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A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse

Abstract

Human babesiosis caused by Babesia microti is an emerging tick-borne zoonosis of increasing importance due to its rising incidence and expanding geographic range1. Infection with this organism, an intraerythrocytic parasite of the phylum Apicomplexa, causes a febrile syndrome similar to malaria2. Relapsing disease is common among immunocompromised and asplenic individuals3,4 and drug resistance has recently been reported5. To investigate the origin and genetic diversity of this parasite, we sequenced the complete genomes of 42 B. microti samples from around the world, including deep coverage of clinical infections at endemic sites in the continental USA. Samples from the continental USA segregate into a Northeast lineage and a Midwest lineage, with subsequent divergence of subpopulations along geographic lines. We identify parasite variants that associate with relapsing disease, including amino acid substitutions in the atovaquone-binding regions of cytochrome b (cytb) and the azithromycin-binding region of ribosomal protein subunit L4 (rpl4). Our results shed light on the origin, diversity and evolution of B. microti, suggest possible mechanisms for clinical relapse, and create the foundation for further research on this emerging pathogen.

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Figure 1: Phylogeny of global B. microti.
Figure 2: Genome-wide population genetic summary statistics.
Figure 3: Time to most recent common ancestry (TMRCA) for continental USA (CUS) samples.
Figure 4: Non-synonymous variants in relapsing cases.

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Acknowledgements

The authors thank R. Tewhey, A. Piantadosi and J. Maguire for feedback and advice, and J. Robbins, J. Katz, J. Gelfand and T. Wieczorek for discussions and assistance with sample collection. The authors acknowledge members of the parasitology and haematology laboratories at Massachusetts General Hospital and Brigham and Women's Hospital for assistance with case identification. P.C.S. and this work are supported by the Broad Institute SPARC programme and the Bill and Melinda Gates Foundation and the Howard Hughes Medical Institute. This work was supported in part by an Infectious Disease Society of America Medical Scholars award, a MIT Division of Health Sciences and/MIT Division of Health Sciences and Technology Research Assistantship to J.E.L. and NIH MSTP grants T32GM007753 to J.E.L. and A.L. S.T. and H.K.G. are supported by NIH U01AI109656 and R41AI078631 and by grants from the Evelyn Lilly Lutz Foundation, the Dorothy Harrison Egan Foundation and the Bill and Melinda Gates Foundation. E.V. was supported by a grant from the National Research Fund for Tick-Borne Diseases.

Author information

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Authors

Contributions

J.E.L. performed experiments, analysed data and wrote the paper. A.D.T. and H.G. performed experiments and analysed data. L.F. performed experiments. K.G.A. analysed data. S.F.S., A.L., S.T., E.R., J.A.B. and P.C.S. analysed data and wrote the paper. S.B., G.M., L.S. and D.M. contributed reagents/materials. E.V. and B.P. contributed materials/reagants and wrote the paper.

Corresponding author

Correspondence to Pardis C. Sabeti.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Methods, Supplementary Text, Supplementary Tables 1-8, Supplementary Figures 1-13 and Supplementary References. (PDF 2335 kb)

Supplementary Dataset 1

Draft assembly of the AW1 strain. (TXT 5806 kb)

Supplementary Dataset 2

Draft assembly of the CR400 strain. (TXT 6077 kb)

Supplementary Dataset 3

Draft assembly of the Hobetsu strain. (TXT 5804 kb)

Supplementary Dataset 4

Sequences of tick-borne pathogens used to generate the SureSelect library. (TXT 41 kb)

Supplementary Dataset 5

Pairwise diversity between Russia and R1 samples for all genes. (XLSX 228 kb)

Supplementary Dataset 6

Full table of genetic diversity for all genes among CUS samples. (XLSX 310 kb)

Supplementary Dataset 7

Full table of dN/dS ratios for all genes. (XLSX 347 kb)

Supplementary Dataset 8

Code used to generate published results. (TXT 10360 kb)

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Lemieux, J., Tran, A., Freimark, L. et al. A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse. Nat Microbiol 1, 16079 (2016). https://doi.org/10.1038/nmicrobiol.2016.79

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