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Inferring Natural Selection Signals in Plasmodium Vivax-Encoded Proteins Having a Potential Role in Merozoite Invasion

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Inferring Natural Selection Signals in Plasmodium Vivax-Encoded Proteins Having a Potential Role in Merozoite Invasion Identificación de señales de selección natural en genes de Plasmodium vivax que codifican proteínas involucradas en el proceso de invasión para determinar su potencial uso en una vacuna antimalárica. Diego Edison Garzón Ospina Tesis Doctoral presentada como requisito para optar al título de Doctor en Ciencias Biomédicas y Biológicas de la Universidad del Rosario Bogotá, 2018 1 Identificación de señales de selección natural en genes de Plasmodium vivax que codifican proteínas involucradas en el proceso de invasión para determinar su potencial uso en una vacuna antimalárica. Estudiante Diego Edison Garzón Ospina Biólogo, Universidad INCCA de Colombia Magister en Ciencias-Microbiología, Universidad Nacional de Colombia Director Manuel Alfonso Patarroyo Gutiérrez M.D., Dr.Sc. Jefe del Departamento de Biología Molecular e Inmunología Fundación Instituto de Inmunología de Colombia (FIDIC) Profesor Titular, Escuela de Medicina y Ciencias de la Salud Universidad del Rosario DOCTORADO EN CIENCIAS BIOMÉDICAS Y BIOLÓGICAS UNIVERSIDAD DEL ROSARIO Bogotá, 2018 2 AGRADECIMIENTOS Quiero dar mis agradecimientos y dedicar este trabajo a mi madre: Martha Ospina Vargas, y a mis hermanos: Yamile Garzón Ospina y Julián David Escobar Ospina, quienes me han acompañado y apoyado en todo momento. A Sindy Paola Buitrago Puentes por su acompañamiento y apoyo durante este tiempo. También agradecer al Dr. Manuel Alfonso Patarroyo Gutiérrez, por haberme acogido en su equipo de trabajo y por apoyarme a lo largo de todos estos años. Quiero agradecer y reconocer la labor de: Andrea Estefanía Ramos, Darwin Andrés Moreno Pérez, Elizabeth Gutiérrez Vásquez, Heidy Daniela Ortiz Suarez, Lady Johanna Forero Rodríguez, Laura Alejandra Ricaurte Contreras, Leidy Paola Reyes, Luis Alfredo Baquero, Paola Andrea Camargo Ayala, Sindy Paola Buitrago Puentes, Ricardo De León Montero y Yimara Grosso Paz, quienes aportaron su tiempo, dedicación y esfuerzo, permitiendo la culminación de este trabajo. Y finalmente, mis agradecimientos al Doctorado, a la Universidad del Rosario y a los Jurados de tesis, quienes amablemente aceptaron la revisión de este trabajo, por sus enriquecedores comentarios y por su tiempo. 3 CONTENIDO LISTA DE TABLAS .............................................................................................................. 7 LISTA DE FIGURAS ............................................................................................................ 8 LISTA DE ANEXOS ............................................................................................................. 9 LISTA DE PUBLICACIONES ............................................................................................ 10 ABREVIATURAS ............................................................................................................... 11 RESUMEN ........................................................................................................................... 12 ABSTRACT ......................................................................................................................... 14 INTRODUCCIÓN GENERAL ............................................................................................ 15 Candidatos a vacuna. ........................................................................................................ 19 Genética y evolución, herramientas para el diseño de vacunas. ....................................... 20 HIPOTESIS DE INVESTIGACIÓN .................................................................................... 23 OBJETIVOS ......................................................................................................................... 24 Objetivo general ................................................................................................................ 24 Objetivos específicos ........................................................................................................ 24 CAPITULO 1 ....................................................................................................................... 25 Introducción ...................................................................................................................... 26 Metodología ...................................................................................................................... 27 Obtención de secuencias y alineamientos. .................................................................... 27 Análisis de las relaciones filogenéticas de los genes pertenecientes a las familias multigénicas. ................................................................................................................. 27 Análisis de diversidad genética e inferencia de señales de selección natural. .............. 28 Resultados y Discusión ..................................................................................................... 30 Conclusiones ..................................................................................................................... 37 4 CAPITULO 2 ....................................................................................................................... 39 Introducción ...................................................................................................................... 40 Metodología ...................................................................................................................... 41 Identificación de selección episódica linaje-específica ................................................. 41 Resultados y discusión ...................................................................................................... 46 Estructura genética y relaciones filogenéticas de la región msp7 en Plasmodium spp. 46 Relaciones filogenéticas de los miembros de msp7 en Plasmodium ............................ 46 Selección positiva linaje-especifica en msp7 ................................................................ 47 Conclusiones ................................................................................................................. 49 CAPITULO 3 ....................................................................................................................... 50 Introducción ...................................................................................................................... 51 Metodología ...................................................................................................................... 51 Verificación de la integridad del ADN. ........................................................................ 51 Determinación de la presencia de infecciones únicas por P. vivax y de diferentes genotipos en las muestras utilizadas.............................................................................. 52 Diseño de iniciadores y amplificación por PCR ........................................................... 53 Purificación y Secuenciación de los fragmentos amplificados. .................................... 53 Análisis de la diversidad genética y de las fuerzas evolutivas en los loci seleccionados. ....................................................................................................................................... 53 Resultados y discusión ...................................................................................................... 55 Conclusiones ..................................................................................................................... 60 CAPITULO 4 ....................................................................................................................... 62 Introducción ...................................................................................................................... 63 Metodología ...................................................................................................................... 64 Resultados y discusión ...................................................................................................... 67 5 Conclusiones ..................................................................................................................... 72 CONCLUSIONES GENERALES ....................................................................................... 74 PERSPECTIVAS GENERALES ......................................................................................... 76 REFERENCIAS ................................................................................................................... 77 ANEXOS .............................................................................................................................. 87 PUBLICACIONES ............................................................................................................... 91 6 LISTA DE TABLAS Tabla 1. Total de muertes causadas por agentes parasitarios en 2013. ................................ 15 Tabla 2. Estimadores de la diversidad genética en 59 genes de P. vivax. ............................ 30 Tabla 3. Razón diversidad nucleotídica/divergencia (π/Κ), índice de neutralidad de la prueba McDonald-Kreitman (NI) y tasas de sustitución no sinónima (dN) y sinónima (dS) para algunos genes de P. vivax evaluados. ........................................................................... 34 Tabla 4. Caracterización in-silico de las proteínas MSP7 .................................................... 45 Tabla 5. Estimadores de diversidad genética........................................................................ 57 Tabla
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