| Background Plague is an infectious disease that seriously endangers human health.Three plague pandemics in human history have been caused over 160 million human deaths worldwide.The most recent pandemic is thought to have originated in Yunnan Province,China during the 19 th century.It spread across ocean to the Americas,Oceania,Africa,and other parts of the world and lasted until the mid-20 th century.Yersinia pestis(Y.pestis),the causative agent of plague,can shape the natural plague focus in suitable habitats.However,Y.pestis in plague foci is not a long persistent,continuous epidemic,it exhibited the characteristics of alternate cycles of epidemic and silent periods.The transfer period can range from several years to decades.Nevertheless,there is insufficient knowledge of genetic relationship and transfer pattern of Y.pestis population for this epidemic-silent interval plague.It is not clear whether the plague epidemic is caused by long-term silent strains in the local plague focus or strains reintroduced from other regions.There are 12 natural plague foci in China currently.In Rattus tanezumi(R.tanezumi)plague foci of Yunnan province,it showed the typical phenomenon of epidemic-silentepidemic cycle.There are abundant strains in both two epidemic periods in Yunnan,which provides a reliable sample set for study of the pattern of epidemic-silent interval plague.In this study,we sequenced the whole genome sequence of 360 Y.pestis strains.The strains were isolated from 1952 to 2016 and collected from12 states or cities in Yunnan Province,China,including two epidemic periods and two silent periods.Through genomic epidemiological analysis of these strains,we can infer genetic diversity,spread and transfer patterns of Y.pestis population in Yunnan.Results and discussion 1.Genomic variation detection and population diversity of Y.pestis strains in Yunnan.We sequenced the genomes of 360 strains isolated from Yunnan R.tanezumi plague foci,which revealed high polymorphism that covered most of the known Y.pestis phylogroups,including 1.ORI2(343 strains),2.MED,1.IN1,1.IN2,1.IN3,1.ORI3,and 2.ANT(17 strains).In total 263 reliable SNPs were identified among 343 Yunnan isolates in the dominant population 1.ORI2.Phylogenetic analysis showed that the 343 Y.pestis strains in Yunnan R.tanezumi plague foci could be divided into two main groups.Sublineage1 mainly included strains of epidemic1 and silent1(pre-silent phase),while sublineage2 mainly included strains of epidemic2 and silent2(post-silent phase).The two main groups diverged from a common ancestor in parallel,i.e.,sublineage2 was not descendant of sublineage1 and vice versa.Through the genetic diversity and evolutionary rate calculation,we found that the root-to-tip divergence of two main groups was significantly positively correlated with the sampling time of Y.pestis,the evolutionary rate and pairwise SNP distance between isolates in sublineage1 were higher than those in sublineage2.Therefore,we inferred that the two plague epidemics in Yunnan were caused by sublineage1 and sublineage2,respectively.The epidemic1 strains of sublineage1 were distributed in Dehong Dai and Jingpo Autonomous Prefecture,Dali Bai Autonomous Prefecture,and Baoshan City.Different from the former,sublineage2 can be further subdivided into four subgroups(named wave1-wave4).By observing the dynamic changes of the four populations over time,we found that wave1 strains were mainly distributed in western Yunnan.Wave2 strains were distributed in western and central Yunnan.Wave3 strains were distributed in western,central,southern,and eastern Yunnan with a short sampling time interval and large geographical span.Wave4 contains silent2 strains,and the geographical range was approximately to wave3.The spread of both plague waves showed an orientation change from west to east.The region that plague lasted for the longest period is Dehong,a prefecture located in western Yunnan and bordering northern Myanmar.2.Spread pattern of Yunnan R.tanezumi plague.To infer spread pattern of Y.pestis in Yunnan Province and its relationship with previously published Y.pestis isolates,we analyzed 343 Y.pestis strains in 1.ORI2 phylogroup by combining sampling time,location,transmission events,and phylogenetic relationships.Phylogenetic analysis revealed that the sublineage1 strains showed trapezoidal distribution,Dali Prefecture strains located near the root of the phylogeny,and their spread is largely confined within the local region.Sublineage2 can be assigned into four waves,we inferred that the epidemic of epidemic2 was composed of multiple waves of sublineage2.We also observed that most of the deep branch strains in sublineage2 were isolated from Dehong Prefecture,suggesting that epidemic2 plague could be originated from the Dehong and then spread to the central,southern,and eastern regions of Yunnan.Finally,in this study,we compared 360 Yunnan strains with the 470 published genomes to reconstruct spatiotemporal transmission of the Y.pestis and further clarify the phylogenetic positions of Yunnan strains in the international isolates.Conclusion This study provides the genome-wide characterization of population structure,genetic diversity,and spread pattern analysis of Y.pestis strains in Yunnan Province from 1952 to 2016.Firstly,we found that the two plague epidemics in Yunnan were caused by two main groups,both of which were descended from a most recent common ancestor.The genetic diversity and evolutionary rate of pre-silent strains were higher than those of post-silent strains.Secondly,we have clarified the spread patterns of plague in Yunnan.Y.pestis strains were mainly concentrated in Dali Prefecture then spread over large areas and persist for a long time during pre-silent phase.In post-silent phase,our data strongly support that the plague originated from Dehong Prefecture and then spread from west to east.Our results provide novel clues for studying the Y.pestis population dynamics and mechanism of the plague epidemic-silent interval,and would be an important support for the works of plague prevention and control. |
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