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International Team Sequences Sleeping Sickness Parasite Genome

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A Wellcome Trust Sanger Institute-led team reported today that they have sequenced the genome of a Trypanosoma brucei subspecies that causes chronic human African trypanosomiasis, or sleeping sickness.

The researchers used whole-genome shotgun sequencing to tackle T. b. gambiense, generating an improved, high-quality draft sequence of its genome. The research, which appears online today in PLoS Neglected Tropical Diseases, reveals that the human pathogen is unexpectedly similar to a reference strain called T. b. brucei that infects other mammals but is harmless to humans.

"Changes in the phenotype — the physical characteristics — seem to be down to more subtle changes in genetic information," lead author Andrew Jackson, a researcher at the Wellcome Trust Sanger Institute, said in a statement.

"Single letter changes in the genome; differences in the number of copies of genes; changes in how the activity of genes is regulated — all of these genetic nuances could play that crucial role in determining why T. b. gambiense behaves so differently to T. b. brucei," he added.

Sleeping sickness, a chronic disease affecting the central nervous system, occurs in many parts of Africa. T. b. gambiense, found in West and Central Africa, is behind more than 90 percent of human cases, the researchers explained. Another subspecies called T. b. rhodesiense causes sleeping sickness cases in East Africa, while T. b. brucei infects wild and domestic mammals but not humans.

For the current study, researchers did whole-genome shotgun sequencing using paired-end reads with the ABI 3737 to sequence plasmid and bacterial artificial chromosome clones from T. b. gambiense DAL 972, which was isolated from a patient in Côte d'Ivoire in the mid-1980s. In the process, they generated enough paired-end reads to cover the genome about eight times.

When they compared the newly sequenced genome with the T. b. brucei 927 reference genome, representing a bovine-infecting strain, the researchers found that the genomes were much the same: on average, 99.2 percent of nucleotides in coding regions of the T. b. gambiense and T. b. brucei genomes were identical.

Although no coding sequences found in T. b. gambiense were missing in T. b. brucei, the bovine strain did contain some coding sequences not found in T. b. gambiense. The researchers also detected nearly 24,000 SNPs in the new genome compared with the reference as well as differences in the diversity of sequences found in repetitive regions of the two genomes.

Among their subsequent analyses of the genome, the researchers also focused on variant surface glycoproteins, or VSGs, in T. b. gambiense, looking for clues about how they differ from those in T. b. brucei. These glycoproteins are found on the surface of the parasite's cells and are used to help it hide from the human immune system.

Again, these VSG regions were fairly similar, with researchers identifying many sequences resembling T. b. brucei's 1,258 VSG coding sequences in the new genome.

"VSGs are among the most-rapidly evolving genes in parasite genomes," senior author Christiane Hertz-Fowler, a researcher at the Sanger Institute, said in a statement. "So we were surprised to find that as many as 88 per cent of VSGs remained consistent between our T. b. brucei and T. b. gambiense genomes."

Even so, she and her co-workers noted, by characterizing VSG patterns from strains found in different locations, it may be possible to learn more about how these correspond to human infection patterns.

"The VSG repertoire is essentially conserved at the level of modular protein domains, which are reorganized by gene conversions into novel mosaics in each strain," the researchers wrote. "Therefore our data are likely to anticipate the archive present in the genomes of other strains, and a definition of total VSG diversity should be achievable through the addition of further sequences in the near future."

With the two T. brucei genome sequences in hand, the team reportedly plans to use these sequences to help characterize additional isolates — work that's expected to help tease apart genetic changes that allow human infection and provide clues about regions of the parasite genome that may be targeted by new treatments.

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