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GENETICS OF ANTIGENIC VARIATION 97 its efficient secretion. The trypanosome appears to monitor both the overall structure of VSG, perhaps through a specific chaperone molecule, and the presence of a GPI anchor. Both components are necessary for efficient exocytosis. Further studies of trypanosomes may illuminate the general roles of GPI anchors in protein sorting, secretion and endocytosis. GENETICS OF ANTIGENIC VARIATION Each VSG is encoded by a unique gene. Variation is usually not generated by contemporaneous recombination events between gene segments, or by fusion of constant and variable regions. Instead, the genome of T. brucei contains hundreds of competent VSG genes, together with a large number of pseudogenes that can nevertheless contribute, through recombination events, to the expressed repertoire. The repertoire is probably evolving and expanding continuously. Although some VSG genes are conserved between different trypanosome isolates, others are unique to particular clones, and the total potential VSG repertoire that exists in the field may be essentially infinite. If there are hundreds of VSG genes, how does the trypanosome determine that only one VSG appears on the cell surface? Part of the answer is that the expressed VSG is always located (or relocated) close to a telomere, in a polycistronic transcription unit that we call an expression site (ES). This appears to be a necessary but insufficient condition for the singularity of VSG expression, because there are several ESs, with very similar structures, that can be turned on and off without discernable changes in sequence or organization. The question then becomes why is only one ES transcribed at any time? This system raises many of the same issues and also represents an interesting paradigm for the general question of how many kinds of cells regulate the expression of one among many similar alleles. In no case is this kind of allelic selectivity completely understood. In mammals there are many examples of allelic exclusion, but ES switching may be a unique example of reversible allelic exclusion, perhaps because trypanosomes are continuously dividing, whereas allelic exclusion is generally an irreversible commitment that occurs at a particular stage of development or cellular differentiation. Olfactory receptors, which are encoded by the largest family – 1000 genes – in mammals, are perhaps the most extensive example of allelic exclusion, with each olfactory neuron expressing a single receptor gene. There are two well characterized classes of VSG expression sites, which differ dramatically in their organization and which operate in the two different infectious stages of the trypanosome life cycle. Both bloodstream and tsetse metacyclic ESs contain a VSG in the most telomere-proximal position, about 1–3 kb upstream of the hexanucleotide (TTAGGG) telomeric repeats. The ESs used in the bloodstream stage are transcribed from a promoter that is typically 30–50 kb upstream of the VSG, and 10–50 kb tracts of a conserved ‘50-bp repeat’ are found upstream of ES promoters (Figure 5.4). Between the promoter and the VSG, ESs typically contain eight to eleven ‘expressionsite-associated genes’ (ESAGs). Some ESAGs are present in multiple copies in some ESs. Some ESAGs appear to be truly unique to ESs, but others are members of larger families that are also found outside the ES (Table 5.1). ESs can also contain fragmentary remnants of ESAG sequences. In contrast, metacyclic ESs appear to be monocistronic: the promoter is immediately upstream from the telomeric VSG. All ESs MOLECULAR BIOLOGY
98 ANTIGENIC VARIATION A ‘Chromosome-internal’ VSG cassettes with ‘70-bp’ repeats and co-transposed regions VSG1 VSG2 VSG3 VSG4 I. VSG duplication and transposition (gene conversion) Pr* Pr ES1 10 7 6 ingi 5 4 8a 8b 3 2 1 VSG5 II. Telomere repair or conversion III. In situ switch from ES1 to ES3 4 8 3 2 1 VSG6 ES2 ES3 ‘50-bp’ repeats IV. Reciprocal ES recombination (not shown) 7 6 5 4 8 3 2 11 1 VSG7 Expression-Site-Associated Genes ‘70-bp’ repeats B ‘50-bp’ repeats ‘70-bp’ repeats CTR Telomere Scale: 10 kb GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT GTGTACTCGCCTGTACTAAAAGTATTCTCACAGGGGTGGCAGTATACTGT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATCAACAATAATGAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAATAATAATAATAATGAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAATGAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATACT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAATAAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAATAATAATGATAAT AGAAGAATGTTGTGAGTGTGTGCAGACGAATATTATAATAGGAACAGTAATAATAATGATAATGATGATAATGATAATGATAATGATAATAATGATAATAAT FIGURE 5.4 (See also Color Plate 3) (A) VSG expression site organization and alternative mechanisms for VSG switching. ESAGs are generally arranged in the order shown, but there can be duplications or triplications of some ESAGs and a duplicated promoter (Pr*) in some ESs. CTR is a region upstream of the VSG known as the co-transposed region: , a VSG pseudogene. (B) examples of the ‘50-bp’ and ‘70-bp’ repeat sequences found upstream of bloodstream-form ES promoters and VSGs, respectively. are transcribed by an RNA polymerase that is resistant to -amanitin, which is a characteristic of Pol I, the polymerase that normally transcribes rRNA. It seems likely that Pol I transcribes rRNA, VSG and procyclin genes in trypanosomes. To understand how this can be, and for further information about transcription in trypanosomes, the reader is referred to Chapter 3. Although both bloodstream and metacyclic ESs are transcribed by Pol I, the sequences of the two promoters differ, and they are probably differently regulated. What is similar is that each cell fully transcribes only one ES. MOLECULAR BIOLOGY
