TY - JOUR
T1 - Population structure shapes copy number variation in malaria parasites
AU - Cheeseman, Ian H.
AU - Miller, Becky
AU - Tan, John C.
AU - Tan, Asako
AU - Nair, Shalini
AU - Nkhoma, Standwell C.
AU - De Donato, Marcos
AU - Rodulfo, Hectorina
AU - Dondorp, Arjen
AU - Branch, Oralee H.
AU - Mesia, Lastenia Ruiz
AU - Newton, Paul
AU - Mayxay, Mayfong
AU - Amambua-Ngwa, Alfred
AU - Conway, David J.
AU - Nosten, François
AU - Ferdig, Michael T.
AU - Anderson, Tim J.C.
N1 - Funding Information:
Molecular work was funded by National Institutes for Health grants R37AI048071 and R01AI075145 (T.J.C.A.) and a Cowles Fellowship (I.H.C.). This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program grant C06 RR013556 and RR017515 from the National Center for Research Resources of the National Institutes of Health. The AT&T Genomics Computing Center supercomputing facilities were supported by the AT&T Foundation and the National Center for Research Resources Grant Number S10 RR029392. We thank the Peruvian community members for participation. We thank patients and staff who contributed to data collection in Thailand (SMRU staff), Cambodia (Chea Nguon, Char Meng Chuor, and Duong Socheat), Laos (Maniphone Khanthavong, Odai Chanthongthip, Bongkot Soonthornsata, Tiengkham Pongvongsa, Samlane Phompida, and Bouasy Hongvanthong), and The Gambia (Michael Walther and Lamin Manneh), Richard Pinapati for assistance with data submission, and MalariaGen for generating the P. falciparum genome resequencing data.
Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - copy number variation
KW - parasitology.
KW - population genetics
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U2 - 10.1093/molbev/msv282
DO - 10.1093/molbev/msv282
M3 - Article
C2 - 26613787
AN - SCOPUS:84964494870
VL - 33
SP - 603
EP - 620
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 3
ER -