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Recapitulating the length polymorphism of RS3, a composite microsatellite implicated in human social behavior, via recombination in Saccharomyces cerevisiae

Kean, C. E.; Radchenko, E. A.; Lindenbaum, N. M.; Materne, G.; Mirkin, S. M.

2025-11-10 genetics
10.1101/2025.11.09.687482 bioRxiv
Show abstract

Arginine Vasopressin (AVP) through its receptor V1a, pivotally modulates social and sexual behaviors in mammals. Differences in gene expression and the resulting behavioral changes have been linked to variation in the 5 flanking region of the encoding gene AVPR1A. In particular, length polymorphism in the composite microsatellite RS3 ((CT)4TT(CT)n(GT)m) is responsible for multiple alleles of AVPR1A in the human population. However, the source of this length variation is unknown. We established a genetically tractable experimental system in Saccharomyces cerevisiae to study the mechanism of instability in the RS3 microsatellite. We successfully recapitulated the full spectrum of the RS3 length polymorphism observed in humans and found that it results from genetic recombination between RS3 sequences. Ultimately, we conclude that R-loop associated genome instability elevates recombination rate and triggers repair via single strand annealing which can result in microsatellite length polymorphism. We speculate that recombination is responsible for RS3 length polymorphism in humans.

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