title: Independent Origin and Global Distribution of Distinct Plasmodium vivax Duffy Binding Protein Gene Duplications.
abstract: BACKGROUND
  Plasmodium vivax causes the majority of malaria episodes outside Africa, but remains a relatively understudied pathogen. The pathology of P. vivax infection depends critically on the parasite's ability to recognize and invade human erythrocytes. This invasion process involves an interaction between P. vivax Duffy Binding Protein (PvDBP) in merozoites and the Duffy antigen receptor for chemokines (DARC) on the erythrocyte surface. Whole-genome sequencing of clinical isolates recently established that some P. vivax genomes contain two copies of the PvDBP gene. The frequency of this duplication is particularly high in Madagascar, where there is also evidence for P. vivax infection in DARC-negative individuals. The functional significance and global prevalence of this duplication, and whether there are other copy number variations at the PvDBP locus, is unknown.
  
  
  RESULTS
  Using whole-genome sequencing and PCR to study the PvDBP locus in P. vivax clinical isolates, we found that PvDBP duplication is widespread in Cambodia. The boundaries of the Cambodian PvDBP duplication differ from those previously identified in Madagascar, meaning that current molecular assays were unable to detect it. The Cambodian PvDBP duplication did not associate with parasite density or DARC genotype, and ranged in prevalence from 20% to 38% over four annual transmission seasons in Cambodia. This duplication was also present in P. vivax isolates from Brazil and Ethiopia, but not India.
  
  
  CONCLUSIONS
  PvDBP duplications are much more widespread and complex than previously thought, and at least two distinct duplications are circulating globally. The same duplication boundaries were identified in parasites from three continents, and were found at high prevalence in human populations where DARC-negativity is essentially absent. It is therefore unlikely that PvDBP duplication is associated with infection of DARC-negative individuals, but functional tests will be required to confirm this hypothesis.
authors: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.|Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Jessica B
authors: JB
authors: Hostetler
authors: Program in Public Health, University of California, Irvine, California, United States of America.
authors: Eugenia
authors: E
authors: Lo
authors: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors: Usheer
authors: U
authors: Kanjee
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Chanaki
authors: C
authors: Amaratunga
authors: National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia.
authors: Seila
authors: S
authors: Suon
authors: National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia.
authors: Sokunthea
authors: S
authors: Sreng
authors: Sampov Meas Referral Hospital, Pursat, Cambodia.
authors: Sivanna
authors: S
authors: Mao
authors: Department of Medical Laboratory Sciences and Pathology, College of Public Health and Medical Sciences, Jimma University, Jimma, Ethiopia.
authors: Delenasaw
authors: D
authors: Yewhalaw
authors: Department of Chemistry, University of Washington, Seattle, Washington, United States of America.|MESA-ICEMR, Goa Medical College and Hospital, Bambolim, Goa, India.
authors: Anjali
authors: A
authors: Mascarenhas
authors: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors: Dominic P
authors: DP
authors: Kwiatkowski
authors: Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
authors: Marcelo U
authors: MU
authors: Ferreira
authors: Department of Chemistry, University of Washington, Seattle, Washington, United States of America.|MESA-ICEMR, Goa Medical College and Hospital, Bambolim, Goa, India.
authors: Pradipsinh K
authors: PK
authors: Rathod
authors: Program in Public Health, University of California, Irvine, California, United States of America.
authors: Guiyun
authors: G
authors: Yan
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors: Rick M
authors: RM
authors: Fairhurst
authors: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors: Manoj T
authors: MT
authors: Duraisingh
authors: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors: Julian C
authors: JC
authors: Rayner
mesh_terms: D000293:Adolescent; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D001938:Brazil; D002160:Cambodia; D002352:Carrier Proteins; D002648:Child; D004375:Duffy Blood-Group System / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005002:Ethiopia; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007194:India; D008270:Madagascar; D016780:Malaria, Vivax / Q000378:metabolism / Q000469:parasitology*; D008297:Male; D010802:Phylogeny; D010966:Plasmodium vivax / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D002352:Carrier Proteins; D004375:Duffy Blood-Group System; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface