A report on the Keystone Symposium on Molecular Helminthology, Copper Mountain, Colorado, USA, 9-13 April 2005

Blaxter, M.

English

PubMed

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Molecular helminthology in the RockiesCitation for published version:Blaxter, M 2005, 'Molecular helminthology in the Rockies' Genome Biology, vol 6, no. 7, 329., 10.1186/gb-2005-6-7-329Digital Object Identifier (DOI):10.1186/gb-2005-6-7-329Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher final version (usually the publisher pdf)Published In:Genome BiologyGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015Genome Biology 2005, 6:329commentreviewsreportsdeposited researchinteractionsinformationrefereed researchMeeting reportMolecular helminthology in the RockiesMark BlaxterAddress: Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, King’s Buildings, Edinburgh EH9 3JT, UK.E-mail: mark.blaxter@ed.ac.ukPublished: 10 June 2005Genome Biology 2005, 6:329 (doi:10.1186/gb-2005-6-7-329)The electronic version of this article is the complete one and can befound online at http://genomebiology.com/2005/6/7/329© 2005 BioMed Central Ltd A report on the Keystone Symposium on MolecularHelminthology, Copper Mountain, Colorado, USA, 9-13April 2005.Introduce most genome biologists to a parasitic worm andtheir thoughts are likely to turn rapidly to exit strategies. Tothe research community gathered recently for a Keystonemeeting on molecular helminthology in Colorado, however,these organisms are fascinating highpoints of evolution, withbiological tricks aplenty and many lessons to teach on thehows and whys of genomic diversity. They are also, ofcourse, major determinants of human health and happinessworldwide. And even if there were faint-hearted fellow trav-ellers at the meeting, 30 inches of snow closing both theairport and the interstate highway ensured that we were alltrapped for the duration.Helminthology is a phylogenetically incorrect discipline,encompassing widely separated parasitic platyhelminths(flatworms) and parasitic nematodes (roundworms). Platy-helminths are members of the Lophotrochozoa, a diversesuperphylum of nonvertebrate animals that includesannelids and molluscs. Nematodes are members of the othermajor group of nonvertebrates, the Ecdysozoa, which alsoincludes arthropods. Their conjunction as ‘helminths’ stemsfrom outmoded systematic concepts but has been preservedbecause these parasites are usefully linked by their lifestylesas metazoan parasites of metazoan hosts. While only a smallsubset of helminth diversity was discussed, the content ofthe meeting should be of interest to anyone with a phylo-genomic bent. In particular, it offered an overview of thefirst genome sequence from any lophotrochozoan and a rich-ness of comparative nematode genome data to place along-side the Caenorhabditis model. Given that the parasiteshave coevolved with their hosts, the coevolution of immuneeffector and immune evasion strategies was also explored.Platyhelminth genomes and functionalgenomics Status updates on the two major parasitic helminth genomeprojects now underway were presented to the assembledresearch communities. The genome sequence from thetrematode flatworm Schistosoma mansoni [http://www.schistodb.org] is nearing completion, as reported in a jointpresentation by Najib El Sayed (The Institute of GenomicResearch (TIGR), Rockville, USA) and Matthew Berriman(The Sanger Institute, Cambridge, UK). The S. mansonigenome is estimated to be approximately 300 megabases(Mb) in size, and extensive expressed sequence tag (EST)and open reading-frame expressed sequence tag (ORESTES)surveys have suggested the ‘usual’ nonvertebrate metazoancount of 15,000 to 20,000 protein-coding genes. TIGR andthe Sanger Institute have been pursuing a whole-genomeshotgun strategy, and reported a ninefold coverage assem-bly. A major issue in assembly has been polymorphism: thestrain of parasite used was not particularly inbred(S. mansoni is an obligately sexual species), and thus assem-bly parameters have had to be finely tuned to accept allelicpolymorphisms. The experience gained in assembly of thisgenome is likely to be invaluable as additional, ‘wild’ non-model organisms join the sequencing queues. TheS. mansoni genome is very rich in repeats and retrotrans-posons, and this feature has made long-range assembly, par-ticularly with fingerprint maps, difficult.The availability of whole-genome shotgun and EST data hasspurred much activity in functional genomic analysis ofS. mansoni. The parasite has a complex life cycle involvingtwo hosts (a snail and a human) and many morphologicalstages, some of which are difficult to access. New data on rel-atively robust, penetrant and persistent RNA interference(RNAi) using small interfering RNAs (siRNAs) directedagainst S. mansoni genes encoding a glucose transporter anda CD36-like scavenger receptor were presented by TimothyYoshino (University of