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Molecular Medical Parasitology
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Molecular Medical Parasitology Edit
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Contents List of contributors Prefa
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List of contributors Mark Blaxter,
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LIST OF CONTRIBUTORS ix Richard. J.
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Preface Parasitology was born as th
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S E C T I O N I MOLECULAR BIOLOGY
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C H A P T E R 1 Parasite genomics M
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TABLE 1.1 Parasite genomes: genome
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GENERATING GENOMICS DATA 7 differen
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GENERATING GENOMICS DATA 9 TABLE 1.
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GENERATING GENOMICS DATA 11 called
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GENERATING GENOMICS DATA 13 200 000
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BIOINFORMATICS AND THE ANALYSIS OF
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THE POST-GENOMICS ERA, AND THE OTHE
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THE PARASITES AND THEIR GENOMES 19
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FURTHER READING 27 treated with a d
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C H A P T E R 2 RNA processing in p
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TRANS-SPLICING 31 cis trans Exon 1
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TRANS-SPLICING 33 snRNPs (small nuc
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TRANS-SPLICING 35 trans cis U2AF35
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RNA EDITING 37 P AAAA... AAAA... AA
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RNA EDITING 39 entire transcript re
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RNA EDITING 41 5 Editing block C Ed
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RNA EDITING 43 microscopy) approach
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FURTHER READING 45 Nilsen, T.W. (19
Page 60 and 61: C H A P T E R 3 Transcription Arthu
Page 62 and 63: UNUSUAL MODES OF TRANSCRIPTION IN T
Page 64 and 65: CLASS I TRANSCRIPTION IN TRYPANOSOM
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Page 72 and 73: SL RNA AND U snRNA GENE TRANSCRIPTI
Page 78 and 79: FURTHER READING 65 and switching in
Page 80 and 81: C H A P T E R 4 Post-transcriptiona
Page 82 and 83: POST-TRANSCRIPTIONAL REGULATION IN
Page 100 and 101: FURTHER READING 87 inhibition, it m
Page 102 and 103: C H A P T E R 5 Antigenic variation
Page 104 and 105: ANTIGENIC VARIATION AT THE STRUCTUR
Page 106 and 107: ANTIGENIC VARIATION AT THE STRUCTUR
Page 108 and 109: VSG Signal sequence Amino-terminal
Page 112 and 113: GENETICS OF ANTIGENIC VARIATION 99
Page 114 and 115: GENETICS OF ANTIGENIC VARIATION 101
Page 116 and 117: IMMUNE RESPONSES TO TRYPANOSOME INF
Page 118 and 119: INNATE RESISTANCE, HUMAN SUSCEPTIBI
Page 120 and 121: ANTIGENIC VARIATION IN MALARIA 107
Page 122 and 123: FURTHER READING 109 ACKNOWLEDGEMENT
Page 124 and 125: C H A P T E R 6 Genetic and genomic
Page 126 and 127: ‘FORWARD’ VS. ‘REVERSE’ GEN
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Page 130 and 131: EXAMPLES OF ‘FORWARD’ GENETIC A
Page 132 and 133: REVERSE GENETICS AND LEISHMANIA VIR
Page 134 and 135: VALIDATION OF CANDIDATE VIRULENCE G
Page 136 and 137: S E C T I O N II BIOCHEMISTRY AND C
Page 138 and 139: C H A P T E R 7 Energy metabolism P
Page 140 and 141: SUBCELLULAR ORGANIZATION OF AMITOCH
Page 142 and 143: CELL MEMBRANE Fructose [b] Glucose
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
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FURTHER READING 153 for use in agri
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CARBOHYDRATE METABOLISM 155 as a hu
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158 ENERGY METABOLISM - APICOMPLEXA
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172 PROTEIN METABOLISM PROTEINS (1)
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174 PROTEIN METABOLISM the C-termin
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176 PROTEIN METABOLISM and also, to
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178 PROTEIN METABOLISM values rangi
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180 PROTEIN METABOLISM of the plasm
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182 PROTEIN METABOLISM in vivo, in
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184 PROTEIN METABOLISM PROLINE Poly
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186 PROTEIN METABOLISM CO 2 Dec-SAM
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188 PROTEIN METABOLISM a cMDH has b
