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Genomic and Transcriptomic Surveys for the Study of Ncrnas with a Focus on Tropical Parasites

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Genomic and Transcriptomic Surveys for the Study of Ncrnas with a Focus on Tropical Parasites PhD Thesis PROGRAMA DE PÓS-GRADUAÇÃO EM BIOINFORMÁTICA UNIVERSIDADE FEDERAL DE MINAS GERAIS Genomic and transcriptomic surveys for the study of ncRNAs with a focus on tropical parasites Mainá Bitar Belo Horizonte February 2015 Universidade Federal de Minas Gerais PhD Thesis PROGRAMA DE PÓS-GRADUAÇÃO EM BIOINFORMÁTICA Genomic and transcriptomic surveys for the study of ncRNAs with a focus on tropical parasites PhD candidate: Mainá Bitar Advisor: Glória Regina Franco Co-advisor: Martin Alexander Smith Mainá Bitar Lourenço Genomic and transcriptomic surveys for the study of ncRNAs with a focus on tropical parasites Versão final Tese apresentada ao Programa Interunidades de Pós-Graduação em Bioinformática do Instituto de Ciências Biológicas da Universidade Federal de Minas Gerais como requisito parcial para a obtenção do título de Doutor em Bioinformática. Orientador: Profa. Dra. Glória Regina Franco BELO HORIZONTE 2015 043 Bitar, Mainá. Genomic and transcriptomic surveys for the study of ncRNAs with a focus on tropical parasites [manuscrito] / Mainá Bitar. – 2015. 134 f. : il. ; 29,5 cm. Orientador: Glória Regina Franco. Coorientador: Martin Alexander Smith. Tese (doutorado) – Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas. Programa de Pós-Graduação em Bioinformática. 1. Bioinformática - Teses. 2. Trypanosoma cruzi. 3. Schistosoma mansoni. 4. Genômica. 5. Transcriptoma. 6. Trans-Splicing. I. Franco, Glória Regina. II. Smith, Martin Alexander. III. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. IV. Título. CDU: 573:004 Ficha catalográfica elaborada por Fabiane C. M. Reis – CRB 6/2680 Esta tese é dedicada à minha mãe, que me deu a liberdade para sonhar e a força para viver a realidade. AGRADECIMENTOS À Chefa, por ser meu exemplo de cientista, professora e de tantas outras coisas. Por me ensinar a ser melhor a cada dia em tudo que eu faço e pela nossa simbiose que vai além da pesquisa. Espero um dia poder retribuir tudo o que você fez por mim desde que essa Gloriosa história começou. À minha mãe e meus avós, por terem tido tanta dedicação a mim e me ensinado tanta coisa. Tudo em mim tem um pouquinho de vocês. À minha família, real e inventada, por ser o lugar para onde sempre quero voltar, seja lá de onde for. Às PriMas (Priscila, Marcela, Marcela e Marina), por terem sido minha casa em todos os sentidos, desde que cheguei em Belo Horizonte. À Pós-Graduação em Bioinformatica da UFMG, em especial à Sheila e ao Vasco, por terem ido muito além de suas obrigações para contribuir com a minha formação cientifica, acadêmica e pessoal. À CAPES, que através dos programas Reuni e Ciência sem Fronteiras abriu novas portas para a minha formação acadêmica e cientifica. Ao LGB, por ter sido a minha segunda casa durante os últimos anos, onde aprendi muito e fiz amigos para toda a vida. Obrigada a todos os que estão ou estiveram no Laboratório e fizeram parte desta tese. Obrigada em especial à Neuza e aos professores Andréa e Carlos Renato, por terem me ensinado tanto sobre as diversas faces da pesquisa e por todas as valiosas discussões. Aos alunos que passaram pelos cursos de Perl e Modelagem Molecular, por terem dividido comigo a experiência de aprender a ensinar, obrigada pela paciência! Obrigada ao Edgar e ao Diego em especial por toda a ajuda. À Ceres, à Maira, à Grazi, à Dani, ao Italo e ao André, por estarem sempre dispostos a me ajudar e pelas risadas e lições ao longo deste doutorado. Às meninas da JeMaDa, que dividiram comigo não somente a casa, mas também a vida, que me apoiaram e me acolheram sempre. À Família Franco, que me adotou com tanto carinho que eu não sei mais onde termina a minha família e começa a de vocês. Nem sei como agradecer. i Às irmãs que a vida me deu, Ana Laura, Yasmin e Laura, com vocês eu aprendi que alguns laços são pra sempre e que a saudade é amor com fuso horário. À Nicole, à Catarina, ao Diego e ao Ike, por serem meus anjos da guarda! Ao Cerne, aos ANJoS e ao Ritmo por terem feito parte da minha vida e ainda estarem comigo sempre. ACKNOWLEDGEMENTS To Dr. John Mattick, for listening to me, for taking the time to teach me and discuss with me and for making this year at the Garvan one of the best of my life in every way. To Dr. Martin Smith for the patience, trust and for being part of this thesis. To Nix for teaching me so much this year and for your friendship. I will carry both things with me forever. Thank you for the enthusiasm and support. To Boris, Dessi, Dom, Guy, Ira, Lotta and all the Mattick Lab group for having us and for everything I have learned this year. I will never forget you. To Luis for being, above all, the best friend I have had in a long time. For the inspiration, for the understanding and for making the most out