Micro-exon Genes Research Articles

Winners vs. losers: Schistosoma mansoni intestinal and liver eggs exhibit striking differences in gene expression and immunogenicity.

The eggs of the blood fluke Schistosoma mansoni are the main cause of the clinical manifestations of chronic schistosomiasis. After laying, the egg "winners" attach to the endothelium of the mesenteric vein and, after a period of development, induce the growth of a small granuloma, which facilitates their passage to the intestinal lumen. Egg "losers" carried by the bloodstream to non-specific tissues also undergo full development and induce large granuloma formation, but their life ends there. Although these trapped eggs represent a dead end in the parasite life cycle, the vast majority of studies attempting to describe the biology of the S. mansoni eggs have studied these liver-trapped "losers" instead of migrating intestinal "winners". This raises the fundamental question of how these eggs differ. With robust comparative transcriptomic analysis performed on S. mansoni eggs isolated 7 weeks post infection, we show that gene expression is critically dependent on tissue localization, both in the early and late stages of development. While mitochondrial genes and venom allergen-like proteins are significantly upregulated in mature intestinal eggs, well-described egg immunomodulators IPSE/alpha-1 and omega-1, together with micro-exon genes, are predominantly expressed in liver eggs. In addition, several proteases and protease inhibitors previously implicated in egg-host interactions display clear tissue-specific gene expression patterns. These major differences in gene expression could be then reflected in the observed different ability of liver and intestinal soluble egg antigens to elicit host immune responses and in the shorter viability of miracidia hatched from liver eggs. Our comparative analysis provides a new perspective on the biology of parasite's eggs in the context of their development and tissue localization. These findings could contribute to a broader and more accurate understanding of parasite eggs interactions with the host, which have historically been often restricted to liver eggs and sometimes inaccurately generalized.

Revisiting Schistosoma mansoni Micro-Exon Gene (MEG) Protein Family: A Tour into Conserved Motifs and Annotation.

Genome sequencing of the human parasite Schistosoma mansoni revealed an interesting gene superfamily, called micro-exon gene (meg), that encodes secreted MEG proteins. The genes are composed of short exons (3-81 base pairs) regularly interspersed with long introns (up to 5 kbp). This article recollects 35 S. mansoni specific meg genes that are distributed over 7 autosomes and one pair of sex chromosomes and that code for at least 87 verified MEG proteins. We used various bioinformatics tools to produce an optimal alignment and propose a phylogenetic analysis. This work highlighted intriguing conserved patterns/motifs in the sequences of the highly variable MEG proteins. Based on the analyses, we were able to classify the verified MEG proteins into two subfamilies and to hypothesize their duplication and colonization of all the chromosomes. Together with motif identification, we also proposed to revisit MEGs' common names and annotation in order to avoid duplication, to help the reproducibility of research results and to avoid possible misunderstandings.

Divide, conquer and reconstruct: How to solve the 3D structure of recalcitrant Micro-Exon Gene (MEG) protein from Schistosoma mansoni.

Micro-Exon Genes are a widespread class of genes known for their high variability, widespread in the genome of parasitic trematodes such as Schistosoma mansoni. In this study, we present a strategy that allowed us to solve the structures of three alternatively spliced isoforms from the Schistoma mansoni MEG 2.1 family for the first time. All isoforms are hydrophobic, intrinsically disordered, and recalcitrant to be expressed in high yield in heterologous hosts. We resorted to the chemical synthesis of shorter pieces, before reconstructing the entire sequence. Here, we show that isoform 1 partially folds in a-helix in the presence of trifluoroethanol while isoform 2 features two rigid elbows, that maintain the peptide as disordered, preventing any structuring. Finally, isoform 3 is dominated by the signal peptide, which folds into a-helix. We demonstrated that combining biophysical techniques, like circular dichroism and nuclear magnetic resonance at natural abundance, with in silico molecular dynamics simulation for isoform 1 only, was the key to solve the structure of MEG 2.1. Our results provide a crucial piece to the puzzle of this elusive and highly variable class of proteins.

TheSchistosoma mansoninuclear receptor FTZ-F1 maintains esophageal gland function via transcriptional regulation ofmeg-8.3.

