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DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

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  • Authors: Richard McCulloch1, Liam J. Morrison2, James P.J. Hall4
  • Editors: Martin Gellert6, Nancy Craig7
    Affiliations: 1: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK; 2: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK; 3: Roslin Institute, University of Edinburgh, UK; 4: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK; 5: Department of Biology, University of York, York, UK; 6: National Institutes of Health, Bethesda, MD; 7: Johns Hopkins University, Baltimore, MD
  • Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
  • Received 23 April 2014 Accepted 29 April 2014 Published 05 March 2015
  • Richard McCulloch, [email protected]
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  • Abstract:

    Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of has revealed a massive archive of >1000 genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on , the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host–trypanosome interaction.

  • Citation: McCulloch R, Morrison L, Hall J. 2015. DNA Recombination Strategies During Antigenic Variation in the African Trypanosome. Microbiol Spectrum 3(2):MDNA3-0016-2014. doi:10.1128/microbiolspec.MDNA3-0016-2014.


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Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of has revealed a massive archive of >1000 genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on , the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host–trypanosome interaction.

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Architecture and singular transcription of variant surface glycoprotein () gene expression sites in . The four line diagrams show cartoon representations of telomeric expression sites. The top diagram shows a generic bloodstream expression site (BES), while the two diagrams below display examples of variant BES ( 48 ) in which pseudogenes (ψ, peach box) are found (BES 14) or where there has been loss of several expression site associated genes (s; dark blue box) or pseudogenes (light blue box) (BES 10). The final line diagram shows a expression site (MES) used in metacyclic form , which are found in the tsetse; here, the RNA polymerase I (Pol I) promoter (flag) does not drive expression of ESAGs, as it does in the BES, but only the (red box), which in all cases is found adjacent to the telomere (telo; vertical line). Upstream of the MES promoter, several pseudogenes have been described, suggesting that these sites were derived from the BES. Arrays of 70-bp DNA repeats in the BES and MES are shown (hatched box), which always appear to be upstream of genes or pseudogenes. Only one BES or MES is actively transcribed at a time in a single cell. A bloodstream form cell is shown, in which the nucleus is diagrammed. The single active BES (red, extended arrow denotes transcription) is shown associated with the expression site body (ESB, small green circle), which is spatially distinct from the nucleolus (large green circle), though both subnuclear structures are sites of RNA Pol I transcription. Silent BES (three are shown in black; truncated arrow denotes limited transcription) do not associate with the ESB or nucleolus.

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
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The variant surface glycoprotein () gene archive in . Whole chromosomes are shown separated by pulsed field gel electrophoresis and stained with ethidium bromide. To the left of the gel, the positions of the megabase chromosomes, intermediate chromosomes and minichromosomes that comprise the nuclear genome are indicated, including the size and number of the different chromosome classes. To the right of the gel, the different loci in which s are found are indicated (bloodstream expression site (BES), mini, array), including the number of s in each locus type and whether they are functional (intact, red box) or are pseudogenic (ψ, peach box). BES denotes s in expression sites that are used in the mammalian bloodstream and are found in the megabase and intermediate chromosomes. Mini denotes s found in the minichromosomes, and array denotes s found in the subtelomeres of the megabase chromosomes. In each case the presence or absence of a number of sequence features in addition to the is shown: the telomere (vertical line), 70-bp repeats (widely hatched box), expression site-associated genes (black box), the RNA Pol I promoter (arrow) and 177-bp repeats (narrow hatched box).