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190 PROTEIN METABOLISM Urea ARGININ
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192 PROTEIN METABOLISM been describ
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194 PROTEIN METABOLISM absence of g
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198 PURINES AND PYRIMIDINES enable
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200 PURINES AND PYRIMIDINES provide
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202 PURINES AND PYRIMIDINES activit
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204 PURINES AND PYRIMIDINES physiol
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206 PURINES AND PYRIMIDINES Amitoch
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208 PURINES AND PYRIMIDINES their a
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210 PURINES AND PYRIMIDINES FIGURE
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214 PURINES AND PYRIMIDINES protein
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220 PURINES AND PYRIMIDINES in Plas
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222 PURINES AND PYRIMIDINES whereas
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226 TRYPANOSOMATID CARBOHYDRATES AF
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228 TRYPANOSOMATID CARBOHYDRATES In
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230 TRYPANOSOMATID CARBOHYDRATES po
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232 TRYPANOSOMATID CARBOHYDRATES LP
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234 TRYPANOSOMATID CARBOHYDRATES re
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236 TRYPANOSOMATID CARBOHYDRATES sc
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A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
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240 TRYPANOSOMATID CARBOHYDRATES Cr
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242 INTRACELLULAR SIGNALING protein
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244 INTRACELLULAR SIGNALING FIGURE
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246 INTRACELLULAR SIGNALING 212.5 2
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248 INTRACELLULAR SIGNALING cycle.
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250 INTRACELLULAR SIGNALING V-H -A
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252 INTRACELLULAR SIGNALING domain)
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254 INTRACELLULAR SIGNALING the kno
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256 INTRACELLULAR SIGNALING from in
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258 INTRACELLULAR SIGNALING FIGURE
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260 INTRACELLULAR SIGNALING ESAG4 (
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262 INTRACELLULAR SIGNALING and ind
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264 INTRACELLULAR SIGNALING ATPase
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266 INTRACELLULAR SIGNALING G11XG
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268 INTRACELLULAR SIGNALING a diffe
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270 INTRACELLULAR SIGNALING rapid l
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272 INTRACELLULAR SIGNALING cells w
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274 INTRACELLULAR SIGNALING PfPPJ i
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276 INTRACELLULAR SIGNALING is cont
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278 PLASTIDS, MITOCHONDRIA, AND HYD
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298 HELMINTH SURFACES Important exc
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300 HELMINTH SURFACES protease inhi
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302 HELMINTH SURFACES volume, there
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304 HELMINTH SURFACES projecting si
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306 HELMINTH SURFACES schistosome t
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308 HELMINTH SURFACES re-establish
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310 HELMINTH SURFACES hepatic cells
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312 HELMINTH SURFACES lungs. Larvae
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314 HELMINTH SURFACES cuticle, whic
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316 HELMINTH SURFACES cuticle in th
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318 HELMINTH SURFACES mec-8 or sym-
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320 HELMINTH SURFACES current, when
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322 HELMINTH SURFACES The cuticle-h
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324 HELMINTH SURFACES are typically
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326 HELMINTH SURFACES or carrier pr
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328 HELMINTH SURFACES of tyrosine-b
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330 HELMINTH SURFACES blood. The ge
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332 HELMINTH SURFACES Mutations in
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334 HELMINTH SURFACES in the hypode
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336 HELMINTH SURFACES (including H-
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338 HELMINTH SURFACES Blaxter, M.L.