Schistosomes infect over 200 million of the world’s poorest people, but unfortunately treatment relies on a single drug. Nuclear hormone receptors are ligand-activated transcription factors that regulate diverse processes in metazoans, yet few have been functionally characterized in schistosomes. During a systematic analysis of nuclear receptor function, we found that an FTZ-F1-like receptor was essential for parasite survival. Using a combination of transcriptional profiling and chromatin immunoprecipitation (ChIP), we discovered that the micro-exon gene meg-8.3 is a transcriptional target of SmFTZ-F1. We found that both Smftz-f1 and meg-8.3 are required for esophageal gland maintenance as well as integrity of the worm’s head. Together, these studies define a new role for micro-exon gene function in the parasite and suggest that factors associated with the esophageal gland could represent viable therapeutic targets.

Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome.

The scientific community identified non stool-based biomarkers as the way forward to support soil-transmitted helminth (STH; Ascaris lumbricoides, Trichuris trichiura and the hookworms Ancylostoma duodenale and Necator americanus) and schistosome (S. mansoni and S. haematobium) deworming programs. This support is needed in making the decision of whether or not to stop preventive chemotherapy intervention efforts and to ultimately transition towards a post-intervention surveillance phase. We applied a two-step micro-array approach to identify antigenic linear epitopes in the STH and S. mansoni proteomes. In a first experiment, we identified antigenic peptides by applying sera from 24 STH and/or S. mansoni infected Ethiopian children on a high-density peptide microarray containing 3.3 million peptides derived from the complete STH and S. mansoni proteomes. A second array experiment with 170,185 peptides that were recognized in the first array was designed to identify non-specific antibody reactivity by applying sera from 24 healthy individuals from Belgium (a non-endemic country). From this array testing cascade, several peptides were identified for STH but none of them appeared to be unique for one species. We therefore concluded that for STH, none of the peptides revealed to be sufficiently sensitive or species specific. For S. mansoni, some promising peptides were identified prompting future investigation. Based on these results, it is unlikely that linear epitopes would be highly useful in detecting species-specific antibody responses to STH in endemic communities. For S. mansoni, one particular peptide of the micro-exon gene 12 (MEG-12) protein deserves further research. In addition, this study emphasizes the need of well-characterized biobanks for biomarker discovery, particularly when the integration of multiple disease programs is envisioned.

Complete representation of a tapeworm genome reveals chromosomes capped by centromeres, necessitating a dual role in segregation and protection

BackgroundChromosome-level assemblies are indispensable for accurate gene prediction, synteny assessment, and understanding higher-order genome architecture. Reference and draft genomes of key helminth species have been published, but little is yet known about the biology of their chromosomes. Here, we present the complete genome of the tapeworm Hymenolepis microstoma, providing a reference quality, end-to-end assembly that represents the first fully assembled genome of a spiralian/lophotrochozoan, revealing new insights into chromosome evolution.ResultsLong-read sequencing and optical mapping data were added to previous short-read data enabling complete re-assembly into six chromosomes, consistent with karyology. Small genome size (169 Mb) and lack of haploid variation (1 SNP/3.2 Mb) contributed to exceptionally high contiguity with only 85 gaps remaining in regions of low complexity sequence. Resolution of repeat regions reveals novel gene expansions, micro-exon genes, and spliced leader trans-splicing, and illuminates the landscape of transposable elements, explaining observed length differences in sister chromatids. Syntenic comparison with other parasitic flatworms shows conserved ancestral linkage groups indicating that the H. microstoma karyotype evolved through fusion events. Strikingly, the assembly reveals that the chromosomes terminate in centromeric arrays, indicating that these motifs play a role not only in segregation, but also in protecting the linear integrity and full lengths of chromosomes.ConclusionsDespite strong conservation of canonical telomeres, our results show that they can be substituted by more complex, species-specific sequences, as represented by centromeres. The assembly provides a robust platform for investigations that require complete genome representation.

Recombinant micro-exon gene 3 (MEG-3) antigens from Schistosoma mansoni failed to induce protection against infection but show potential for serological diagnosis

Sequence databases on Schistosoma mansoni have revealed micro-exon gene (MEGs) families. Many of these genes are highly expressed in parasite life cycle stages associated with the mammalian host infection and appear to be involved in immune evasion by schistosomes. So, we believe that MEG-coding proteins would make potential candidates for vaccine development or diagnosis for schistosomiasis. Here, we study MEG-3.2 and MEG-3.4, members of the MEG-3 family. Recombinant (r) proteins were produced and formulated with Freund's adjuvant for vaccination of mice. Immunization with recombinant MEG-3.2 or MEG-3.4 formulation generated high levels of IgG1 antibodies. Additionally, vaccination also induced a mixed Th1/Th2/Th17-type of response, since IFN-γ, IL-5 and IL-17 cytokines were detected in the supernatant of spleen cell cultures; however it failed to induce reduction in parasitic worm burden. Finally, the recombinant proteins were evaluated in a serological assay using human samples. Schistosome-infected individuals showed higher levels of both IgG and IgM against rMEG-3.2 compared to non-infected individuals, while only IgM anti-rMEG-3.4 antibodies were elevated in infected patients. Therefore, between both studied molecules, MEG-3.2 protein is the antigen that shows potential to compose a serological diagnosis test for schistosomiasis.

