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.

Department of Biochemical Sciences Sapienza University of Rome 00185 Rome Italy

Department of Chemistry Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences 16500 Prague Czech Republic

Department of Zoology and Fisheries Center of Infectious Animal Diseases Czech University of Life Sciences 16500 Prague Czech Republic

UMR 5280 Institute of Analytical Sciences Université de Lyon CNRS Université Claude Bernard Lyon 1 69100 Villeurbanne France

Zobrazit více v PubMed

Lander E.S., Linton L.M., Birren B., Nusbaum C. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921. doi: 10.1038/35057062. PubMed DOI

Venter J.C., Adams M.D., Myers E.W., Li P.W., Mural R.J., Sutton G.G., Smith H.O., Yandell M., Evans C.A., Holt R.A., et al. The Sequence of the Human Genome. Science. 2001;291:1304–1351. doi: 10.1126/science.1058040. PubMed DOI

Alliance of Genome Resources Consortium. Agapite J., Albou L.-P., A Aleksander S., Alexander M., Anagnostopoulos A.V., Antonazzo G., Argasinska J., Arnaboldi V., Attrill H., et al. Harmonizing model organism data in the Alliance of Genome Resources. GENETICS. 2022;220:iyac022. doi: 10.1093/genetics/iyac022. PubMed DOI PMC

Zerlotini A., Oliveira G. The contributions of the Genome Project to the study of schistosomiasis. Mem. Inst. Oswaldo Cruz. 2010;105:367–369. doi: 10.1590/S0074-02762010000400003. PubMed DOI

Berriman M., Haas B.J., LoVerde P.T., Wilson R.A., Dillon G.P., Cerqueira G.C., Mashiyama S.T., Al-Lazikani B., Andrade L.F., Ashton P.D., et al. The genome of the blood fluke Schistosoma mansoni. Nature. 2009;460:352–358. doi: 10.1038/nature08160. PubMed DOI PMC

Silva L.L., Marcet-Houben M., Nahum L.A., Zerlotini A., Gabaldón T., Oliveira G. The Schistosoma mansoni phylome: Using evolutionary genomics to gain insight into a parasite’s biology. BMC Genom. 2012;13:617. doi: 10.1186/1471-2164-13-617. PubMed DOI PMC

Philippsen G.S. Transposable Elements in the Genome of Human Parasite Schistosoma mansoni: A Review. Trop. Med. Infect. Dis. 2021;6:126. doi: 10.3390/tropicalmed6030126. PubMed DOI PMC

Venancio T.M., Wilson R.A., Verjovski-Almeida S., DeMarco R. Bursts of transposition from non-long terminal repeat retrotransposon families of the RTE clade in Schistosoma mansoni. Int. J. Parasitol. 2010;40:743–749. doi: 10.1016/j.ijpara.2009.11.013. PubMed DOI

Hull R., Dlamini Z. The role played by alternative splicing in antigenic variability in human endo-parasites. Parasites Vectors. 2014;7:53. doi: 10.1186/1756-3305-7-53. PubMed DOI PMC

Davis R.E., Davis A.H., Carroll S.M., Rajkovic A., Rottman F.M. Tandemly Repeated Exons Encode 81-Base Repeats in Multiple, Developmentally Regulated Schistosoma mansoni Transcripts. Mol. Cell. Biol. 1988;8:4745–4755. doi: 10.1128/mcb.8.11.4745-4755.1988. PubMed DOI PMC

DeMarco R., Mathieson W., Manuel S.J., Dillon G.P., Curwen R.S., Ashton P.D., Ivens A.C., Berriman M., Verjovski-Almeida S., Wilson R.A. Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts. Genome Res. 2010;20:1112–1121. doi: 10.1101/gr.100099.109. PubMed DOI PMC

Howe K.L., Bolt B.J., Shafie M., Kersey P., Berriman M. WormBase ParaSite—A comprehensive resource for helminth genomics. Mol. Biochem. Parasitol. 2017;215:2–10. doi: 10.1016/j.molbiopara.2016.11.005. PubMed DOI PMC

Wilson R.A., Li X.H., MacDonald S., Neves L.X., Vitoriano-Souza J., Leite L.C.C., Farias L.P., James S., Ashton P.D., DeMarco R., et al. The Schistosome Esophagus Is a ‘Hotspot’ for Microexon and Lysosomal Hydrolase Gene Expression: Implications for Blood Processing. PLoS Neglected Trop. Dis. 2015;9:e0004272. doi: 10.1371/journal.pntd.0004272. PubMed DOI PMC

