Retracing the path of evolution: polymorphisms of aspA codon 363 shape the fitness of Yersinia pestis

Yersinia pestis, the etiologic agent of plague, is a genetically monomorphic pathogen. By screening 1085 published Y. pestis genomes, we identified an unusual mutation hotspot within codon 363 of the aspartate ammonia-lyase gene aspA with at least six alleles in the population. Our investigation delves into the significance of the polymorphism at the aspA codon 363 and its impact on the fitness of Y. pestis strains. Notably, we found that the dominating TTG allele (L363), resulting in AspA inactivation, confers a fitness advantage to Y. pestis when competing with other bacteria inhabiting a similar niche, due to elevated expression of pesticin. However, the TTG strain exhibits fitness deficits under various stress conditions compared to the GTG strain (V363), which expresses an active AspA. Drawing from these observations, we propose an evolutionary hypothesis for Y. pestis at the aspA codon 363 locus. It is inferred that GTG represented the ancestral state at this locus. However, the TTG strain swiftly dominated populations in the early evolutionary stage of Y. pestis, likely owing to the V363L substitution that conferred a competitive advantage to Y. pestis over other bacteria. Subsequently, spontaneous mutations emerged, reinstating AspA activity, thereby offering fitness advantages across diverse environments and get fixed within the population. Our findings portraited a scenario of inactivating-restoring mutations relay in Y. pestis microevolution, shedding new lights on the evolutional dynamics of pathogens.