title: Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum.
abstract: The malaria parasite Plasmodium falciparum has a great capacity for evolutionary adaptation to evade host immunity and develop drug resistance. Current understanding of parasite evolution is impeded by the fact that a large fraction of the genome is either highly repetitive or highly variable and thus difficult to analyze using short-read sequencing technologies. Here, we describe a resource of deep sequencing data on parents and progeny from genetic crosses, which has enabled us to perform the first genome-wide, integrated analysis of SNP, indel and complex polymorphisms, using Mendelian error rates as an indicator of genotypic accuracy. These data reveal that indels are exceptionally abundant, being more common than SNPs and thus the dominant mode of polymorphism within the core genome. We use the high density of SNP and indel markers to analyze patterns of meiotic recombination, confirming a high rate of crossover events and providing the first estimates for the rate of non-crossover events and the length of conversion tracts. We observe several instances of meiotic recombination within copy number variants associated with drug resistance, demonstrating a mechanism whereby fitness costs associated with resistance mutations could be compensated and greater phenotypic plasticity could be acquired.
authors.affiliation: MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Alistair
authors.initials: A
authors.lastname: Miles
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Zamin
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Vauterin
authors.affiliation: MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Richard
authors.initials: R
authors.lastname: Pearson
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Michel
authors.initials: M
authors.lastname: Theron
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Kelda
authors.initials: K
authors.lastname: Gould
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Daniel
authors.initials: D
authors.lastname: Mead
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Eleanor
authors.initials: E
authors.lastname: Drury
authors.affiliation: Bowdoin College, Brunswick, Maine 04011, USA;
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA;
authors.forename: Valentin
authors.initials: V
authors.lastname: Ruano Rubio
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA;
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.affiliation: Department of Biochemistry, Medical School, Mount Kenya University, 01000 Thika, Kenya; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mwangi
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA;
authors.forename: Upeka
authors.initials: U
authors.lastname: Samarakoon
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom;
authors.forename: Lisa
authors.initials: L
authors.lastname: Ranford-Cartwright
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Ferdig
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892-9806, USA;
authors.forename: Karen
authors.initials: K
authors.lastname: Hayton
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892-9806, USA;
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892-9806, USA;
authors.forename: Thomas
authors.initials: T
authors.lastname: Wellems
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Julian
authors.initials: J
authors.lastname: Rayner
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; Department of Statistics, University of Oxford, Oxford OX1 3LB, United Kingdom.
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
authors.affiliation: MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, United Kingdom; Malaria Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
mesh_terms: D002874:Chromosome Mapping; D056915:DNA Copy Number Variations / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D014644:Genetic Variation; D018503:Genome, Protozoan / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000235:genetics* / Q000469:parasitology; D008540:Meiosis / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic / Q000235:genetics