of everything. You make me believe that time and distance are very relative. ii ABSTRACT Non-coding RNAs (ncRNAs) have been studied in great detail in the last decade, culminating in the current view of widespread molecules playing important roles in virtually all cell processes in all kingdoms of life. The tropical parasites Schistosoma mansoni (the causative agent of schistosomiasis) and Trypanosoma cruzi (the causative agent of Chagas disease) have complex life-cycles involving different hosts and environments and thus requiring a refined regulation of gene expression. In this sense, ncRNAs are known to be broad regulators of gene expression at multiple levels and more detailed surveys to identify such RNAs and the mechanisms in which they are involved are of great importance in the context of these parasites. To assess the roles and features of ncRNAs in tropical parasites, I have studied the mechanism of spliced-leader trans-splicing (SLTS) i n S. mansoni and further expanded the study to involve all species in which this mechanism is currently known and also performed a thorough survey to identify new ncRNAs in the genome of T. cruzi. The SLTS mechanism is known to be present in species of seven different phyla. The molecular characteristics of the spliced-leader (SL) RNA and the set of transcripts processed by the SLTS RNA were studied both in S. mansoni and further in ~150 species. Main findings include the sequence of the SL RNA exon being conserved among different species of a given phylum and more divergent when species from different phyla are compared, however the overall structure of the SL RNA is more conserved in all phyla than its sequence. Additionally, when analyzing the transcripts that receive the SL sequence, I have observed that these include genes from unrelated classes and have no clear bias to any specific function. The genome of T. cruzi was scanned in search of non-annotated ncRNAs, using both sequence-based and structure-based search algorithms and different databases. As iii a result, I report 1,595 unique ncRNA candidates, more than 700 of these representing new findings. Interestingly, the most abundant classes of new ncRNAs include snoRNAs, RNase P RNAs and miRNAs. The first are known to be widespread in the genome of Trypanosoma brucei (the causative agent of the sleeping sickness) and play important roles in the modification and putative stabilization of rRNAs. RNase P RNAs were not previously reported in trypanosomatids and to date only a protein-only RNase P complex was believed to be present in such organisms. The identification of miRNAs candidates in the genome of T. cruzi was surprising given that the parasite does not harbour a classic RNAi machinery and therefore further analyses should be conducted to prove this finding. Lastly, RNA candidates involved with regulation of gene expression that are believed to be exclusive of prokaryotes were also found, raising questions about how their function could be performed in this eukaryotic parasite. iv RESUMO RNAs não-codificadores têm sido estudados em detalhes na última década, culminando na visão recente de que estes são moléculas ubíquas que desempenham papel importante em virtualmente todos os processos biológicos em todos os reinos da vida. Os parasitos tropicais Schistosoma mansoni (agente causador da esquistosomose) e Trypanosoma cruzi (agente causador da Doença de Chagas) têm ciclos de vida complexos envolvendo diferentes hospedeiros e ambientes, necessitando portanto de uma refinada regulação da expressão gênica. Nesse sentido, os ncRNAs são reconhecidamente reguladores da expressão gênica em vários níveis e inspeções mais detalhadas para identificar tais RNAs e os mecanismos nos quais estes estão envolvidos são de grande importância no contexto destes parasitos. Para avaliar as funções e as características dos ncRNAs em parasitos tropicais, o mecanismo de spliced-leader trans- splicing (SLTS) foi estudado em S. mansoni e, posteriormente, o estudo foi expandido para incluir todas as espécies nas quais o mecanismo é atualmente conhecido. Além disso, uma inspeção minuciosa foi realizada para identificar novos ncRNAs no genoma de T. cruzi. O mecanismo de SLTS já foi descrito em espécies de sete diferentes filos. As características moleculares do RNA spliced-leader (SL) e o conjunto de transcritos processados pelo mecanismo de SLTS foram estudados em ambos em S. mansoni e posteriormente em ~150 espécies. Os principais achados incluem a sequência do éxon do SL RNA, a qual é conservada dentre diferentes espécies de um mesmo filo e mais divergentes quando espécies de diferentes filos são comparadas. No entanto, a estrutura tridimensional geral do SL RNA é mais conservada em todos os filos do que sua sequência. Adicionalmente, quando os transcritos que recebem a sequência SL foram analisados, observou-se que estes incluem genes de classes não relacionadas e não v parecem estar enviesados para nenhuma função especifica.
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