Anderson L., Amaral M.S., Beckedorff F., Silva L.F., Dazzani B., Oliveira K.C., Almeida G.T., Gomes M.R., Pires D.S., Setubal J.C., et al. Schistosoma mansoni Egg, Adult Male and Female Comparative Gene Expression Analysis and Identification of Novel Genes by RNA-Seq. PLoS Neglected Trop. Dis. 2015;9:e0004334. doi: 10.1371/journal.pntd.0004334. PubMed DOI PMC

Li X.H., de Castro-Borges W., Parker-Manuel S., Vance G.M., Demarco R., Neves L.X., Evans G.J., Wilson R.A. The schistosome oesophageal gland: Initiator of blood processing. PLoS Neglected Trop. Dis. 2013;7:e2337. doi: 10.1371/journal.pntd.0002337. PubMed DOI PMC

Lu Z., Sankaranarayanan G., Rawlinson K.A., Offord V., Brindley P.J., Berriman M., Rinaldi G. The Transcriptome of Schistosoma mansoni Developing Eggs Reveals Key Mediators in Pathogenesis and Life Cycle Propagation. Front. Trop. Dis. 2021;2:713123. doi: 10.3389/fitd.2021.713123. PubMed DOI PMC

The UniProt Consortium. Bateman A., Martin M.-J., Orchard S., Magrane M., Ahmad S., Alpi E., Bowler-Barnett E.H., Britto R., Bye-A-Jee H., et al. UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2023;51:D523–D531. doi: 10.1093/nar/gkac1052. PubMed DOI PMC

Altschul S.F., Madden T.L., Schäffer A.A., Zhang J., Zhang Z., Miller W., Lipman D.J. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389–3402. doi: 10.1093/nar/25.17.3389. PubMed DOI PMC

Notredame C., Higgins D.G., Heringa J. T-coffee: A novel method for fast and accurate multiple sequence alignment. J. Mol. Biol. 2000;302:205–217. doi: 10.1006/jmbi.2000.4042. PubMed DOI

Lassmann T., Sonnhammer E.L.L. Kalign, Kalignvu and Mumsa: Web servers for multiple sequence alignment. Nucleic Acids Res. 2006;34:W596–W599. doi: 10.1093/nar/gkl191. PubMed DOI PMC

Edgar R.C. MUSCLE: Multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32:1792–1797. doi: 10.1093/nar/gkh340. PubMed DOI PMC

Madeira F., Pearce M., Tivey A.R.N., Basutkar P., Lee J., Edbali O., Madhusoodanan N., Kolesnikov A., Lopez R. Search and sequence analysis tools services from EMBL-EBI in 2022. Nucleic Acids Res. 2022;50:W276–W279. doi: 10.1093/nar/gkac240. PubMed DOI PMC

Saitou N., Nei M. The neighbor-joining method: A new method for reconstructing evolutionary trees. Mol. Biol. Evol. 1987;4:406–425. doi: 10.1093/oxfordjournals.molbev.a040454. PubMed DOI

Löytynoja A., Goldman N. Phylogeny-Aware Gap Placement Prevents Errors in Sequence Alignment and Evolutionary Analysis. Science. 2008;320:1632–1635. doi: 10.1126/science.1158395. PubMed DOI

Letunic I., Bork P. Interactive Tree of Life (iTOL) v5: An online tool for phylogenetic tree display and annotation. Nucleic Acids Res. 2021;49:W293–W296. doi: 10.1093/nar/gkab301. PubMed DOI PMC

Crooks G.E., Hon G., Chandonia J.-M., Brenner S.E. WebLogo: A Sequence Logo Generator. Genome Res. 2004;14:1188–1190. doi: 10.1101/gr.849004. PubMed DOI PMC

Gasteiger E., Hoogland C., Gattiker A., Duvaud S., Wilkins M.R., Appel R.D., Bairoch A. Protein Identification and Analysis Tools on the Expasy Server. In: Walker J.M., editor. the Proteomics Protocols Handbook. Humana Press; Totowa, NJ, USA: 2005. pp. 571–607.

