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Background  Plague, caused by the bacterium  Yersinia pestis , is a highly infectious, zoonotic disease. Hundreds of human plague cases are reported across the world annually. Qinghai Plateau is one of the most severely affected plague regions in China, with more than 240 fatal cases of  Y .  pestis  in the last 60 years. Conventional epidemiologic analysis has effectively guided the prevention and control of local plague transmission; however, molecular genetic analysis is more effective for investigating population diversity and transmission. In this report, we employed different genetic markers to analyze the population structure of  Y .  pestis  in Qinghai Plateau.    Methodology/Principal finding  We employed a two-step hierarchical strategy to analyze the phylogeny of 102 Qinghai Plateau isolates of  Y .  pestis , collected between 1954 and 2011. First, we defined the genealogy of  Y .  pestis  by constructed minimum spanning tree based on 25 key SNPs. Seven groups were identified, with group 1.IN2 being identified as the dominant population. Second, two methods, MLVA and CRISPR, were applied to examine the phylogenetic detail of group 1.IN2, which was further divided into three subgroups. Subgroups of 1.IN2 revealed a clear geographic cluster, possibly associated with interaction between bacteriophage and  Y .  pestis . More recently,  Y .  pestis  populations appear to have shifted from the east toward the center and west of Qinghai Plateau. This shift could be related to destruction of the local niche of the original plague focus through human activities. Additionally, we found that the abundance and relative proportion of 1.IN2 subgroups varied by decade and might be responsible for the fluctuations of plague epidemics in Qinghai Plateau.    Conclusion/Significance  Molecular genotyping methods provided us with detailed information on population diversity and the spatial-temporal distribution of dominant populations of  Y .  pestis , which will facilitate future surveillance, prevention, and control of plague in Qinghai Plateau.

Genetic diversity and spatial-temporal distribution of Yersinia pestis in Qinghai Plateau, China