Molecular biology of trypanosome antigenic variation.
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abstract
African trypanosomes have evolved a complex mechanism for sequentially expressing one, and only one, VSG gene from a repertoire of several hundred to several thousand VSG genes. Intrachromosomal VSG genes are only transcribed after they have been duplicatively transposed to one of at least several telomere-linked expression sites. During the switch to the expression of another VSG gene, these ELCs are usually lost but sometimes linger in the genome. VSG genes already located near telomeres can be transcribed either in situ or via duplicative transposition to an expression site near another telomere. Therefore, proximity to a telomere is necessary but not sufficient for transcription. Other unknown factors are involved and are the subject of intense investigation in a number of laboratories. The 5' termini of the mRNAs for many, if not all, trypanosome proteins contain the same 35 nucleotides about which there are also many questions waiting to be answered. In one sense our knowledge of VSG gene regulation has now reached the level of sophistication at which other eucaryotic gene regulation systems are understood, and its further elucidation is stymied by the same bottleneck as research on these other systems. That is to say, we know that VSG gene regulation occurs at the transcriptional level, the structures of several genes and their flanking regions have been determined, and experimental conditions for identifying differential expression of the genes have been established. However, we can say very little about the precise molecular details that control the transcription initiation of the VSG gene. Nor can we say much about the events that trigger the switch from the transcription of one telomere-linked VSG gene to another. The experimental reason for this current roadblock in further understanding variation is much the same as with other eucaryotic gene regulation systems. We have to rely on molecular biology techniques as substitutes for the rigorous application of the tools of genetics. Without genetic mutants that affect gene regulation, it is difficult to ask specific questions about the regulation mechanisms. Because trypanosome genetic techniques are developing slowly, the study of antigenic variation will probably need to depend on these molecular biology approaches for at least a while longer. One technical advance would be the development of a trypanosome transformation system. The ability to introduce specific VSG genes into the parasite may not answer all of the questions about antigenic variation but it would permit the design of many novel experiments. The characterization of amplified DNA regions in a methotrexate-resistant strain of Leishmania tropica (13, 37), a related organism, provides hope that it may be possible to isolate trypanosome genes that can be used as drug resistance markers for testing various transformation procedures. Perhaps the major lesson to emerge from the past 5 years of research is that trypanosomes have a sufficient number of unique and interesting features to keep researchers occupied for many years to come.