Duvaud S., Gabella C., Lisacek F., Stockinger H., Ioannidis V., Durinx C. Expasy, the Swiss Bioinformatics Resource Portal, as designed by its users. Nucleic Acids Res. 2021;49:W216–W227. doi: 10.1093/nar/gkab225. PubMed DOI PMC

Philippsen G.S., Wilson R.A., DeMarco R. Accelerated evolution of schistosome genes coding for proteins located at the host-parasite interface. Genome Biol. Evol. 2015;7:431–443. doi: 10.1093/gbe/evu287. PubMed DOI PMC

Mathieson W., Wilson R.A. A comparative proteomic study of the undeveloped and developed Schistosoma mansoni egg and its contents: The miracidium, hatch fluid and secretions. Int. J. Parasitol. 2010;40:617–628. doi: 10.1016/j.ijpara.2009.10.014. PubMed DOI

Fneich S., Théron A., Cosseau C., Rognon A., Aliaga B., Buard J., Duval D., Arancibia N., Boissier J., Roquis D., et al. Epigenetic origin of adaptive phenotypic variants in the human blood fluke Schistosoma mansoni. Epigenetics Chromatin. 2016;9:27. doi: 10.1186/s13072-016-0076-2. PubMed DOI PMC

Vlaminck J., Lagatie O., Dana D., Mekonnen Z., Geldhof P., Levecke B., Stuyver L.J. Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome. PLoS Neglected Trop. Dis. 2021;15:e0009369. doi: 10.1371/journal.pntd.0009369. PubMed DOI PMC

Mambelli F.S., Figueiredo B., Morais S., Assis N., Fonseca C., Oliveira S. Recombinant micro-exon gene 3 (MEG-3) antigens from Schistosoma mansoni failed to induce protection against infection but show potential for serological diagnosis. Acta Trop. 2020;204:105356. doi: 10.1016/j.actatropica.2020.105356. PubMed DOI

Lopes J.L.S., Orcia D., Araujo A.P.U., DeMarco R., Wallace B.A. Folding Factors and Partners for the Intrinsically Disordered Protein Micro-Exon Gene 14 (MEG-14) Biophys. J. 2013;104:2512–2520. doi: 10.1016/j.bpj.2013.03.063. PubMed DOI PMC

Orcia D., Zeraik A.E., Lopes J.L., Macedo J.N., dos Santos C.R., Oliveira K.C., Anderson L., Wallace B., Verjovski-Almeida S., Araujo A.P., et al. Interaction of an esophageal MEG protein from schistosomes with a human S100 protein involved in inflammatory response. Biochim. Biophys Acta. Gen. Subj. 2017;1861:3490–3497. doi: 10.1016/j.bbagen.2016.09.015. PubMed DOI

Martins V.P., Morais S.B., Pinheiro C.S., Assis N.R.G., Figueiredo B.C.P., Ricci N.D., Alves-Silva J., Caliari M.V., Oliveira S.C. 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. PLoS Neglected Trop. Dis. 2014;8:e2750. doi: 10.1371/journal.pntd.0002750. PubMed DOI PMC

Felizatti A.P., Zeraik A.E., Basso L.G., Kumagai P.S., Lopes J.L., Wallace B., Araujo A.P., DeMarco R. Interactions of amphipathic α-helical MEG proteins from Schistosoma mansoni with membranes. Biochim. Biophys Acta Biomembr. 2020;1862:183173. doi: 10.1016/j.bbamem.2019.183173. PubMed DOI

Nedvedova S., Guillière F., Miele A.E., Cantrelle F.-X., Dvorak J., Walker O., Hologne M. Divide, conquer and reconstruct: How to solve the 3D structure of recalcitrant Micro-Exon Gene (MEG) protein from Schistosoma mansoni. PLoS ONE. 2023;18:e0289444. doi: 10.1371/journal.pone.0289444. PubMed DOI PMC

Romero A.A., Cobb S.A., Collins J.N.R., Kliewer S.A., Mangelsdorf D.J., Collins J.J., 3rd The Schistosoma mansoni nuclear receptor FTZ-F1 maintains esophageal gland function via transcriptional regulation of meg-8.3. PLoS Pathog. 2021;17:e1010140. doi: 10.1371/journal.ppat.1010140. PubMed DOI PMC

Farias L.P., Vance G.M., Coulson P.S., Vitoriano-Souza J., Neto A.P.d.S., Wangwiwatsin A., Neves L.X., Castro-Borges W., McNicholas S., Wilson K.S., et al. Epitope Mapping of Exposed Tegument and Alimentary Tract Proteins Identifies Putative Antigenic Targets of the Attenuated Schistosome Vaccine. Front. Immunol. 2021;11:624613. doi: 10.3389/fimmu.2020.624613. PubMed DOI PMC

Soares J.B.C., Maya-Monteiro C.M., Bittencourt-Cunha P.R., Atella G.C., Lara F.A., D’avila J.C., Menezes D., Vannier-Santos M.A., Oliveira P.L., Egan T.J., et al. Extracellular lipid droplets promote hemozoin crystallization in the gut of the blood fluke Schistosoma mansoni. FEBS Lett. 2007;581:1742–1750. doi: 10.1016/j.febslet.2007.03.054. PubMed DOI