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International Team Resequences Trio of Leprosy Pathogen Genomes

NEW YORK (GenomeWeb News) – The genome sequence of the leprosy-causing pathogen Mycobacterium leprae is almost identical regardless of when or where the strain was collected, a study in yesterday's advance, online edition of Nature Genetics reveals.

An international research team used Sanger and Illumina methods to re-sequence the genomes of M. leprae strains from Brazil, Thailand, and the US. By comparing these genomes with a previously sequenced reference strain from India, the team identified about 80 informative SNPs, which they then used to genotype hundreds of modern-day M. leprae strains and a dozen or so strains collected from ancient human remains.

So far, all of the sequenced and genotyped M. leprae strains are remarkably similar to one another, senior author Stewart Cole, a microbial pathogenesis researcher at the École Polytechnique Fédérale de Lausanne's Global Health Institute, told GenomeWeb Daily News.

Leprosy is a chronic condition characterized by skin, bone, respiratory, and nerve damage. Rod-shaped M. leprae bacteria cause the disfiguring disease.

Based on the sequence of the first M. leprae genome — from an Indian strain called TN that Cole and his colleagues first sequenced nearly a decade ago — researchers knew that the M. leprae genetic code is rife with pseudogenes, a pattern that's consistent with reductive evolution, Cole noted.

Even so, he explained, relatively few polymorphisms have been identified in M. leprae so far. Past genotyping studies have uncovered just four M. leprae SNP types, leaving researchers few genetic tools for genotyping and epidemiological studies of the leprosy pathogen.

For the latest paper, Cole and his team used Sanger sequencing to sequence the 3.27 million base genome of a M. leprae strain from Brazil called Br4293 to about six times coverage. When the researchers compared the newly sequenced Brazilian leprosy strain with the TN reference genome, they found 155 SNPs, 31 variable number tandem repeats, and eight small insertions and deletions.

The team also used the Illumina Genome Analyzer II to re-sequence two other M. leprae strains — the Thai 53 strain from Thailand and the NHDP63 strain from the US — to 38 times coverage and 46 times coverage, respectively.

Using this second-generation approach, the team was able to re-sequence M. leprae in days rather than months, Cole noted. He also touted the Illumina sequencing technology for its "fantastic" coverage of the M. leprae genome and ability to generate sequence from contaminated samples.

When the researchers compared the sequences from all four sequenced strains, they found that the genomes were 99.995 percent identical to one another.

Between the four strains sequenced to date, the team found a total of just a couple hundred variants, mostly SNPs, as well as five pseudogenes.

"In terms of the diagnosis, treatment, and prevention of leprosy, this is extremely encouraging," Cole and his co-authors wrote, "as it means that antigenic drift in M. leprae should be negligible and the sequences of drug targets will not vary."

The team subsequently used 84 of the most informative SNPs to genotype about 400 M. leprae strains from around the world. In so doing, the researchers found 16 SNP subtypes, each of which tended to cluster within certain geographic areas.

"What we found was that there was a very strong correlation between the country of origin and the genotype," Cole said.

And, he explained, those patterns are offering clues about how the leprosy pathogen spread around the world as well as how this process corresponded to human migration patterns. For instance, the team concluded that leprosy likely infiltrated Asia via two distinct routes: one from the south and a second from the north along the so-called "Silk Road" from Europe.

The team was also able to isolate centuries-old M. leprae DNA from the bones of humans who died in the 4th to 15th centuries in Egypt, Hungary, Turkey, Croatia, England, and Denmark. Again, genotyping experiments suggested these strains were very similar to one another and to modern day M. leprae strains in the US and elsewhere.

Overall the researchers' analyses indicate that the leprosy pathogen probably originated in or around East Africa, similar to early humans. To test this, Cole and his colleagues eventually hope to sequence strains from that region — a daunting task since the pathogen grows slowly and can't be cultured in the lab.

"We desperately want to get some samples from East Africa," Cole said.

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