Wisconsin, Madison, USA). JasonCorrenti (University of Pennsylvania, Philadelphia, USA)described continuing RNAi effects on a cathepsin B proteasefrom treated larvae through to adult schistosomes in themammalian bloodstream. RNAi was also used to investigatethe roles of possible drug targets such as peroxiredoxins, asreported by Ahmed Abd El-Aziz Sayed (Illinois State Univer-sity, Normal, USA), and serotonin signaling, as described byNicholas Patocka (McGill University, Montreal, Canada). Inboth cases RNAi identified these targets as essential forworm survival. RNAi could be used as a rapid first screen ofthe drug-target potential of genes identified in the parasitegenome sequence. Christoph Grevelding (Institute for Para-sitology, Giessen, Germany) reported attempts at transgene-sis, but as yet only transient transfection has been achieved. Nematode genomic diversityNematode enthusiasts were also well served at the meeting,with one nearly complete and one preliminary whole-genome shotgun survey of parasite genomes and evidence ofreliable RNAi and transgenesis in important parasitespecies. Of course, for the nematodes, stellar comparatorsare available, with the fully characterized genome ofCaenorhabditis elegans and drafts for other Caenorhabditisspecies. Elodie Ghedin (TIGR) updated us on the genomesequence of Brugia malayi, a tissue-dwelling human para-site and a causative agent of elephantiasis, based on an 8.5-fold coverage whole-genome shotgun assembly. At 80 Mbthe B. malayi genome appears to be smaller than that ofC. elegans and, as average gene size is larger, Brugia mayhave less than 70% of the number of genes of its free-livingdistant relative. As many B. malayi genes are absent fromC. elegans but present in other metazoans, the genetic dis-parity may be even more extreme. As Vincent Laudet (EcoleNormale Supérieure, Lyon, France) discussed in the keynoteaddress, the C. elegans proteome is famously marked out byhaving more than 250 nuclear hormone receptors comparedto the normal number of 20-30 in other metazoans.B. malayi has a normal number of nuclear hormone recep-tors, but it appears to have a superfluity of phospholipaseA2-like domains and von Willebrand factor domains. Are theseassociated with its parasitic lifestyle? Makedonka Mitreva(Washington University School of Medicine, St Louis, USA)presented a single-pass whole-genome shotgun of thegenome of the hookworm Ancylostoma caninum, identify-ing a high proportion of repetitive sequence (approximately28%) but so far only around 10,000 genes in 72 Mb ofunique sequence. A. caninum is closer, phylogeneticallyspeaking, to C. elegans than either is to B. malayi, and thecomparison is likely to aid not just parasitology but alsocomprehension of the model organism genome.Another idiosyncratic feature of the C. elegans genome is thepresence of over 2,000 operons, consisting of two to eightgenes cotranscribed from a single promoter. Pre-mRNAsfrom these operons are resolved into monocistronic mRNAsthrough trans-splicing. Trans-splicing is also used on manyC. elegans genes not in operons. Trans-splicing is present ina wide phylogenetic range of eukaryotes, but its evolutionaryorigins remain obscure. While trans-splicing is found inapparently all nematodes, the enthusiasm of C. elegans (andclose relatives) for operons may be a limited speciality asGhedin reported identification of only around 40 operons inthe B. malayi genome. Richard Davis (University of Col-orado Health Sciences Center, Denver, USA) discussed thebiology of trans-splicing, and suggested that the phenome-non may be associated more with sanitizing 5’ UTRs (ensur-ing that they have no out-of-frame stop codons) than withmRNA stability or promotion of translation. Importantly, hereminded us that platyhelminths do trans-splicing too, andthat components specific to trans-splicing may be excellentdrug targets.Parasites know more about our immune systemthan we doA third theme of the meeting, involving both flatworms androundworms, concerned the interactions between parasitesand their hosts. Helminth parasites have been evolving sideby side with the mammalian immune system for many mil-lions of years, and ‘know’ how to manipulate it, often to dev-astating effect. Kalyanasundaram Ramaswamy (Universityof Illinois, Rockford, USA) has focused on the invasion ofschistosome larvae through the skin, and reported the iden-tification of unique flatworm products that have nodetectable similarity to any of the mammalian componentsof the pathways affected but still effectively silence or divertthe resident innate immune system. William Harnett (Uni-versity of Strathclyde, Glasgow, UK) has identified a glycanmodification on proteins secreted by filarial nematodes thatis a potent downregulator of damaging allergic responses,even in murine models of arthritic disease. Maria Yazdan-bakhsh (Leiden University Medical Center, Leiden, TheNetherlands) described how helminth infections bias