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
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Hierarchy of variant surface glycoprotein () gene switching by recombination during infections by . The graph depicts the log of the number of cells in a cow up to 70 days after infection (day 0). The schematic below details the timing of activation, by switching, of the different found in the genome ( type): silent telomeric s (telomere) are activated more frequently than intact, subtelomeric array s (array), which in turn are activated more frequently than pseudogenes (pseudo). Gene conversion is the most frequent route for the above activation events, and the features associated with gene conversion of each type are diagrammed. The expressed before a switch (blue box) is transcribed (dotted arrow) from a bloodstream expression site (BES), in which the is adjacent to the telomere (vertical line) and flanked upstream by 70-bp repeats (hatched box) and expression site associated genes (s; black boxes). The amount of sequence copied during gene conversion is shown. For telomeric s the sequence copied normally encompasses the open reading frame (red box) and extends upstream to the 70-bp repeats, but also can extend further upstream into the s if the silent is in an inactive BES; the downstream conversion limit may be the end of the , but can also extend to the telomere from either a minichromosome or inactive BES. Gene conversion of an intact subtelomeric array is more limited in the range of sequence copied. In segmental gene conversion parts of multiple, normally nonfunctional pseudogenes (orange, red or brown boxes) are combined to generate a novel mosaic ; though this is shown to occur in the BES, it is not known if this is the location of gene assembly. Note also, the pseudogene donors are shown for convenience as a contiguous array; in fact, segmental gene conversions using adjacent genes have never been observed.

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
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Complexity of variant surface glycoprotein () mosaics formed by segmental gene conversion in . (A) Where the 3′ boundary of segmental gene conversion occurs within the coding sequence of the (3′ donation), part or all of the previously expressed C-terminal-domain-(CTD) -encoding region of is retained, allowing the expression of a large contingent of silent s (red box) that contain frameshifts or stop codons towards their 3′ ends (frameshift or premature stop codon indicated by an asterisk); as in Fig. 3 , the recipient (blue) is shown in the bloodstream expression site (BES) and the extent of conversion is indicated (NTD denotes N-terminal domain). Donors of s formed in this way were found to share little sequence similarity over their whole sequence. (B) Mosaic s can allow (partial) expression of pseudogene s. Donors of s (pink box) formed in this way share relatively high levels of sequence similarity (73% identity at the nucleotide level). (C) Segmental gene conversion yields diverse products: the diagram shows nine different s detected during chronic infections ( 124 ); different donors are indicated in different colours, with 3′ donors indicated by hatching.

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
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Models for variant surface glycoprotein () recombination during antigenic variation in . (A) Recombination is shown initiated by a DNA double-strand break (DSB) in the 70 bp repeats (hatched box) upstream of the (black arrow) in the bloodstream expression site (BES) (s and promoter are not shown). Only factors that have been examined for a role in switching are indicated; those shown in color have been found to act, while those for whom no evidence of a role in switching has been found are shown in gray. DSB processing to reveal 3′ single-stranded ends is, in part, catalyzed by MRE11-RAD50-XRS2/NBS1 (MRX), generating a substrate on which RAD51 forms a nucleoprotein filament; note, however, that a further exonuclease (not shown) normally acts with MRX of both ends of the DSB are processed. RAD51 function is mediated by a number of factors: BRCA2 influences RAD51 filament dynamics, while the detailed roles of RAD51 paralogs (RAD51-3, RAD51-4, RAD51-5 and RAD51-6 in ) are unclear. RAD51 catalyzes repair by homology-dependent invasion of the single-stranded end into intact DNA (gray lines), containing a silent (gray arrow). Mismatch repair constrains homologous recombination to act only on sufficiently homologous sequences. Three pathways for DSB repair have been described and may contribute to switching. (B) DSB repair; here, newly synthesized DNA is copied from the intact DNA duplex and remains base-paired, generating Holliday junction structures whose enzymatic resolution can lead to gene conversion with (not shown) or without (shown) crossover of flanking sequence. In , RMI1-TOP3 has been shown to suppress crossover, by perhaps acting on the Holliday junctions. (C) Synthesis-dependent strand annealing; here, newly synthesized DNA is displaced from the intact duplex and reanneals with homologous sequence at the DSB, allowing synthesis of the other strand. Break-induced replication is shown in (D); in this mechanism, an origin-independent replication fork forms on the strand invasion intermediate allowing replication to the chromosome end.

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0016-2014
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