Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis
- aState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
- bBeijing Genomics Institute-Shenzhen, Shenzhen 518083, China;
- cMedical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London W2 1PG, United Kingdom;
- dUniversity College London Genetics Institute, Department of Genetics Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
- eQinghai Institute for Endemic Diseases Prevention and Control, Xining 811602, Qinghai Province, China;
- fXinjiang Center for Disease Control and Prevention, Urumiqi 830002, Xijiang province, China;
- gYunnan Institute for Epidemic Diseases Control and Research, Dali 671000, Yunnan Province, China;
- hInstitute of Health Quarantine, Chinese Academy of Inspection and Quarantine, Beijing 100025, China;
- iMilitary Center for Disease Control and Prevention, Beijing 100850, China;
- jMax von Pettenkofer Institute, Ludwig-Maximilians-University, Munich 80336, Germany; and
- kEnvironmental Research Institute, University College Cork, Cork, Ireland
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Edited* by W. Ford Doolittle, Dalhousie University, Halifax, NS, Canada, and approved November 29, 2012 (received for review April 10, 2012)

Abstract
The genetic diversity of Yersinia pestis, the etiologic agent of plague, is extremely limited because of its recent origin coupled with a slow clock rate. Here we identified 2,326 SNPs from 133 genomes of Y. pestis strains that were isolated in China and elsewhere. These SNPs define the genealogy of Y. pestis since its most recent common ancestor. All but 28 of these SNPs represented mutations that happened only once within the genealogy, and they were distributed essentially at random among individual genes. Only seven genes contained a significant excess of nonsynonymous SNP, suggesting that the fixation of SNPs mainly arises via neutral processes, such as genetic drift, rather than Darwinian selection. However, the rate of fixation varies dramatically over the genealogy: the number of SNPs accumulated by different lineages was highly variable and the genealogy contains multiple polytomies, one of which resulted in four branches near the time of the Black Death. We suggest that demographic changes can affect the speed of evolution in epidemic pathogens even in the absence of natural selection, and hypothesize that neutral SNPs are fixed rapidly during intermittent epidemics and outbreaks.
Footnotes
↵1Y.C., C.Y., Y.Y., D.L., Yanjun Li, T.J., and L.A.W. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: f.balloux{at}ucl.ac.uk, m.achtman{at}ucc.ie, songyajun88{at}gmail.com, wangj{at}genomics.org.cn, or ruifuyang{at}gmail.com.
Author contributions: Y.C., Y.S., Jun Wang, and R.Y. designed research; Y.C., Yanjun Li, Z.G., X.X., X.W., D.Z., and Z.D. performed research; T.J., Z.W., Y.Z., N.Q., M.W., Z.Q., H. Wang, Jing Wang, S.Y., and A.R. contributed new reagents/analytic tools; Y.C., C.Y., Y.Y., D.L., T.J., L.A.W., L.X., H.Z., H. Wu, X.Y., H.C., Yingrui Li, D.F., F.B., M.A., Y.S., and R.Y. analyzed data; and Y.C., T.J., L.A.W., D.F., F.B., M.A., Y.S., and R.Y. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
Data deposition: Raw genome data have been deposited in the National Center for Biotechnology Information/Short Read archive database, www.ncbi.nlm.nih.gov/sra (accession no SRA010790; individual genome assemblies have been deposited under accession nos. ADOV00000000 47685–ADTI00000000 47685). The accession numbers for each strain are listed in Dataset S1.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1205750110/-/DCSupplemental.
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