Interactions of amphipathic α-helical MEG proteins from Schistosomamansoni with membranes

Micro Exon Gene (MEG) proteins are thought to play major roles in the infection and survival of parasitic Schistosoma mansoni worms in host organisms. Here, the physical chemical properties of two small MEG proteins found in the genome of S. mansoni, named MEG-24 and MEG-27, were examined by a combination of biophysical techniques such as differential scanning calorimetry, tensiometry, circular dichroism, fluorescence, and electron spin resonance spectroscopies. The proteins are surface active and structurally arranged as cationic amphipathic α-helices that can associate with lipid membranes and cause their disruption. Upon adsorption to lipid membranes, MEG-27 strongly affects the fluidity of erythrocyte ghost membranes, whereas MEG-24 forms pores in erythrocytes without modifying the ghost membrane fluidity. Whole–mount in situ hybridization experiments indicates that MEG-27 and MEG-24 transcripts are located in the parasite esophagus and subtegumental cells, respectively, suggesting a relevant role of these proteins in the host-parasite interface. Taken together, these characteristics lead us to propose that these MEG proteins may interact with host cell membranes and potentially modulate the immune process using a similar mechanism as that described for α-helical membrane–active peptides.

Quantitative Proteomics of Enriched Esophageal and Gut Tissues from the Human Blood Fluke Schistosoma mansoni Pinpoints Secreted Proteins for Vaccine Development.

Schistosomes are blood-dwelling helminth parasites that cause schistosomiasis, a debilitating disease resulting in inflammation and, in extreme cases, multiple organ damage. Major challenges to control the transmission persist, and the discovery of protective antigens remains of critical importance for vaccine development. Rhesus macaques can self-cure following schistosome infection, generating antibodies that target proteins from the tegument, gut, and esophagus, the last of which is the least investigated. We developed a dissection technique that permitted increased sensitivity in a comparative proteomics profiling of schistosome esophagus and gut. Proteome analysis of the male schistosome esophagus identified 13 proteins encoded by microexon genes (MEGs), 11 of which were uniquely located in the esophageal glands. Based on this and transcriptome information, a QconCAT was designed for the absolute quantification of selected targets. MEGs 12, 4.2, and 4.1 and venom allergen-like protein 7 were the most abundant, spanning over 245 million to 6 million copies per cell, while aspartyl protease, palmitoyl thioesterase, and galactosyl transferase were present at <1 million copies. Antigenic variation by alternative splicing of MEG proteins was confirmed together with a specialized machinery for protein glycosylation/secretion in the esophagus. Moreover, some gastrodermal secretions were highly enriched in the gut, while others were more uniformly distributed throughout the parasite, potentially indicating lysosomal activity. Collectively, our findings provide a more rational, better-oriented selection of schistosome vaccine candidates in the context of a proven model of protective immunity.

Identification and Analysis of Micro-Exon Genes in the Rice Genome.

Micro-exons are a kind of exons with lengths no more than 51 nucleotides. They are generally ignored in genome annotation due to the short length, whereas recent studies indicate that they have special splicing properties and important functions. Considering that there has been no genome-wide study of micro-exons in plants up to now, we screened and analyzed genes containing micro-exons in two indica rice varieties in this study. According to the annotation of Zhenshan 97 (ZS97) and Minghui 63 (MH63), ~23% of genes possess micro-exons. We then identified micro-exons from RNA-seq data and found that >65% micro-exons had been annotated and most of novel micro-exons were located in gene regions. About 60% micro-exons were constitutively spliced, and the others were alternatively spliced in different tissues. Besides, we observed that approximately 54% of genes harboring micro-exons tended to be ancient genes, and 13% were Oryza genus-specific. Micro-exon genes were highly conserved in Oryza genus with consistent domains. In particular, the predicted protein structures showed that alternative splicing of in-frame micro-exons led to a local structural recombination, which might affect some core structure of domains, and alternative splicing of frame-shifting micro-exons usually resulted in premature termination of translation by introducing a stop codon or missing functional domains. Overall, our study provided the genome-wide distribution, evolutionary conservation, and potential functions of micro-exons in rice.

