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Contingency genes are common in pathogenic microbes and enable, through pre-emptive mutational events, rapid, clonal switches in phenotype that are conducive to survival and proliferation in hosts. Antigenic variation, which is a highly successful survival strategy employed by eubacterial and eukaryotic pathogens, involves large repertoires of distinct contingency genes that are expressed differentially, enabling evasion of host acquired immunity. Most, but not all, antigenic variation systems make extensive use of subtelomeres. Study of model systems has shown that subtelomeres have unusual properties, including reversible silencing of genes mediated by proteins binding to the telomere, and engagement in ectopic recombination with other subtelomeres. There is a general theory that subtelomeric location confers a capacity for gene diversification through such recombination, although experimental evidence is that there is no increased mitotic recombination at such loci and that sequence homogenisation occurs. Possible benefits of subtelomeric location for pathogen contingency systems are reversible gene silencing, which could contribute to systems for gene switching and mutually exclusive expression, and ectopic recombination, leading to gene family diversification. We examine, in several antigenic variation systems, what possible benefits apply.

African trypanosomes are unicellular, eukaryotic parasites that live extracellularly in a wide range of mammals, including humans. They have a surface coat, composed of variant surface glycoprotein (VSG), which probably is essential and acts as a defence against general innate immunity and against acquired immunity directed at invariant surface antigens. In effect, the VSG is the only antigen that the host can target, and each trypanosome expresses only one VSG. To counter specific antibodies againts the VSG, trypanosomes periodically undergo antigenic variation, the change to expression of another VSG. Antigenic variation belongs to the general survival strategy of enhanced phenotypic variation, where a subset of ‘contigency’ genes of viruses, bacteria and parasites hypermutate, allowing adaptation to hostile or changing environments. A fundamental feature of antigenic variation is its link with the population dynamics of trypanosomes within the single host. Antigenic variants appear hierachically within the mammalian host, with a mixture of order and randomness. The underlying mechanisms of this are not understood, although differential VSG gene activation may play a prominent part. Trypanosome antigenic variation has evolved a second arm in which the infective metalcyclic population in the tsetse fly expresses a defined mixture of VSGs, although again each trypanosome expresses a single VSG. Differential VSG expression enhances transmission to new hosts, in the case of blood-stream trypanosomes by prolonging infection, and in the metacyclic population by generating diversity that may counter existing partial immunity in reservoir hosts. Antigenic variation employs a huge repertoire of VSG genes. Only one is expressed at a time bloodstream trypanosomes, as a result of transcription being restricted to a set of about 20 bloodstream expression sites ( BES s), which are at chromosome telomeres. Only one BES is active at a time, probably through transcriptional elongation being inhibited in the silent BES s. Although transcriptional switching between BES s can effect a VSG switch, the most prolific switch route involves homologous recombination of deoxyribonucleic acid, usually by the copying of a silent gene into a BES . Hierarchical expression of VSGs may be dictated in part by the different types of locus occupied by VSG genes. The VSG genes expressed int the metacyclic population also occupy telomeric sites, which appear to be derived from BES s but have a simpler structure. Their differential expression is achieved by random transcriptional activation; the detailed story requires direct study of the metacylic stage itself. Available evidence suggests that the VSG originated as a surface receptor, and it can be proposed that a number of selective events have contributed to the evolution of the complex, multisystem phenomenon that antigenic variation has become.

Antigenic variation is an immune evasion strategy used by African trypanosomes, in which the parasites periodically switch the expression of VSG genes that encode their protective variant surface glycoprotein coat. Two main routes exist for VSG switching: changing the transcriptional status between an active and an inactive copy of the site of VSG expression, called the bloodstream VSG expression site, or recombination reactions that move silent VSGs or VSG copies into the actively transcribed expression site. Nothing is known about the proteins that control and catalyze these switching reactions. This study describes the cloning of a trypanosome gene encoding RAD51, an enzyme involved in DNA break repair and genetic exchange, and analysis of the role of the enzyme in antigenic variation. Trypanosomes genetically inactivated in the RAD51 gene were shown to be viable, and had phenotypes consistent with lacking functional expression of an enzyme of homologous recombination. The mutants had an impaired ability to undergo VSG switching, and it appeared that both recombinational and transcriptional switching reactions were down-regulated, indicating that RAD51 either catalyzes or regulates antigenic variation. Switching events were still detectable, however, so it appears that trypanosome factors other than RAD51 can also provide for antigenic variation.