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Antimicrobial Agents and Chemotherapy, December 2009, p. 5173-5180, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00045-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Characteristics of Genetic Hitchhiking around Dihydrofolate Reductase Gene Associated with Pyrimethamine Resistance in Plasmodium falciparum Isolates from India{triangledown} ,{dagger}

Vanshika Lumb,1 Manoj K. Das,2 Neeru Singh,3 Vas Dev,2 Wajihullah,4 and Yagya D. Sharma1*

Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India,1 National Institute of Malaria Research, 22 Shamnath Marg, New Delhi 110007, India,2 Regional Medical Research Center for Tribals, Jabalpur, Madhya Pradesh, India,3 Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India4

Received 13 January 2009/ Returned for modification 19 April 2009/ Accepted 9 September 2009

Sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum has been widespread across continents, causing the major hurdle of controlling malaria. Resistance is encoded mainly by point mutations in P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) target genes. To study the origin and evolution of pyrimethamine resistance on the Indian subcontinent, microsatellite markers flanking the pfdhfr gene were mapped. Here we describe the characteristics of genetic hitchhiking around the pfdhfr gene among 190 P. falciparum isolates. These isolates were collected from five different geographical regions of India (Uttar Pradesh, Madhya Pradesh, Assam, Orissa, and Andaman and Nicobar Islands) where malarial transmission rates and levels of drug resistance vary across regions. Among the isolates, we observed a significant reduction in genetic variation in the ±20-kb vicinity of the mutant pfdhfr alleles due to hitchhiking. This reduction in genetic diversity was more prominent around quadruple pfdhfr alleles (heterozygosity [He] = 0.23) than around double (He = 0.365) and single (He = 0.465) mutant alleles. Asymmetry in the selective sweep flanking the pfdhfr alleles was observed with regional isolates, emphasizing the drug usage with the parasite population. All the pfdhfr alleles share a single microsatellite haplotype and seem to have originated from a single progenitor similar to that of Southeast Asian (Thailand) pfdhfr mutants. Results of the present study also indicate that the emergence of drug-resistant alleles is a recent phenomenon in India compared to Southeast Asian countries.

* Corresponding author. Mailing address: Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Phone: 91 11 26588145. Fax: 91 11 26589286. E-mail: ydsharma_aiims{at}yahoo.com

{triangledown} Published ahead of print on 28 September 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, December 2009, p. 5173-5180, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00045-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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