The Schistosome Esophagus Is a ‘Hotspot’ for Microexon and Lysosomal Hydrolase Gene Expression: Implications for Blood Processing

BackgroundThe schistosome esophagus is divided into anterior and posterior compartments, each surrounded by a dense cluster of gland cell bodies, the source of distinct secretory vesicles discharged into the lumen to initiate the processing of ingested blood. Erythrocytes are lysed in the lumen, leucocytes are tethered and killed and platelets are eliminated. We know little about the proteins secreted from the two glands that mediate these biological processes.Methodology/Principal FindingsWe have used subtractive RNA-Seq to characterise the complement of genes that are differentially expressed in a head preparation, compared to matched tissues from worm tails. The expression site of representative highlighted genes was then validated using whole munt in situ hybridisation (WISH). Mapping of transcript reads to the S. mansoni genome assembly using Cufflinks identified ~90 genes that were differentially expressed >fourfold in the head preparation; ~50 novel transcripts were also identified by de novo assembly using Trinity. The largest subset (27) of secreted proteins was encoded by microexon genes (MEGs), the most intense focus identified to date. Expression of three (MEGs 12, 16, 17) was confirmed in the anterior gland and five (MEGs 8.1, 9, 11, 15 and 22) in the posterior gland. The other major subset comprised nine lysosomal hydrolases (aspartyl proteases, phospholipases and palmitoyl thioesterase), again localised to the glands.ConclusionsA proportion of the MEG-encoded secretory proteins can be classified by their primary structure. We have suggested testable hypotheses about how they might function, in conjunction with the lysosomal hydrolases, to mediate the biological processes that occur in the esophagus lumen. Antibodies bind to the esophageal secretions in both permissive and self-curing hosts, suggesting that the proteins represent a novel panel of untested vaccine candidates. A second major task is to identify which of them can serve as immune targets.

Accelerated evolution of schistosome genes coding for proteins located at the host-parasite interface.

Study of proteins located at the host–parasite interface in schistosomes might provide clues about the mechanisms utilized by the parasite to escape the host immune system attack. Micro-exon gene (MEG) protein products and venom allergen-like (VAL) proteins have been shown to be present in schistosome secretions or associated with glands, which led to the hypothesis that they are important components in the molecular interaction of the parasite with the host. Phylogenetic and structural analysis of genes and their transcripts in these two classes shows that recent species-specific expansion of gene number for these families occurred separately in three different species of schistosomes. Enrichment of transposable elements in MEG and VAL genes in Schistosoma mansoni provides a credible mechanism for preferential expansion of gene numbers for these families. Analysis of the ratio between synonymous and nonsynonymous substitution rates (dN/dS) in the comparison between schistosome orthologs for the two classes of genes reveals significantly higher values when compared with a set of a control genes coding for secreted proteins, and for proteins previously localized in the tegument. Additional analyses of paralog genes indicate that exposure of the protein to the definitive host immune system is a determining factor leading to the higher than usual dN/dS values in those genes. The observation that two genes encoding S. mansoni vaccine candidate proteins, known to be exposed at the parasite surface, also display similar evolutionary dynamics suggests a broad response of the parasite to evolutionary pressure imposed by the definitive host immune system.

Transcriptional profiling of the oesophageal gland region of male worms of Schistosoma mansoni

The intestinal tract of schistosomes opens at the mouth and leads into the foregut or oesophageal region that is lined with syncytium continuous with the apical cytoplasm of the tegument. The oesophagus is surrounded by a specialised gland, the oesophageal gland. This gland releases materials into the lumen of the oesophagus and the region is thought to initiate the lysis of erythrocytes and neutralisation of immune effectors of the host. The oesophageal region is present in the early invasive schistosomulum, a stage potentially targetable by anti-schistosome vaccines. We used a 44k oligonucleotide microarray to identify highly up-regulated genes in microdissected frozen sections of the oesophageal gland of male worms of S. mansoni. We show that 122 genes were up-regulated 2-fold or higher in the oesophageal gland compared with a whole male worm tissue control. The enriched genes included several associated with lipid metabolism and transmembrane transport as well as some micro-exon genes. Since the oesophageal gland is important in the initiation of digestion and the fact that it develops early after invasion of the mammalian host, further study of selected highly up-regulated functionally important genes in this tissue may reveal new anti-schistosome intervention targets for schistosomiasis control.