thewhole of the immune system, making infected populationsless susceptible to allergy. She has identified a single schisto-some membrane lipid component that mirrors theseimmunomodulatory effects. Parasite-derived immunomodu-lators have promise as therapeutics for many immune-related pathologies, including asthma.As metazoans, helminth parasites share core regulatory,developmental and homeostatic pathways with their hosts,and evidence is mounting that parasites sense, respond toand manipulate their hosts’ signaling milieux. To reach matu-rity, S. mansoni requires host cytokine interleukin-7, asreported by Isabelle Wolowczuk (Institut Pasteur, Lille,France), and the thyroid hormone thyroxine, as described byJames McKerrow (University of California, San Francisco,USA), but whether these effects are direct or via some localenvironmental changes remains unclear. The cestodeEchinococcus multilocularis, another nasty flatworm parasite329.2 Genome Biology 2005, Volume 6, Issue 7, Article 329 Blaxter http://genomebiology.com/2005/6/7/329Genome Biology 2005, 6:329with a predilection for the liver, has an ability to grow un-noticed by the host for years. Klaus Brehm (University ofWürzburg, Germany) presented a stunning overview of con-served insulin, fibroblast growth factor and transforminggrowth factor-β (TGF-β) receptor pathways in Echinococcusthat mediate its survival in an in vitro analog of the liverphase. Strikingly, E. multilocularis recognizes humaninsulin and bone morphogenetic protein 2 (a TGF-β-familyligand) through its insulin and TGF receptor pathways, andthese stimulations were necessary for survival. This flat-worm displays convergent recognition of mammaliancytokines and signals based on co-option of ancient, con-served signaling modules to new functions.Plans are already in place to complete another 5 to 7 nema-tode genomes in the next two or three years, and the queueof successful species can only grow longer. The challengenow is to get the tools in place to analyze, interpret and testthe functions implied by genome sequences. This meetingshowed that the community is aware of this challenge andshould be ready for the deluge of data expected.commentreviewsreportsdeposited researchinteractionsinformationrefereed researchhttp://genomebiology.com/2005/6/7/329                                                                Genome Biology 2005, Volume 6, Issue 7, Article 329 Blaxter  329.3Genome Biology 2005, 6:329

Molecular helminthology in the Rockies

     Edinburgh Research Explorer                                      Molecular helminthology in the RockiesCitation for published version:Blaxter, M 2005, 'Molecular helminthology in the Rockies', Genome Biology, vol. 6, no. 7, 329.https://doi.org/10.1186/gb-2005-6-7-329Digital Object Identifier (DOI):10.1186/gb-2005-6-7-329Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:Genome BiologyGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 29. Nov. 2025Genome Biology 2005, 6:329commentreviewsreportsdeposited researchinteractionsinformationrefereed researchMeeting reportMolecular helminthology in the RockiesMark BlaxterAddress: Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, King’s Buildings, Edinburgh EH9 3JT, UK.E-mail: mark.blaxter@ed.ac.ukPublished: 10 June 2005Genome Biology 2005, 6:329 (doi:10.1186/gb-2005-6-7-329)The electronic version of this article is the complete one and can befound online at http://genomebiology.com/2005/6/7/329© 2005 BioMed Central Ltd A report on the Keystone Symposium on MolecularHelminthology, Copper Mountain, Colorado, USA, 9-13April 2005.Introduce most genome biologists to a parasitic worm andtheir thoughts are likely to turn rapidly to exit strategies. Tothe research community gathered recently for a Keystonemeeting on molecular helminthology in Colorado, however,these organisms are fascinating highpoints of evolution, withbiological tricks aplenty and many lessons to teach on thehows and whys of genomic diversity. They are also, ofcourse, major determinants of human health and happinessworldwide. And even if there were faint-hearted fellow trav-ellers at the meeting, 30 inches of snow closing both theairport and the interstate highway ensured that we were alltrapped for the duration.Helminthology is a phylogenetically incorrect discipline,encompassing widely separated parasitic platyhelminths(flatworms) and parasitic nematodes (roundworms). Platy-helminths are members of the Lophotrochozoa, a diversesuperphylum of nonvertebrate animals that includesannelids and molluscs. Nematodes are members of the othermajor group of nonvertebrates, the Ecdysozoa, which alsoincludes arthropods. Their conjunction as ‘helminths’ stemsfrom outmoded systematic concepts but has been preservedbecause these parasites are usefully linked by their lifestylesas metazoan parasites of metazoan hosts. While only a smallsubset of helminth diversity was discussed, the content ofthe meeting