up pairing, but here we have shown that it creates a problem for fidelity of the process, in that avidity effects allow even weakly paired loci to zip up, leading to potentially incorrect associations
Our simulations (Figure 3A) indicate that random active forces, even when they are only applied at the telomeres, can enhance the discrimination in meiotic homology pairing
Summary
The pairing of homologous chromosomes in meiosis underlies all of Mendelian genetics, and yet its biophysical basis is poorly understood. Assessment of correct versus incorrect pairing partners is hypothesized to rely either on DNA-level sequence homology testing, requiring that transient base pairing occurs on a rapid time scale as the chromosomes move around, or else to rely on a chromosomespecific pattern of cohesins that would serve as a bar-code and allow homologs to recognize each other without the need for single-strand invasion and base pairing (Ishiguro et al, 2014). Another early theory for homolog recognition proposed proteins that recognize chromosome-specific sequences (Maguire 1984), a mechanism that is known to operate in C. elegans (Phillips and Dernburg, 2006). The fact that motion could play both roles raises the question, for future research, of which role is more important
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