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DO5883929COR.Pdf UNIVERSIDADE DE SÃO PAULO FACULDADE DE ZOOTECNIA E ENGENHARIA DE ALIMENTOS PÂMELA ALMEIDA ALEXANDRE Abordagem de biologia de sistemas para a determinação de mecanismos moleculares associados à eficiência alimentar de bovinos Nelore Pirassununga 2018 PÂMELA ALMEIDA ALEXANDRE Abordagem de biologia de sistemas para a determinação de mecanismos moleculares associados à eficiência alimentar de bovinos Nelore Versão corrigida Tese apresentada à Faculdade de Zootecnia e Engenharia de Alimentos da Universidade de São Paulo, como parte dos requisitos para obtenção do Título de Doutora em Ciências do programa de pós-graduação em Biociência Animal. Área de concentração: Genética, Biologia Molecular e Celular. Orientador: Prof. Dr. Heidge Fukumasu Pirassununga 2018 PÂMELA ALMEIDA ALEXANDRE Abordagem de biologia de sistemas para a determinação de mecanismos moleculares associados à eficiência alimentar de bovinos Nelore Tese apresentada à Faculdade de Zootecnia e Engenharia de Alimentos da Universidade de São Paulo, como parte dos requisitos para obtenção do Título de Doutora em Ciências do programa de pós-graduação em Biociência Animal. Data de aprovação: 25/01/2019 Banca Examinadora: Prof. Dr. Heidge Fukumasu Faculdade de Zootecnia e Engenharia de Alimentos – Universidade de São Paulo Presidente da Banca Examinadora Prof. Dr. Fernando Sebastián Baldi Rey Universidade Estadual Paulista “Júlio de Mesquita Filho” - Campus Jaboticabal Prof. Dr. José Bento Sterman Ferraz Faculdade de Zootecnia e Engenharia de Alimentos – Universidade de São Paulo Dra. Aline Silva Mello César Escola Superior de Agricultura “Luiz de Queiroz” – Universidade de São Paulo Dr. Miguel Henrique de Almeida Santana Faculdade de Zootecnia e Engenharia de Alimentos – Universidade de São Paulo Dra. Polyana Cristine Tizioto NGS Soluções Genômicas Aos meus amados pais, Heleni e Wanderlei, pelos valores ensinados e apoio incondicional em cada passo da minha jornada. Dedico AGRADECIMENTOS À minha família pelo apoio e pela segurança que sempre me proporcionaram. Agradeço especialmente aos meus pais. Minhas conquistas sempre serão de vocês. Ao professor Heidge, meu orientador há 9 anos. Tudo que eu sou academicamente devo a você e, como dizem que não existe ex-orientador, acho que vou continuar devendo. Obrigada pela oportunidade. Ao professor Bento pelo apoio e amizade. Feliz o dia em que entrei em sua sala em busca de conselho. De lá para cá tudo de bom que já aconteceu na minha carreira tem a sua mão e por isso, pelos cafés e boas conversas, vou ser sempre grata. À minha “marida” Yonara pela paciência e companheirismo ao longo de tantos anos. Por dividir a casa, a vida, os cachorros, os sonhos e as frustrações. À Tássia (Mulan), minha gêmea de coração, por dividir os mesmos planos e sonhos e assim, não deixar eu me sentir sozinha. Obrigada pela companhia mesmo à distância. Ao querido amigo Kazu por estar sempre por perto, pela paciência em ouvir sobre pesquisa por horas, pelos “rolês” mais inesperados e oportunidades de irritar seus alunos (rs). A todos os amigos do LOCT. Que o grupo siga crescendo unido e com cada vez mais sucesso. Obrigada aos amigos: Pedros pelas conversas e caronas, Pedrinho Ratto pela ajuda em vários momentos, Gabi Ribeiro por revisar a tese, e à Arina pela ajuda indispensável no laboratório sempre que precisei. A todos os amigos do GMAB pela companhia. Ao Gerson, companheiro de conversas e aventuras científicas. Obrigada especialmente à Elisângela pela disposição em ajudar todas as milhares de vezes que precisei. Sem você essa tese não existiria. To professor Haja Kadarmideen for the opportunity to spend 6 weeks at the University of Copenhagen and to Gianluca for the friendship and all the help during this period. During my time in Denmark, I was lucky enough to spend time and learn from incredible people I will never forget: Suraya, Marcella, Viktor, and Lisette. To Laercio (Juca) Porto-Neto for the support and for making possible my six- months internship at CSIRO, Australia; to Toni Reverter for accepting to teach and supervise me; and to Marina Naval-Sanchez for the analysis performed and the help with the manuscript. These amazing people are co-authors of the first experiment in this thesis and responsible for my personal and professional growth during my time in Australia. À Faculdade de Zootecnia e Engenharia de Alimentos da Universidade de São Paulo, onde estou a 12 anos, pela oportunidade de me formar Zootecnista, Mestre em Ciências e agora Doutora em Ciências. Obrigada aos professores que contribuíram para minha formação, tanto compartilhando conhecimento quanto me inspirando com seu exemplo. À FAPESP pelas bolsas de doutorado (Proc. 2015/22276-3) e estágio de pesquisa no exterior (BEPE Proc. 2017/14707-0) e pelo auxílio financeiro (Temático Proc. 2014/07566-2). À CAPES pela bolsa de doutorado. Ao Banco Santander pela bolsa de mobilidade internacional. “May your choices reflect your hopes, not your fears.” Nelson Mandela RESUMO ALEXANDRE, P. A. Abordagem de biologia de sistemas para a determinação de mecanismos moleculares associados à eficiência alimentar de bovinos Nelore. XXX f. Tese (Doutorado) – Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, 2018. A eficiência alimentar (EA) é um fenótipo complexo, controlado por diversos processos biológicos. Determinar e entender esses processos é fundamental para selecionar animais superiores ou mesmo orientar decisões de manejo com o objetivo de aumentar a produtividade e diminuir o impacto ambiental da pecuária. Neste trabalho, propusemos analisar a EA através de uma abordagem de biologia de sistemas, baseada em transcriptômica multitecidual, a fim de gerar um entendimento sistêmico dessa característica. Para isso, 18 animais extremos para consumo alimentar residual foram selecionados a partir de um grupo de 98 bovinos Nelore machos inteiros e tiveram seu transcriptoma de hipotálamo, pituitária, adrenal, músculo e fígado sequenciado (RNAseq). Os reads gerados foram alinhados com o genoma de referência bovino (UMD3.1), filtrados e a expressão de cada gene foi estimada. A partir desses dados três abordagens de análises de dados foram desenvolvidas. Na primeira, cinco critérios de inclusão foram definidos para selecionar genes e construir uma rede de co-expressão para os cinco tecidos, de forma que além de indicarmos diversos genes e processos associados à EA, também fomos capazes de determinar dois genes reguladores, o NR2F6 e o TGFB1. Na segunda abordagem focamos no eixo hipotálamo-pituitária-adrenal, também utilizando análises de co-expressão, mas dessa vez sem partir de prévia seleção de genes e concluímos que o sistema de recompensa do cérebro pode estar envolvido no estímulo para maior consumo de alimentos observado no grupo de baixa EA. Finalmente, com a terceira abordagem, identificamos RNAs longos não codificadores (lncRNAs) expressos nos cinco tecidos e encontramos 30 transcritos expressos diferencialmente entre a alta e baixa EA na pituitária, músculo e adrenal, sendo que alguns deles se mostraram relacionados a processos já previamente demostrados como sendo associados a essa característica. Concluímos que, apesar de não conseguirmos determinar nesse momento o papel da maior susceptibilidade ao estresse, reportado na literatura para animais de baixa EA, no estímulo para maior ingestão de alimentos desse grupo, o sistema de recompensa hipotalâmico parece estar envolvido nesse processo. A maior ingestão pode ser a causa da resposta inflamatória observada no fígado, sendo ela de origem bacteriana, indicada pela maior concentração de endotoxina sérica nos animais menos eficientes. O maior turnover de proteínas no músculo de animais de baixa EA já havia sido indicado como um dos fatores que levam ao maior gasto energético nesses indivíduos e foi confirmado nesse trabalho. Além de alguns fatores de transcrição serem indicados como reguladores centrais desse fenótipo, lncRNAs também parecem ter função regulatória importante na EA. Palavras-chave: consumo alimentar residual, conversão alimentar, eixo hipotálamo- pituitária-adrenal, fígado, inflamação, músculo, RNAseq, co-expressão gênica, RNA longo não codificador ABSTRACT ALEXANDRE, P. A. Systems biology approach for determination of molecular mechanisms associated with feed efficiency in Nellore cattle. 143 f. PhD Thesis – Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, 2018. Feed efficiency (FE) is a complex phenotype, controlled by several biological processes. Determining and understanding these processes is fundamental to select superior animals or even guide management decisions, aiming to increase productivity and reduce the environmental impact of livestock. In this work, we propose to analyze FE through a systems biology approach, based on multi-tissue transcriptomics, in order to generate a systemic understanding of this trait. For this purpose, 18 extreme animals for residual feed intake were selected from a group of 98 male Nellore cattle and had their hypothalamus, pituitary, adrenal gland, muscle and liver transcriptome sequenced (RNAseq). Reads generated were aligned with the bovine reference genome (UMD3.1), filtered and the expression of each gene was estimated. From these data three experiments were developed. In the first one, five inclusion criteria were defined to select genes and to construct a network of coexpression for the five tissues, so that besides indicating several genes and processes associated with EA, we were also able
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