Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing.
Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Magnus
M
Manske
Olivo
O
Miotto
Susana
S
Campino
Sarah
S
Auburn
Jacob
J
Almagro-Garcia
Gareth
G
Maslen
Jack
J
O'Brien
Abdoulaye
A
Djimde
Ogobara
O
Doumbo
Issaka
I
Zongo
Jean-Bosco
JB
Ouedraogo
Pascal
P
Michon
Ivo
I
Mueller
Peter
P
Siba
Alexis
A
Nzila
Steffen
S
Borrmann
Steven M
SM
Kiara
Kevin
K
Marsh
Hongying
H
Jiang
Xin-Zhuan
XZ
Su
Chanaki
C
Amaratunga
Rick
R
Fairhurst
Duong
D
Socheat
Francois
F
Nosten
Mallika
M
Imwong
Nicholas J
NJ
White
Mandy
M
Sanders
Elisa
E
Anastasi
Dan
D
Alcock
Eleanor
E
Drury
Samuel
S
Oyola
Michael A
MA
Quail
Daniel J
DJ
Turner
Valentin
V
Ruano-Rubio
Dushyanth
D
Jyothi
Lucas
L
Amenga-Etego
Christina
C
Hubbart
Anna
A
Jeffreys
Kate
K
Rowlands
Colin
C
Sutherland
Cally
C
Roper
Valentina
V
Mangano
David
D
Modiano
John C
JC
Tan
Michael T
MT
Ferdig
Alfred
A
Amambua-Ngwa
David J
DJ
Conway
Shannon
S
Takala-Harrison
Christopher V
CV
Plowe
Julian C
JC
Rayner
Kirk A
KA
Rockett
Taane G
TG
Clark
Chris I
CI
Newbold
Matthew
M
Berriman
Bronwyn
B
MacInnis
Dominic P
DP
Kwiatkowski
D000483:Alleles; D044822:Biodiversity; D018503:Genome, Protozoan; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis