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Aggregated Variant Analysis in Exomes from Familial and Early Onset Meniere Disease Patients

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Aggregated Variant Analysis in Exomes from Familial and Early Onset Meniere Disease Patients ANÁLISIS AGREGADO DE VARIANTES EN EL EXOMA DE PACIENTES CON ENFERMEDAD DE MENIERE FAMILIAR E INICIO PRECOZ Tesis doctoral con mención internacional Aggregated variant analysis in exomes from familial and early onset Meniere disease patients International PhD Thesis PROGRAMA DE DOCTORADO EN BIOMEDICINA (B11.56.1) Author: Pablo Román-Naranjo Varela Director: José Antonio López Escámez Editor: Universidad de Granada. Tesis Doctorales Autor: Pablo Román-Naranjo Varela ISBN: 978-84-1306-571-7 URI: http://hdl.handle.net/10481/63304 2 4 Agradecimientos Esta tesis doctoral no podría haberse realizado sin la ayuda o colaboración de muchas personas. Como no puede ser de otra manera, a los primeros que tengo que agradecer son a mi familia, en especial a mis padres. Las tres mudanzas en tres años parece que han merecido la pena. Gracias por mostrarme siempre vuestro apoyo. Espero que podamos celebrar esto todos juntos. Por otro lado, el culpable (para bien) de que me encuentre escribiendo este texto es mi director de tesis. Muchas gracias, Antonio. Gracias por confiar en mí y darme la oportunidad de empezar en esto de la ciencia. Vine a ciegas a Granada, haciendo un máster que poco o nada tiene que ver con lo que estoy haciendo ahora, pero que me permitió entrar al grupo a través del TFM. Decisiones y casualidades que te cambian la vida. Grado en Bioquímica en Sevilla, Máster en Ingeniería tisular, doctorado en biomedicina haciendo de bioinformático reconvertido en Granada. Normal que no lo tuviera muy claro cuando empecé. Pese a todo, el camino ha llegado a buen puerto. Camino que, por otra parte, te has encargado de que fuera lo más recto posible. Es muy de agradecer tu entusiasmo por el área en el que trabajas, entusiasmo que se me ha contagiado en las horas bajas, que, aunque pocas, las ha habido. Cambiando de tercio, aunque no mucho, es turno de agradecer a todos los compañeros con los que he tenido la suerte de compartir laboratorio. Por afinidad con el tema de la tesis, estoy especialmente agradecido a Teresa Requena y a Álvaro Gallego. Muchas gracias a ambos. Gracias Tere porque, aunque cuando llegué no estabas por el lab19 (estabas de estancia), cuando volviste me ayudaste como la que más. Ahora, que vuelves a no estar en el laboratorio, se te echa mucho de menos. Gracias Álvaro porque, a día de hoy, aun me sigues ayudando cuando tengo cualquier tipo de duda. Espero compartir contigo más esa frase de “y esa es mi historia”. Compañera de batallas, muito obrigado. Si bien al principio no te entendía casi nada, a medida que ha pasado el tiempo me has convertido en medio portugués. He pasado muy buenos momentos durante esta etapa contigo, y siempre que has podido, me has ayudado (casi siempre, aún recuerdo el hielo de la qPCR). Muchas gracias, Marisa. We have shared many moments together while working in the lab and I hope to continue doing so. Sana, thank you very much for those funny moments and I hope I have copied this correctly). Estrella, aunque tienes tus momentos como) پیﻻ ,laughs todos, eres la alegría del laboratorio. Es un gusto trabajar contigo. Alba y Olga, habéis llegado hace poco, pero ya habéis participado de una manera u otra en esto. Espero poder compartir con vosotras buenos momentos en el futuro. Newyorkina, no me he olvidado de ti. Eras el alma del laboratorio y me dio mucha pena que te fueras. Me has ayudado mucho, quizá más de lo que crees. Muchas gracias, Lidia. Although they are not part of the group where I have done this 5 Thesis, they helped me a lot during my stay in Luxembourg. Thank you very much Marie-Laure Magnani, you were a great support for me before and after my arrival. Thank you very much Patrick May, Dheeraj Bobbili and Stephan Gebel, because thanks to you, I learned there a large part of the methodological basis of this Thesis. No me quiero olvidar de nadie, y no me puedo olvidar de todos los médicos que han participado en este estudio. Por suerte, sois muchos los que buscáis un rato después de vuestro trabajo para colaborar con nosotros, y eso es muy de agradecer, ya que si no esto no sería posible. Muchas gracias Juanma, Patricia y María del Carmen. Sois parte esencial del trabajo que se realiza en Granada. También me gustaría destacar a los doctores Andrés Soto (Complexo Hospitalario Universitario de Santiago de Compostela) e Ismael Arán (Complexo Hospitalario de Pontevedra), por vuestra labor a la hora de facilitarnos muestras y datos clínicos para la realización del trabajo de investigación que posibilita esta Tesis. Este cambio de párrafo es intencionado. Es intencionado porque merecen mención aparte. Muchas gracias a todos los pacientes con la enfermedad de Meniere que han participado en este trabajo. Muchas gracias a la Asociación Síndrome de Meniere España (ASMES) y a todos sus socios, ya que han sido ellos los que, con sus donaciones, han hecho que yo haya podido vivir durante estos tres años cosas que ni me imaginaba cuando salí de Sevilla. Ellos han financiado mi estancia en el grupo y han sido parte fundamental de todo esto. Muchas gracias por invitarme a la asamblea que celebrasteis en Sevilla. Fue inspiradora y aun me emociono cuando me acuerdo. Me gustaría mencionar a María José Fraile, por su atención e interés en la evolución de mi trabajo. También mencionar a Roberto, Juan Pedro, Merche, Gema, Fran y Marcos, pasamos un buen día en Sevilla. Espero que entre todos podamos encontrar algún día la solución a este problema llamado enfermedad de Meniere. Yo, gracias a vosotros, dejo aquí mi granito de arena. Gracias de verdad. 6 7 Index Grants and funding ..................................................................................................................... 11 Resumen ..................................................................................................................................... 13 Abstract ....................................................................................................................................... 15 Abbreviations.............................................................................................................................. 17 1. Introduction ........................................................................................................................ 21 1.1. The inner ear ............................................................................................................... 21 1.1.1. Anatomy and function of the cochlea................................................................ 22 1.1.2. Anatomy and function of the vestibular system ............................................... 24 1.2. Meniere’s disease ....................................................................................................... 24 1.2.1. Clinical symptoms ............................................................................................... 25 1.2.2. Diagnosis and classification of patients ............................................................. 26 1.2.3. Epidemiology ...................................................................................................... 27 1.2.4. Treatments .......................................................................................................... 28 1.2.5. Pathophysiology ................................................................................................. 28 1.3. Basis and state of the art of human genetics ............................................................ 29 1.3.1. From genes to proteins ...................................................................................... 30 1.3.2. Genetic variants .................................................................................................. 31 1.4. Genetics of hearing loss and Meniere’s disease ........................................................ 34 2. Hypothesis .......................................................................................................................... 37 3. Objectives ........................................................................................................................... 38 4. Methods .............................................................................................................................. 39 4.1. Diagnosis of cases ....................................................................................................... 39 4.2. DNA extraction and WES ............................................................................................ 39 4.3. Bioinformatics ............................................................................................................. 40 4.3.1. Data generation and pre-processing .................................................................. 40 4.3.2. Generation of callsets ......................................................................................... 41 4.3.3. Variants quality assessment ............................................................................... 42 8 4.3.4. Variant annotation ............................................................................................. 42 4.3.5. Variant filtering ................................................................................................... 43 4.3.6. Callsets analysis strategy .................................................................................... 44 4.3.7. Variant prioritization .......................................................................................... 44 4.3.8. Variant validation ..............................................................................................
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