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Resequencing Study IDs Genetic Diversity in Neglected Disease Pathogen

NEW YORK (GenomeWeb News) – Using high-throughput resequencing, a team of Swiss and African scientists has started mapping genomic variation in Mycobacterium ulcerans — the parasite behind a neglected tropical disease called Buruli ulcer.

The researchers sequenced the genomes of two M. ulcerans strains from Ghana and one from Japan. When they compared the genomes with the reference sequence, generated from a Ghanaian strain, the team detected more than 26,000 SNPs in the Japanese strain. But they also detected nearly 175 variants in the African strains and subsequently identified more than a dozen Ghanaian haplotypes, suggesting it's possible to genotype and track M. ulcerans — even in African communities with very similar strains.

That, in turn, may help researchers understand how Buruli ulcer is transmitted and spread, senior author Gerd Pluschke, a molecular immunology researcher at the Swiss Tropical Institute, told GenomeWeb Daily News.

Buruli ulcer is a neglected tropical disease characterized by necrotic skin and soft tissue that can become chronic ulcers. It occurs in parts of Asia, the Western Pacific, and Latin America, but is particularly common in West Africa, where it affects children and young adults.

Little is known about how the disease is transmitted, Pluschke said. Past research suggests the causative agent — a mycobacterium in the same family as tuberculosis and leprosy-causing bacteria — comes from the environment. But while outbreaks are more common in regions with stagnant or slow flowing water bodies, Pluschke noted, it's unclear whether the disease is transmitted by water itself or through an insect or animal vector.

Two distinct M. ulcerans lineages have been identified: an ancestral lineage found in Asia, South America, and Mexico that closely resembles a fish pathogen called M. marinum and a more pathogenic and virulent lineage found in Africa and Australia.

In 2007, French researchers sequenced an M. ulcerans reference strain, isolated in Ghana. So far, though, it has been difficult to track African strains given their genetic homogeneity, Pluschke said, noting that the strains identified in Africa appear to be clonal and recently introduced.

In an effort to get a better handle on the genomic variation in M. ulcerans, Pluschke and his team resequenced the genomes of two M. ulcerans strains from Ghana and one from Japan. They used single end reads from a Roche 454 Genome Sequencer FLX and Illumina Genome Analyzer to sequence each genome, housed on a 5.6 million base circular chromosome and a 174,000 base plasmid. The team also used NimbleGen comparative genome sequencing arrays to assess parts of the Japanese strain.

When they compared the genome of the Japanese strain with the reference strain, the researchers identified 26,564 SNPs. On the other hand, the team found just 173 SNPs in the two newly sequenced Ghanaian strains with the reference.

"The low genetic diversity and high linkage disequilibrium within Ghanaian isolates supports the hypothesis that the M. ulcerans population spread over the African continent has gone through a severe bottleneck during adaptation to a possibly host-specific environment and has not yet accumulated much sequence diversity," the researchers wrote.

When the researchers applied the knowledge from the sequencing experiment, developing assays looking at 68 of the SNPs, they found that such genotyping could classify another 54 Ghanaian M. ulcerans strains into 13 haplotypes.

Based on these findings, the researchers estimate that Ghanaian M. ulcerans strains diverged from the ancestral Japanese strains between 394,000 and 529,000 years ago. Meanwhile, they suspect that the strains further diverged within Ghana about 1,000 to 3,000 years ago.

Pluschke said he is encouraged by the fact that they were able to find genetic differences within the Ghanaian strains — even if these differences were limited to just a few SNPs in some cases.

He and his colleagues are applying such information to track and characterize Buruli ulcer's spread — work that they plan to publish in the future. "What we've now found … is actually a more focal distribution, which excludes certain modes of transmission," Pluschke said.

The researchers are using real time PCR assays to characterize the SNPs, Pluschke explained, though he says they may explore other genotyping methods as additional M. ulcerans genomes are sequenced and new SNPs discovered.

The team has already assembled a large strain collection from an area in Ghana and may begin gathering strains from other parts of Africa, such as Cameroon, Pluschke said. They are also collaborating with Australian researchers who are sequencing additional M. ulcerans strains through a consortium involving research groups from Africa, Europe, Australia, and the US that is funded by the Optimus Foundation, he noted.

A more complete understanding of the M. ulcerans genome may have implications for vaccine production. And, Pluschke added, learning how the disease spreads could point to environmental risk factors that can be altered to prevent disease transmission. "The identification of preventable risks could come out of transmission studies," he said.

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