should be of interest to anyone with a phylo-genomic bent. In particular, it offered an overview of thefirst genome sequence from any lophotrochozoan and a rich-ness of comparative nematode genome data to place along-side the Caenorhabditis model. Given that the parasiteshave coevolved with their hosts, the coevolution of immuneeffector and immune evasion strategies was also explored.Platyhelminth genomes and functionalgenomics Status updates on the two major parasitic helminth genomeprojects now underway were presented to the assembledresearch communities. The genome sequence from thetrematode flatworm Schistosoma mansoni [http://www.schistodb.org] is nearing completion, as reported in a jointpresentation by Najib El Sayed (The Institute of GenomicResearch (TIGR), Rockville, USA) and Matthew Berriman(The Sanger Institute, Cambridge, UK). The S. mansonigenome is estimated to be approximately 300 megabases(Mb) in size, and extensive expressed sequence tag (EST)and open reading-frame expressed sequence tag (ORESTES)surveys have suggested the ‘usual’ nonvertebrate metazoancount of 15,000 to 20,000 protein-coding genes. TIGR andthe Sanger Institute have been pursuing a whole-genomeshotgun strategy, and reported a ninefold coverage assem-bly. A major issue in assembly has been polymorphism: thestrain of parasite used was not particularly inbred(S. mansoni is an obligately sexual species), and thus assem-bly parameters have had to be finely tuned to accept allelicpolymorphisms. The experience gained in assembly of thisgenome is likely to be invaluable as additional, ‘wild’ non-model organisms join the sequencing queues. TheS. mansoni genome is very rich in repeats and retrotrans-posons, and this feature has made long-range assembly, par-ticularly with fingerprint maps, difficult.The availability of whole-genome shotgun and EST data hasspurred much activity in functional genomic analysis ofS. mansoni. The parasite has a complex life cycle involvingtwo hosts (a snail and a human) and many morphologicalstages, some of which are difficult to access. New data on rel-atively robust, penetrant and persistent RNA interference(RNAi) using small interfering RNAs (siRNAs) directedagainst S. mansoni genes encoding a glucose transporter anda CD36-like scavenger receptor were presented by TimothyYoshino (University of Wisconsin, Madison, USA). JasonCorrenti (University of Pennsylvania, Philadelphia, USA)described continuing RNAi effects on a cathepsin B proteasefrom treated larvae through to adult schistosomes in themammalian bloodstream. RNAi was also used to investigatethe roles of possible drug targets such as peroxiredoxins, asreported by Ahmed Abd El-Aziz Sayed (Illinois State Univer-sity, Normal, USA), and serotonin signaling, as described byNicholas Patocka (McGill University, Montreal, Canada). Inboth cases RNAi identified these targets as essential forworm survival. RNAi could be used as a rapid first screen ofthe drug-target potential of genes identified in the parasitegenome sequence. Christoph Grevelding (Institute for Para-sitology, Giessen, Germany) reported attempts at transgene-sis, but as yet only transient transfection has been achieved. Nematode genomic diversityNematode enthusiasts were also well served at the meeting,with one nearly complete and one preliminary whole-genome shotgun survey of parasite genomes and evidence ofreliable RNAi and transgenesis in important parasitespecies. Of course, for the nematodes, stellar comparatorsare available, with the fully characterized genome ofCaenorhabditis elegans and drafts for other Caenorhabditisspecies. Elodie Ghedin (TIGR) updated us on the genomesequence of Brugia malayi, a tissue-dwelling human para-site and a causative agent of elephantiasis, based on an 8.5-fold coverage whole-genome shotgun assembly. At 80 Mbthe B. malayi genome appears to be smaller than that ofC. elegans and, as average gene size is larger, Brugia mayhave less than 70% of the number of genes of its free-livingdistant relative. As many B. malayi genes are absent fromC. elegans but present in other metazoans, the genetic dis-parity may be even more extreme. As Vincent Laudet (EcoleNormale Supérieure, Lyon, France) discussed in the keynoteaddress, the C. elegans proteome is famously marked out byhaving more than 250 nuclear hormone receptors comparedto the normal number of 20-30 in other metazoans.B. malayi has a normal number of nuclear hormone recep-tors, but it appears to have a superfluity of phospholipaseA2-like domains and von Willebrand factor domains. Are theseassociated with its parasitic lifestyle? Makedonka Mitreva(Washington University School of Medicine, St Louis, USA)presented a single-pass whole-genome shotgun of thegenome of the hookworm Ancylostoma caninum, identify-ing a high proportion of repetitive sequence (approximately28%) but so far only around 10,000 genes in 72 Mb ofunique sequence. A. caninum is closer, phylogeneticallyspeaking, to