Chapter 17 : The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen,

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As a parasite that causes a variety of chronic human and livestock diseases in Africa and elsewhere, the trypanosome needs to overcome a number of grand challenges mounted, directly or indirectly, by its wide range of hosts. In general, the adaptations are all to do with the generation, diversification, and regulation of hypervariant, multigene families, the most important of which encodes thousands of variant surface glycoprotein (VSG) isoforms. To understand how the various interlinked processes in antigenic variation contribute to and are served by genome adaptations, it is necessary first to describe what we know, phenotypically and genotypically, about this variation system. Uniquely to the African trypanosomes that use antigenic variation, there is also a set of minichromosomes, number ~100. There is a set of potential transcription units, known as bloodstream expression sites (BES), adjacent to the telomeres of some of the megabase chromosomes and numbering 5 to 15 per genome, depending on the strain. The main function of BES is to provide transcription loci for VSG. Mechanisms for singular and differential expression of VSG center on the BES, which emphasizes the pivotal role of the expression site in antigenic variation. Importantly, short indels of a few bases also occur, creating frame-shifting: pseudogene formation. The other types of VSG locus also display signs of change through recombination, although fewer data are available.

Citation: Barry J. 2012. The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen, , p 286-302. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch17
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Image of FIGURE 1

The VSG protein and gene cassette. (A) Quaternary structure of the ILTat 1.24 VSG dimer (image courtesy of Mark Carrington), with the N-terminal domain (monomers purple or green) to the left and the C-terminal domain (both monomers orange) to the right. (B) Diagram of the VSG primary structure, showing signal peptide (light blue), the N-terminal domain (purple) with secondary structure indicated, and the C-terminal domain (orange). Accompanying the primary structure is an identity histogram of ILTat 1.24 and the six top ClustalW hits in the genome strain queried with the ILTat 1.24 VSG (N-and C-terminal domains queried separately), showing that conservation is greatest at the downstream end of the C-terminal domain. (C) Silent cassette, in which the coding sequence is color-coded to match the protein diagrams. The 70-bp tract delimiting the upstream end of the cassette is indicated by a hatched arrow. Beneath is a Jalview ( ) image of the alignment of two cassettes retrieved by ILTat 1.24 querying of the genome strain in geneDB (http://old.genedb.org/genedb/tryp/index.jsp), stretching 2,000 bp upstream and 200 bp downstream of the coding sequence. Extended vertical lines denote the cassette ends and the start codon. The only significant identity is at the cassette flanks. doi:10.1128/9781555817213.ch17f01

Citation: Barry J. 2012. The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen, , p 286-302. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch17
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Image of FIGURE 2

The genome. To the left are images of ethidium bromide-stained pulsed-field gel separations of genomic DNA of two strains of (images courtesy of Sara Melville); the positions and sizes of, and numbers within, each chromosome size class are shown alongside. To the right are maps of typical loci from the four genome compartments inhabited by . On the maps, solid-colored arrows indicate s, white arrows indicate other open reading frames, black vertically hatched arrows indicate 70-bp repeat tracts (shown as vertical lines when there are very few repeats in the tract), colored vertically hatched arrows indicate other repeat tracts (which have no direct role in antigenic variation), multiply repeated arrows with blue X's indicate telomere repeat tracts, right-angled arrows indicate promoters, and the flash symbol indicates active . The karyotypic locations of the genome compartments are indicated. doi:10.1128/9781555817213.ch17f02

Citation: Barry J. 2012. The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen, , p 286-302. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch17
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Image of FIGURE 3

switching. Maps of the genome compartments are as in Fig. 2 , and the five types of switch that have been observed in vivo in normally switching trypanosomes are depicted, in order of their probability in the switching hierarchy. Two BES are shown centrally, the left one with the and some of its flanks deleted following a spontaneous break that initiates recombinational switching. (1) A minichromosome donates a duplicate running from its 70-bp repeat tract to perhaps the end of the chromosome; (2) a silent BES donates as for switch type 1; (3) there is a reversible transcriptional switch between two BES (note that this mechanism would not be prompted by the break-deletion events in the active BES); (4) a cassette is duplicated from an intact array gene, replacing the cassette in the active BES—the 3′ limit of duplication could be anywhere from the start of the C-terminal domain-encoding sequence to within the 3′ UTR of the (5) one or more segments from one or more array (pseudo)s segmentally convert the in the BES. doi:10.1128/9781555817213.ch17f03

Citation: Barry J. 2012. The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen, , p 286-302. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch17
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Image of FIGURE 4

evolution. (A) The basic evolutionary protocol operating on the array. Benefits to the trypanosome of gene duplication are shown to the left, and benefits of divergence are shown to the right. (B) Divergence of recently duplicated N-terminal domains. ClustalW nucleotide alignments of high-identity N-terminal domains identified in the genome strain are displayed as Jalview images ( ). Each image shows identity as black and difference as white. The percent peptide and nucleotide identities of each pair are shown. The highest-identify pair shows some base substitutions (point mutations) and short indels, as well as one cluster of substitutions or a segmental conversion from another gene. Similar substitutions, short indels, and a segmental conversion are evident in the second pair, while the remaining two pairs show too many differences to allow interpretation. Examination of many such pairs shows no particular preference in the position of mutations. doi:10.1128/9781555817213.ch17f04

Citation: Barry J. 2012. The Fundamental Contribution of Genome Hypervariability to the Success of a Eukaryotic Pathogen, , p 286-302. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch17
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