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Protozomics: trypanosomatid parasite genetics comes of age

Nature Reviews Genetics volume 4, pages 11–19 (2003)Cite this article

Key Points

  • Trypanosomatid protozoans are responsible for some of the most devastating and, as yet, poorly controlled diseases of tropical and semi-tropical countries.

  • In the past ten years, a comprehensive molecular genetic 'toolkit' has become available for their study, including efficient methods of transient and stable DNA transfection, expression vectors, homologous gene replacements and transposon mutagenesis.

  • Classical genetics is difficult in African trypanosomes due to the requirement for a tsetse fly colony, and it is impossible in Leishmania, as proved by unsuccessful laboratory crosses.

  • In trypanosomes, RNA interference (RNAi) technology has proved an especially powerful tool as it can be readily applied to inactivate transcripts from any gene. By contrast, RNAi methods have so far been unsuccessful in Leishmania, possibly because it has lost this pathway and therefore normally tolerates significant levels of endogenous double-stranded RNAs.

  • Forward genetics in Leishmania has been established using powerful selections for mutants and functional rescue after cosmid library transfection.

  • RNAi 'knockdown' libraries have recently enabled forward genetics approaches in trypanosomes.

  • Differences in the efficacy of genetic methods in Leishmania and trypanosomes have steered investigators to focus on different aspects of parasite biology in these organisms.

Abstract

Trypanosomatid protozoans cause important diseases of humans and their domestic livestock. Various molecular genetic tools are now allowing rapid progress in understanding many of the unique aspects of the molecular and cell biology of these organisms. Diploidy and the lack or difficulty of sexual crossing has been a challenge for forward genetics, but powerful selections and functional complementation have helped to overcome it in Leishmania. RNA interference has been adapted for forward genetics in trypanosomes, in which it is also a powerful tool for reverse genetics. Interestingly, the efficacy of different genetic tools has steered research into different aspects of the biology of these parasites.

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Figure 1: Comparison of forward genetics in Leishmania and Trypanosoma brucei.

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Acknowledgements

I thank K. Robinson and members of my lab, P. Sharp, J. Donelson, N. Fasel, J. Patterson, R. Tarleton and S. Turco for stimulating discussions and suggestions, and D. Dobson for reading this manuscript. S.M.B. is supported by grants from the National Institutes of Health.

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  1. Department of Molecular Microbiology, Washington University Medical School, St Louis, 63110, Missouri, USA

    Stephen M. Beverley

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FURTHER INFORMATION

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Woods Hole Molecular Parasitology Meeting abstracts

Glossary

ANTIGENIC VARIATION

The changing of the surface antigens by a pathogen to evade the immune response of the host.

SPECTRAL DISEASE

Infections that can manifest in several forms, often varying greatly in severity and symptoms in different individuals, probably reflecting differences in the immune response of the host.

PHAGOLYSOSOME

A vacuole in a cell in which a phagocytosed particle is digested.

ENDOSYMBIONT

An organism which lives in the cells of a host organism in a mutualistic relationship or while doing no apparent harm.

POLYCISTRONIC TRANSCRIPTION

The transcription of two or more adjacent open reading frames after a single transcription initiation event. In trypanosomatids, this might extend more than 60 kb and encompass dozens of open reading frames.

BENT DNA

Intrinsically bent DNA arises from a series of 8–10 adenine residues on the same strand that is thought to assist in packaging it into a tight network.

KINETOPLAST

An organelle in the mitochondrion that consists of a large concatenated DNA network of both minicircles (each with an intrinsically 'bent' sequence and guide RNAs required for RNA editing) and maxicircles (which encode genes that are typically associated with mitochondrial DNA in other organisms). It is a defining feature of the protozoan order Kinetoplastida, to which the trypanosomes belong.

GLYCOSOME

A subcellular compartment, related to the peroxisome, originally named because it contains glycolytic enzymes, although other enzymes have subsequently been found there.

ACIDOCALCISOME

An organelle that contains high concentrations of calcium and polyphosphates. Its role is poorly understood, but it might function as a reservoir for calcium in intracellular signalling and for energy.

FLAGELLAR POCKET

A 'pocket-like' invagination of the cellular membrane from which the flagellum arises in trypanosomatids.

EPISOME

A replicon that can exist either extrachromosomally or when integrated into the bacterial chromosome.

ANEUPLOID

Having an unbalanced chromosome number. An example is trisomy.

POLYPLOID

Having more than two complete sets of chromosomes (two sets being the prevalent diploid state).

LOSS OF HETEROZYGOSITY

(LOH). A loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome mis-segregration.

PANNING

A technique for isolating parasite subpopulations; monoclonal antibodies or lectins are attached to solid supports over which parasite populations are passed and allowed to attach; after washing, bound parasites are eluted and recovered.

FLUORESCENCE ACTIVATED CELL SORTING

(FACS). The separation of cells or chromosomes by their fluorescence and light-scattering properties, which are measured as the particles flow in a liquid stream past laser beams. The stream is then broken into droplets, and selected droplets are electrically charged and deflected into collection vessels as they pass through an electric field.

MASS SPECTROMETRY

A technique that provides accurate information about the molecular mass of complex molecules. It can identify extremely small amounts of proteins by their mass-fragment spectra.

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Beverley, S. Protozomics: trypanosomatid parasite genetics comes of age. Nat Rev Genet 4, 11–19 (2003). https://doi.org/10.1038/nrg980

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