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Adaptive Copy Number Evolution in Malaria Parasites

Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evide...

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Autores principales: Nair, Shalini, Miller, Becky, Barends, Marion, Jaidee, Anchalee, Patel, Jigar, Mayxay, Mayfong, Newton, Paul, Nosten, François, Ferdig, Michael T., Anderson, Tim J. C.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570623/
https://www.ncbi.nlm.nih.gov/pubmed/18974876
http://dx.doi.org/10.1371/journal.pgen.1000243
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author Nair, Shalini
Miller, Becky
Barends, Marion
Jaidee, Anchalee
Patel, Jigar
Mayxay, Mayfong
Newton, Paul
Nosten, François
Ferdig, Michael T.
Anderson, Tim J. C.
author_facet Nair, Shalini
Miller, Becky
Barends, Marion
Jaidee, Anchalee
Patel, Jigar
Mayxay, Mayfong
Newton, Paul
Nosten, François
Ferdig, Michael T.
Anderson, Tim J. C.
author_sort Nair, Shalini
collection PubMed
description Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evidence that gch1 CNP is an adaptive consequence of selection by antifolate drugs, which target enzymes downstream in this pathway. (1) We compared gch1 CNP in parasites from Thailand (strong historical antifolate selection) with those from neighboring Laos (weak antifolate selection). Two percent of chromosomes had amplified copy number in Laos, while 72% carried multiple (2–11) copies in Thailand, and differentiation exceeded that observed at 73 synonymous SNPs. (2) We found five amplicon types containing one to greater than six genes and spanning 1 to >11 kb, consistent with parallel evolution and strong selection for this gene amplification. gch1 was the only gene occurring in all amplicons suggesting that this locus is the target of selection. (3) We observed reduced microsatellite variation and increased linkage disequilibrium (LD) in a 900-kb region flanking gch1 in parasites from Thailand, consistent with rapid recent spread of chromosomes carrying multiple copies of gch1. (4) We found that parasites bearing dhfr-164L, which causes high-level resistance to antifolate drugs, carry significantly (p = 0.00003) higher copy numbers of gch1 than parasites bearing 164I, indicating functional association between genes located on different chromosomes but linked in the same biochemical pathway. These results demonstrate that CNP at gch1 is adaptive and the associations with dhfr-164L strongly suggest a compensatory function. More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation.
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spelling pubmed-25706232008-10-31 Adaptive Copy Number Evolution in Malaria Parasites Nair, Shalini Miller, Becky Barends, Marion Jaidee, Anchalee Patel, Jigar Mayxay, Mayfong Newton, Paul Nosten, François Ferdig, Michael T. Anderson, Tim J. C. PLoS Genet Research Article Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evidence that gch1 CNP is an adaptive consequence of selection by antifolate drugs, which target enzymes downstream in this pathway. (1) We compared gch1 CNP in parasites from Thailand (strong historical antifolate selection) with those from neighboring Laos (weak antifolate selection). Two percent of chromosomes had amplified copy number in Laos, while 72% carried multiple (2–11) copies in Thailand, and differentiation exceeded that observed at 73 synonymous SNPs. (2) We found five amplicon types containing one to greater than six genes and spanning 1 to >11 kb, consistent with parallel evolution and strong selection for this gene amplification. gch1 was the only gene occurring in all amplicons suggesting that this locus is the target of selection. (3) We observed reduced microsatellite variation and increased linkage disequilibrium (LD) in a 900-kb region flanking gch1 in parasites from Thailand, consistent with rapid recent spread of chromosomes carrying multiple copies of gch1. (4) We found that parasites bearing dhfr-164L, which causes high-level resistance to antifolate drugs, carry significantly (p = 0.00003) higher copy numbers of gch1 than parasites bearing 164I, indicating functional association between genes located on different chromosomes but linked in the same biochemical pathway. These results demonstrate that CNP at gch1 is adaptive and the associations with dhfr-164L strongly suggest a compensatory function. More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation. Public Library of Science 2008-10-31 /pmc/articles/PMC2570623/ /pubmed/18974876 http://dx.doi.org/10.1371/journal.pgen.1000243 Text en Nair et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Nair, Shalini
Miller, Becky
Barends, Marion
Jaidee, Anchalee
Patel, Jigar
Mayxay, Mayfong
Newton, Paul
Nosten, François
Ferdig, Michael T.
Anderson, Tim J. C.
Adaptive Copy Number Evolution in Malaria Parasites
title Adaptive Copy Number Evolution in Malaria Parasites
title_full Adaptive Copy Number Evolution in Malaria Parasites
title_fullStr Adaptive Copy Number Evolution in Malaria Parasites
title_full_unstemmed Adaptive Copy Number Evolution in Malaria Parasites
title_short Adaptive Copy Number Evolution in Malaria Parasites
title_sort adaptive copy number evolution in malaria parasites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570623/
https://www.ncbi.nlm.nih.gov/pubmed/18974876
http://dx.doi.org/10.1371/journal.pgen.1000243
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