title: A high resolution case study of a patient with recurrent Plasmodium vivax infections shows that relapses were caused by meiotic siblings.
abstract: Plasmodium vivax infects a hundred million people annually and endangers 40% of the world's population. Unlike Plasmodium falciparum, P. vivax parasites can persist as a dormant stage in the liver, known as the hypnozoite, and these dormant forms can cause malaria relapses months or years after the initial mosquito bite. Here we analyze whole genome sequencing data from parasites in the blood of a patient who experienced consecutive P. vivax relapses over 33 months in a non-endemic country. By analyzing patterns of identity, read coverage, and the presence or absence of minor alleles in the initial polyclonal and subsequent monoclonal infections, we show that the parasites in the three infections are likely meiotic siblings. We infer that these siblings are descended from a single tetrad-like form that developed in the infecting mosquito midgut shortly after fertilization. In this natural cross we find the recombination rate for P. vivax to be 10 kb per centimorgan and we further observe areas of disequilibrium surrounding major drug resistance genes. Our data provide new strategies for studying multiclonal infections, which are common in all types of infectious diseases, and for distinguishing P. vivax relapses from reinfections in malaria endemic regions. This work provides a theoretical foundation for studies that aim to determine if new or existing drugs can provide a radical cure of P. vivax malaria.
authors.affiliation: Biomedical Sciences Program, School of Medicine, University of California, San Diego, La Jolla, California, United States of America; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Andrew Taylor
authors.initials: AT
authors.lastname: Bright
authors.affiliation: Biomedical Sciences Program, School of Medicine, University of California, San Diego, La Jolla, California, United States of America; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Manary
authors.affiliation: Scripps Genomic Medicine, The Scripps Translational Science Institute, La Jolla, California, United States of America; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Tewhey
authors.affiliation: Grupo Salud y Comunidad, Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia.
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Arango
authors.affiliation: Biomedical Sciences Program, School of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Tina
authors.initials: T
authors.lastname: Wang
authors.affiliation: Scripps Genomic Medicine, The Scripps Translational Science Institute, La Jolla, California, United States of America; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada; Provincial Laboratory for Public Health, Edmonton, Alberta, Canada.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Yanow
authors.affiliation: Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000328:Adult; D014644:Genetic Variation; D018503:Genome, Protozoan; D005838:Genotype; D006801:Humans; D016780:Malaria, Vivax / Q000469:parasitology*; D008297:Male; D010966:Plasmodium vivax / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D011995:Recombination, Genetic; D012008:Recurrence; D017422:Sequence Analysis, DNA