quinta-feira, 12 de janeiro de 2012

Next-generation sequencing reveals clues to a parasite’s drug resistance

Fonte: blog.f1000

Leishmaniases are a complex of diseases caused by parasites that are transmitted by sandflies to an estimated 12 million people in 88 countries annually. In her latest evaluation, Microbiologist and F1000 evaluator Marilyn Parsons draws attention to a new genomic investigation of the Leishmania donovani version of the diverse species of parasite, which causes the most devastating form of the disease – visceral leishmaniasis – in large parts of Asia and Africa.

The research, led by Sanger Institute scientists working with colleagues in India, Nepal, Belgium, London, Glasgow, and Berlin, describes the use of next-generation sequencing technologies to produce a high-quality reference sequence of one line of L. donovani. Comparisons among 16 more clinical lines isolated from patients in Nepal uncovered clues about the evolution of drug resistance in the strain.

The work, published in December in Genome Research, is notable for its success using rapid new sequencing technologies to bring genomic knowledge to epidemiological studies in the field. The authors note that efforts to eliminate visceral leishmaniasis in Bangladesh, India, and Nepal have been hampered by L. donovani’s drug resistance. Epidemiological studies point a re-emergence of the disease in the region since DDT-spraying campaigns in the 1960s. Though the varieties of L. donovani are relatively homogenous, their susceptibility to antimonial drugs is highly variable. The authors’ whole genome sequence data revealed genetic structure that was not shown by multilocus typing within the 17 strains and suggested that drug resistance has emerged multiple times in the closely related set.

Their study also documented, for the first time, extensive variation in chromosomal copy number on a genome-wide basis in clinical lines. Parsons, whose own lab at the Seattle Biomedical Research Institute studies cell structure and function of parasites including leishmaniasis, writes:

While the field has suspected that chromosomal copy number was somewhat variable in Leishmania, this study shows it is perhaps more rampant than thought, with only 9 of the 36 chromosomes appearing to be disomic in all strains. The copy number plasticity clearly has relevance for the evolution of drug resistance now and for future drugs.

The authors conclude that dynamic selective pressures resulting from changes in drug policy on the Indian subcontinent are likely to “mould the genome of this parasite.” Their approach proves the usefulness of new sequencing technologies for creating a reference and then monitoring the evolution of any parasite from within an affected region.

Downing T, Imamura H, Decuypere S, Clark TG, Coombs GH, Cotton JA, Hilley JD, de Doncker S, Maes I, Mottram JC, Quail MA, Rijal S, Sanders M, Schönian G, Stark O, Sundar S, Vanaerschot M, Hertz-Fowler C, Dujardin JC, & Berriman M (2011).

Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance.

Genome research, 21 (12), 2143-56 PMID: 22038251

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