title: Characterization of within-host Plasmodium falciparum diversity using next-generation sequence data.
abstract: Our understanding of the composition of multi-clonal malarial infections and the epidemiological factors which shape their diversity remain poorly understood. Traditionally within-host diversity has been defined in terms of the multiplicity of infection (MOI) derived by PCR-based genotyping. Massively parallel, single molecule sequencing technologies now enable individual read counts to be derived on genome-wide datasets facilitating the development of new statistical approaches to describe within-host diversity. In this class of measures the F(WS) metric characterizes within-host diversity and its relationship to population level diversity. Utilizing P. falciparum field isolates from patients in West Africa we here explore the relationship between the traditional MOI and F(WS) approaches. F(WS) statistics were derived from read count data at 86,158 SNPs in 64 samples sequenced on the Illumina GA platform. MOI estimates were derived by PCR at the msp-1 and -2 loci. Significant correlations were observed between the two measures, particularly with the msp-1 locus (P = 5.92×10(-5)). The F(WS) metric should be more robust than the PCR-based approach owing to reduced sensitivity to potential locus-specific artifacts. Furthermore the F(WS) metric captures information on a range of parameters which influence out-crossing risk including the number of clones (MOI), their relative proportions and genetic divergence. This approach should provide novel insights into the factors which correlate with, and shape within-host diversity.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom. sa3@sanger.ac.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.forename: Magnus
authors.initials: M
authors.lastname: Manske
authors.forename: Gareth
authors.initials: G
authors.lastname: Maslen
authors.forename: Valentina
authors.initials: V
authors.lastname: Mangano
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcock
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Jean Bosco
authors.initials: JB
authors.lastname: Ouédraogo
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000483:Alleles; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D044822:Biodiversity; D002050:Burkina Faso; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008302:Mali; D008957:Models, Genetic; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000953:Antigens, Protozoan