Genome sequences of three important parasites have been published, revealing some peculiar aspects of trypanosomatid biology that provide important clues for drug development. Information contained in the genomes of Trypanosoma cruzi (the agent of Chagas disease), Trypanosoma brucei (the agent of sleeping sickness) and Leishmania major (the agent of leishmaniasis) is revealed after some 100 years of research aimed at preventing and treating these diseases, which are widespread in the Southern Hemisphere.

Three genome papers, accompanied by further analyses papers — most notably, the comparative genomic analysis of El-Sayed and Myler et al. — are the result of an international collaborative effort. They are somewhat unusual: although each paper focuses on the genome of a particular protozoan, it also presents a cross-species comparison of selected aspects of trypanosomatid biology. The paper on T. cruzi discusses DNA replication and repair machinery, as well as retrotransposon content; the paper on T. brucei compares metabolic pathways and aspects of cell biology; and the paper on T. major describes unusual aspects of gene expression in these organisms.

The haploid genomes of these three parasites range from 25 to 55 Mb. They share a core of ∼6,200 conserved genes and their genomes show a high degree of synteny. Strikingly, most genes are arranged in long directional clusters, which are most probably transcribed polycistronically and subsequently processed into separate mRNAs. Although the three genomes seem to encode few transcriptional regulators, they encode an uncharacteristically high number of proteins with RNA-binding motifs. These observations support previous suggestions that trypanosome gene expression is mainly regulated post-transcriptionally. The lack of sophisticated transcriptional control has another interesting implication — increased expression levels are achieved through gene duplication or amplification.

Aspects of DNA replication and repair are curiously different in trypanosomatids from the rest of the eukaryotes. Genes that are implicated in response to oxidative stress are missing from these genomes, as are those that encode the non-homologous end-joining machinery. In addition, the replication-initiation machinery is more reminiscent of that found in the Archaea than the eukaryote version.

Although related, each of these parasites has evolved a different strategy for parasitic survival. For example, the switching of variant surface glycoprotein (VSG) expression in T. brucei is a textbook mechanism for evading the host's immune response. Although much is known about VSGs already, genome sequencing revealed that most of them form subtelomeric arrays and are defective — only 7% of analysed VSGs were functional. Arrays of defective VSGs could serve as an important reservoir of variation.

The quirks and peculiarities of trypanosomatid biology are of great biological and evolutionary interest. But importantly, they also have clear practical implications. Trypanosome-specific protein kinases, bacteria-like mitochondrial DNA polymerases and specific surface-protein modifications can all be explored as potential drug targets. We can now look forward to some effective treatments and perhaps the prevention of three important diseases, and so our luck might be changing in what until now was a losing battle.