Sm10.3, a member of the micro-exon gene 4 (MEG-4) family, induces erythrocyte agglutination in vitro and partially protects vaccinated mice against Schistosoma mansoni infection.

BackgroundThe parasitic flatworm Schistosoma mansoni is a blood fluke that causes schistosomiasis. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Numerous antigens that are expressed at the interface between the parasite and the mammalian host have been assessed. Among the most promising molecules are the proteins present in the tegument and digestive tract of the parasite.Methodology/Principal FindingsIn this study, we evaluated the potential of Sm10.3, a member of the micro-exon gene 4 (MEG-4) family, for use as part of a recombinant vaccine. We confirmed by real-time PCR that Sm10.3 was expressed at all stages of the parasite life cycle. The localization of Sm10.3 on the surface and lumen of the esophageal and intestinal tract in adult worms and lung-stage schistosomula was confirmed by confocal microscopy. We also show preliminary evidence that rSm10.3 induces erythrocyte agglutination in vitro. Immunization of mice with rSm10.3 induced a mixed Th1/Th2-type response, as IFN-γ, TNF-α, and low levels of IL-5 were detected in the supernatant of cultured splenocytes. The protective effect conferred by vaccination with rSm10.3 was demonstrated by 25.5–32% reduction in the worm burden, 32.9–43.6% reduction in the number of eggs per gram of hepatic tissue, a 23.8% reduction in the number of granulomas, an 11.8% reduction in the area of the granulomas and a 39.8% reduction in granuloma fibrosis.Conclusions/SignificanceOur data suggest that Sm10.3 is a potential candidate for use in developing a multi-antigen vaccine to control schistosomiasis and provide the first evidence for a possible role for Sm10.3 in the blood feeding process.

Folding Factors and Partners for the Intrinsically Disordered Protein Micro-Exon Gene 14 (MEG-14)

The micro-exon genes (MEG) of Schistosoma mansoni, a parasite responsible for the second most widely spread tropical disease, code for small secreted proteins with sequences unique to the Schistosoma genera. Bioinformatics analyses suggest the soluble domain of the MEG-14 protein will be largely disordered, and using synchrotron radiation circular dichroism spectroscopy, its secondary structure was shown to be essentially completely unfolded in aqueous solution. It does, however, show a strong propensity to fold into more ordered structures under a wide range of conditions. Partial folding was produced by increasing temperature (in a reversible process), contrary to the behavior of most soluble proteins. Furthermore, significant folding was observed in the presence of negatively charged lipids and detergents, but not in zwitterionic or neutral lipids or detergents. Absorption onto a surface followed by dehydration stimulated it to fold into a helical structure, as it did when the aqueous solution was replaced by nonaqueous solvents. Hydration of the dehydrated folded protein was accompanied by complete unfolding. These results support the identification of MEG-14 as a classic intrinsically disordered protein, and open the possibility of its interaction/folding with different partners and factors being related to multifunctional roles and states within the host.

Synchrotron Radiation Circular Dichroism Spectroscopy of MEG14, an Intrinsically Disordered Protein

The micro-exon genes (MEG) identified in the genome of Schistossoma mansoni, a flatworm parasite responsible for the second most widespread tropical disease, code for a class of small secreted proteins that are highly expressed in the human host stage. Due to the high variability in primary structure of the MEG proteins, the parasite is thought to recruit them to trick the host immune system; however, their specific function is still not understood. We have examined the secondary structure of MEG14, a member of this family, as well as the effects of a range of physical-chemical factors on its conformation, using synchrotron radiation circular dichroism (SRCD) spectroscopy and Oriented-SRCD. The SRCD spectrum of MEG14 in aqueous solution exhibits a strong minimum at 198 nm and a small positive band at 182 nm, corresponding a high content of disordered structure (>80%). However, disorder-to-order transitions that lead to the induction of an alpha-helix structure in MEG14 were noted by the addition of trifluoroethanol (≥ 50%) with negative peak at 208 and 222 nm and a stronger positive peak at 192 with a shoulder at 175 nm. This ordering effect was also produced by increasing temperature (in a reversible process), the presence of negatively charged lipids (like POPG and SDS), and absorption on a silica surface, followed by dehydration. Taken together with consideration of its primary structure (high content of charged and proline residues, low content of aromatic and/or hydrophobic residues), these results support the classification of MEG14 as good model of an intrinsically disordered protein, and suggest the possibility of its interaction with different partners in the host to produce multifunctional roles.(Support by grants from FAPESP, CNPq, MCTI, and the U.K. BBRSC, and beamtime from the ANKA, ISA and Soleil Synchrotrons)

