title: Population Structure Shapes Copy Number Variation in Malaria Parasites.
abstract: If copy number variants (CNVs) are predominantly deleterious, we would expect them to be more efficiently purged from populations with a large effective population size (Ne) than from populations with a small Ne. Malaria parasites (Plasmodium falciparum) provide an excellent organism to examine this prediction, because this protozoan shows a broad spectrum of population structures within a single species, with large, stable, outbred populations in Africa, small unstable inbred populations in South America and with intermediate population characteristics in South East Asia. We characterized 122 single-clone parasites, without prior laboratory culture, from malaria-infected patients in seven countries in Africa, South East Asia and South America using a high-density single-nucleotide polymorphism/CNV microarray. We scored 134 high-confidence CNVs across the parasite exome, including 33 deletions and 102 amplifications, which ranged in size from <500 bp to 59 kb, as well as 10,107 flanking, biallelic single-nucleotide polymorphisms. Overall, CNVs were rare, small, and skewed toward low frequency variants, consistent with the deleterious model. Relative to African and South East Asian populations, CNVs were significantly more common in South America, showed significantly less skew in allele frequencies, and were significantly larger. On this background of low frequency CNV, we also identified several high-frequency CNVs under putative positive selection using an FST outlier analysis. These included known adaptive CNVs containing rh2b and pfmdr1, and several other CNVs (e.g., DNA helicase and three conserved proteins) that require further investigation. Our data are consistent with a significant impact of genetic structure on CNV burden in an important human pathogen.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX ianc@txbiomed.org.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Cheeseman
authors.affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame.
authors.forename: Becky
authors.initials: B
authors.lastname: Miller
authors.affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame.
authors.forename: John C
authors.initials: JC
authors.lastname: Tan
authors.affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame.
authors.forename: Asako
authors.initials: A
authors.lastname: Tan
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Shalini
authors.initials: S
authors.lastname: Nair
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Standwell C
authors.initials: SC
authors.lastname: Nkhoma
authors.affiliation: Lab. Genetica Molecular, IIBCAUDO, Universidad De Oriente, Cumana, Venezuela.
authors.forename: Marcos
authors.initials: M
authors.lastname: De Donato
authors.affiliation: Lab. Genetica Molecular, IIBCAUDO, Universidad De Oriente, Cumana, Venezuela.
authors.forename: Hectorina
authors.initials: H
authors.lastname: Rodulfo
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Arjen
authors.initials: A
authors.lastname: Dondorp
authors.affiliation: Division of Parasitology, Department of Microbiology, New York University School of Medicine.
authors.forename: Oralee H
authors.initials: OH
authors.lastname: Branch
authors.affiliation: Laboratorio De Investigaciones De Productos Naturales Y Antiparasitarios, Universidad Nacional De La Amazonia Peruana, Iquitos, Peru.
authors.forename: Lastenia Ruiz
authors.initials: LR
authors.lastname: Mesia
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
authors.forename: Paul
authors.initials: P
authors.lastname: Newton
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Medical Research Council Unit, Fajara, Banjul, The Gambia.
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.affiliation: Medical Research Council Unit, Fajara, Banjul, The Gambia Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Tim J C
authors.initials: TJ
authors.lastname: Anderson
mesh_terms: D056915:DNA Copy Number Variations; D005787:Gene Frequency; D005828:Genetics, Population; D018503:Genome, Protozoan; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008288:Malaria / Q000469:parasitology; D010961:Plasmodium / Q000235:genetics*; D010963:Plasmodium falciparum / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D015203:Reproducibility of Results; D012641:Selection, Genetic
keywords: copy number variation; parasitology.; population genetics