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Researchers Characterize Genomic Variation in Flesh-Eating Disease Parasites

NEW YORK (GenomeWeb News) – Two new studies in Genome Research are revealing the genomic diversity — primarily structural and copy number polymorphisms — that exists in Leishmania species, parasites transmitted by sand flies that cause the flesh-eating condition leishmaniasis.

The severity and nature of leishmaniasis infections can vary dramatically, ranging from skin lesions to disfiguring disease and sometimes-fatal internal infections. The form that the disease takes depends, in part, on which of the 21 Leishmania parasite species is involved. For instance, leishmaniasis caused by Leishmania major parasites typically affect the skin while L. donovani species have been implicated in a severe form of leishmaniasis, known as visceral leishmaniasis, that attacks a person's internal organs.

"There are many species of the parasite that can cause different forms of the disease and require different forms of treatment," University of Glasgow researcher Jeremy Mottram, said in a statement. "This can also cause problems for diagnosis."

To look at this further, Mottram and his co-authors from several centers in the UK and elsewhere sequenced the genome of an L. donovani isolate from a patient in Nepal. They then used that genome as a reference to characterize more than a dozen re-sequenced L. donovani isolates with variable drug responses that had been collected from patients with visceral leishmaniasis in Nepal and India.

Although they found some individual nucleotide changes, the copy number changes and structural variations between the strains were much more pronounced. These alterations affected not only genes but also chromosomes, in some cases leading to the production of circularized pieces of DNA or episomes that were independent of the common Leishmania chromosomes.

"Against a background of relative genetic homogeneity, we found extensive variation in chromosome copy number between our lines," the researchers wrote. "Other forms of structural variation were significantly associated with drug resistance, notably including gene dosage and the copy number of an experimentally-verified circular episome present in all lines and described here for the first time."

For the reference genome sequencing stage of the study, the team used Roche 454 GS FLX Titanium and Illumina Genome Analyzer platforms to sequence a Nepalese L. donovani isolate. They then re-sequenced 16 isolates from Nepal's Terai region and Bihar state in India that had shown a range of treatment responses and compared them to the L. donavani reference genome.

Analyses of the 17 L. donovani genomes uncovered more than 3,500 SNPs, along with transport and drug resistance-related genes that appear to have been subject to positive selection in the genomes.

But much of the genetic variation that the researchers saw in the genomes involved structural variations and changes in gene and chromosome copy numbers.

"We show that the evolution of these organisms is driven not only by single-letter changes in their genetic codes, but also by larger mutations in the copy numbers of genes and entire chromosomes," Wellcome Trust Sanger Institute researcher Matthew Berriman, co-corresponding author on the L. donovani sequencing study, said in a statement.

Indeed, in an accompanying study, Berriman and some members of the same team found similar copy number variations when they compared genome sequences for four other Leishmania species. For that analysis, researchers used Sanger and Illumina sequencing to generate a reference genome for L. mexicana, a Leishmania species linked to skin infections, from a Guatemalan L. mexicana isolate.

In the same study, they also improved on existing genome sequences for three more species — L. major, L. infantum, and L. braziliensis — before comparing the copy number and other genome patterns for species and strains associated with various forms of leishmaniasis.

Overall, their findings indicated that copy number alterations are more common in Leishmania than SNP or gene content variations. For example, the team found around 8,000 predicted genes in each of the genomes but just two genes that were specific to L. mexicana. In contrast, though, their comparisons uncovered numerous copy number changes in the genomes, both at the gene and chromosome levels.

"We discovered that different species of the Leishmania parasite share a large number of similar genes," Mottram said, "but the genomes are structured in different ways and with extensive variation in the numbers of chromosomes."

Based on their findings so far, researchers suspect that the varying features of Leishmania parasites and the infections they cause may be a consequence of such copy number variability.

"It is largely the different genome structure, including the copy number of genes and as a result, the amount of proteins expressed by these genes that cause differences between the species and hence clinical forms of the disease," University of Glasgow parasitology researcher Nicholas Dickens, who was co-first author on the copy number study, said in a statement.

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