C. elegans than either is to B. malayi, and thecomparison is likely to aid not just parasitology but alsocomprehension of the model organism genome.Another idiosyncratic feature of the C. elegans genome is thepresence of over 2,000 operons, consisting of two to eightgenes cotranscribed from a single promoter. Pre-mRNAsfrom these operons are resolved into monocistronic mRNAsthrough trans-splicing. Trans-splicing is also used on manyC. elegans genes not in operons. Trans-splicing is present ina wide phylogenetic range of eukaryotes, but its evolutionaryorigins remain obscure. While trans-splicing is found inapparently all nematodes, the enthusiasm of C. elegans (andclose relatives) for operons may be a limited speciality asGhedin reported identification of only around 40 operons inthe B. malayi genome. Richard Davis (University of Col-orado Health Sciences Center, Denver, USA) discussed thebiology of trans-splicing, and suggested that the phenome-non may be associated more with sanitizing 5’ UTRs (ensur-ing that they have no out-of-frame stop codons) than withmRNA stability or promotion of translation. Importantly, hereminded us that platyhelminths do trans-splicing too, andthat components specific to trans-splicing may be excellentdrug targets.Parasites know more about our immune systemthan we doA third theme of the meeting, involving both flatworms androundworms, concerned the interactions between parasitesand their hosts. Helminth parasites have been evolving sideby side with the mammalian immune system for many mil-lions of years, and ‘know’ how to manipulate it, often to dev-astating effect. Kalyanasundaram Ramaswamy (Universityof Illinois, Rockford, USA) has focused on the invasion ofschistosome larvae through the skin, and reported the iden-tification of unique flatworm products that have nodetectable similarity to any of the mammalian componentsof the pathways affected but still effectively silence or divertthe resident innate immune system. William Harnett (Uni-versity of Strathclyde, Glasgow, UK) has identified a glycanmodification on proteins secreted by filarial nematodes thatis a potent downregulator of damaging allergic responses,even in murine models of arthritic disease. Maria Yazdan-bakhsh (Leiden University Medical Center, Leiden, TheNetherlands) described how helminth infections bias thewhole of the immune system, making infected populationsless susceptible to allergy. She has identified a single schisto-some membrane lipid component that mirrors theseimmunomodulatory effects. Parasite-derived immunomodu-lators have promise as therapeutics for many immune-related pathologies, including asthma.As metazoans, helminth parasites share core regulatory,developmental and homeostatic pathways with their hosts,and evidence is mounting that parasites sense, respond toand manipulate their hosts’ signaling milieux. To reach matu-rity, S. mansoni requires host cytokine interleukin-7, asreported by Isabelle Wolowczuk (Institut Pasteur, Lille,France), and the thyroid hormone thyroxine, as described byJames McKerrow (University of California, San Francisco,USA), but whether these effects are direct or via some localenvironmental changes remains unclear. The cestodeEchinococcus multilocularis, another nasty flatworm parasite329.2 Genome Biology 2005, Volume 6, Issue 7, Article 329 Blaxter http://genomebiology.com/2005/6/7/329Genome Biology 2005, 6:329with a predilection for the liver, has an ability to grow un-noticed by the host for years. Klaus Brehm (University ofWürzburg, Germany) presented a stunning overview of con-served insulin, fibroblast growth factor and transforminggrowth factor-β (TGF-β) receptor pathways in Echinococcusthat mediate its survival in an in vitro analog of the liverphase. Strikingly, E. multilocularis recognizes humaninsulin and bone morphogenetic protein 2 (a TGF-β-familyligand) through its insulin and TGF receptor pathways, andthese stimulations were necessary for survival. This flat-worm displays convergent recognition of mammaliancytokines and signals based on co-option of ancient, con-served signaling modules to new functions.Plans are already in place to complete another 5 to 7 nema-tode genomes in the next two or three years, and the queueof successful species can only grow longer. The challengenow is to get the tools in place to analyze, interpret and testthe functions implied by genome sequences. This meetingshowed that the community is aware of this challenge andshould be ready for the deluge of data expected.commentreviewsreportsdeposited researchinteractionsinformationrefereed researchhttp://genomebiology.com/2005/6/7/329                                                                Genome Biology 2005, Volume 6, Issue 7, Article 329 Blaxter  329.3Genome Biology 2005, 6:329

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Molecular helminthology in the Rockies

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