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340 ENERGY METABOLISM IN HELMINTHS
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360 NEUROTRANSMITTERS CO 2 H NH 2 G
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362 NEUROTRANSMITTERS TABLE 15.1 An
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364 NEUROTRANSMITTERS more arms tha
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366 NEUROTRANSMITTERS the surroundi
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368 NEUROTRANSMITTERS proteins requ
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370 NEUROTRANSMITTERS FIGURE 15.11
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372 NEUROTRANSMITTERS FIGURE 15.13
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374 NEUROTRANSMITTERS sensitivity t
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376 NEUROTRANSMITTERS TABLE 15.3 Cl
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378 NEUROTRANSMITTERS crossed the c
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380 NEUROTRANSMITTERS have been tes
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382 NEUROTRANSMITTERS C-terminals a
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384 NEUROTRANSMITTERS Davis and Str
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386 NEUROTRANSMITTERS Cephalic gang
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388 NEUROTRANSMITTERS myoexcitation
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390 NEUROTRANSMITTERS is phosphoryl
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392 NEUROTRANSMITTERS many other an
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398 DRUG RESISTANCE of some of the
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400 DRUG RESISTANCE It is now estim
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402 DRUG RESISTANCE is again assume
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404 DRUG RESISTANCE An alternative
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406 DRUG RESISTANCE clinical eviden
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408 DRUG RESISTANCE FIGURE 16.4 Fol
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410 DRUG RESISTANCE Using similar s
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412 DRUG RESISTANCE whether these r
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414 DRUG RESISTANCE FIGURE 16.5 Str
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416 DRUG RESISTANCE FIGURE 16.6 Try
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418 DRUG RESISTANCE has permitted e
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420 DRUG RESISTANCE FIGURE 16.7 Dru
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422 DRUG RESISTANCE near future. Th
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424 DRUG RESISTANCE million new inf
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426 DRUG RESISTANCE some 50 million
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428 DRUG RESISTANCE pharynx, the bo
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430 DRUG RESISTANCE efforts for glo
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432 DRUG RESISTANCE and resistance
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434 MEDICAL IMPLICATIONS TABLE 17.1
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436 MEDICAL IMPLICATIONS TABLE 17.1
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438 MEDICAL IMPLICATIONS transmissi
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440 MEDICAL IMPLICATIONS H 2 C H H
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442 MEDICAL IMPLICATIONS parasites
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444 MEDICAL IMPLICATIONS neuropsych
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446 MEDICAL IMPLICATIONS of toxic f
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448 MEDICAL IMPLICATIONS Future con
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450 MEDICAL IMPLICATIONS Melarsopro
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452 MEDICAL IMPLICATIONS prevention
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454 MEDICAL IMPLICATIONS resulting
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456 MEDICAL IMPLICATIONS for S. ste
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458 MEDICAL IMPLICATIONS are though
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460 MEDICAL IMPLICATIONS FIGURE 17.
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462 MEDICAL IMPLICATIONS Marr, J.J.
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464 INDEX Aldolase, 143 Plasmodium
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466 INDEX Ascofuranone, 143 ASCUT-1
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468 INDEX Cnidarians, RNA trans-spl
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470 INDEX Entamoeba, 125 Ca 2 metab
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472 INDEX Glucose-6-phosphate dehyd
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474 INDEX Ivermectin, 398, 427, 455
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476 INDEX Maduramicin, 412 Major va
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478 INDEX Nitric oxide: neurotransm
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480 INDEX calcium-binding proteins,
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482 INDEX Pyrimidine transport, 200
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484 INDEX Succinate:rhodoquinone ox
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486 INDEX genome, 21 survey sequenc
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488 INDEX U small nuclear RNA (snRN
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