Virulence factors of schistosomes

This review considers whether the products of schistosomes in the mammalian host can be considered as virulence factors. These include: the cercarial secretions used in infection, those of the migrating schistosomulum, surface-exposed proteins of adult worms in the portal system and their gut vomitus in the context of immune evasion, secretions of the egg facilitating its escape from gut tissues and micro-exon gene products.

Self/nonself recognition in Tuber melanosporum is not mediated by a heterokaryon incompatibility system

Vegetative incompatibility is a widespread phenomenon in filamentous ascomycetes, which limits formation of viable heterokaryons. Whether this phenomenon plays a role in maintaining the homokaryotic state of the hyphae during the vegetative growth of Tuber spp. Gene expression, polymorphism analysis as well as targeted in vitro experiments allowed us to test whether a heterokaryon incompatibility (HI) system operates in Tuber melanosporum. HI is controlled by different genetic systems, often involving HET domain genes and their partners whose interaction can trigger a cell death reaction. Putative homologues to HI-related genes previously characterized in Neurospora crassa and Podospora anserina were identified in the T. melanosporum genome. However, only two HET domain genes were found. In many other ascomycetes HET domains have been found within different genes including some members of the NWD (NACHT and WD-repeat associated domains) gene family of P. anserina. More than 50 NWD homologues were found in T. melanosporum but none of these contain a HET domain. All these T. melanosporum paralogs showed a conserved gene organization similar to the microexon genes only recently characterized in Schistosoma mansoni. Expression data of the annotated HI-like genes along with low allelic polymorphism suggest that they have cellular functions unrelated to HI. Moreover, morphological analyses did not provide evidence for HI reactions between pairs of genetically different T. melanosporum strains. Thus, the maintenance of the genetic integrity during the vegetative growth of this species likely depends on mechanisms that act before hyphal fusion.

Exploring the Schistosoma mansoni adult male transcriptome using RNA-seq

Schistosoma mansoni is one of the agents of schistosomiasis, a chronic and debilitating disease. Here we present a transcriptome-wide characterization of adult S. mansoni males by high-throughput RNA-sequencing. We obtained 1,620,432 high-quality ESTs from a directional strand-specific cDNA library, resulting in a 26% higher coverage of genome bases than that of the public ESTs available at NCBI. With a 15×-deep coverage of transcribed genomic regions, our data were able to (i) confirm for the first time 990 predictions without previous evidence of transcription; (ii) correct gene predictions; (iii) discover 989 and 1196 RNA-seq contigs that map to intergenic and intronic genomic regions, respectively, where no gene had been predicted before. These contigs could represent new protein-coding genes or non-coding RNAs (ncRNAs). Interestingly, we identified 11 novel Micro-exon genes (MEGs). These data reveal new features of the S. mansoni transcriptional landscape and significantly advance our understanding of the parasite transcriptome.

Gene structure and splicing in schistosomes

Schistosomes are blood dwelling platyhelminths with a complex life cycle and persist in the definitive host during decades, indicating that they are very successful parasites. The challenge of infecting two hosts from different evolutionary branches, namely an invertebrate snail and a vertebrate, suggests that Schistosomes must display a very sophisticated genetic program to circumvent all the barriers imposed by the hosts' immune systems. Recent large-scale genome and transcriptome data from Schistosomes are facilitating the analysis of gene structure and splicing. Studying the structure of genes coding for secreted proteins is of particular interest since these proteins mediate processes in the host-parasite interface. Recent description of Micro-Exon Genes (MEGs), polymorphic mucin genes (SmPoMucs) and venom allergen-like (SmVALs) proteins with unusual gene structure apparently oriented towards generation of protein variability through alternate splicing, and the presence of multiple copies of these genes, indicate that the parasite developed a sophisticated system to interact with its hosts. This opens up opportunities for further studies with the use of proteomic techniques to better characterize the protein variability created by these systems and their role in parasite survival. Complete description of the functions of these variable proteins will greatly contribute to our understanding of host-parasite interactions.