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Genetic Investigation in Non-Obstructive Azoospermia: from the X Chromosome to The

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Genetic Investigation in Non-Obstructive Azoospermia: from the X Chromosome to The DOTTORATO DI RICERCA IN SCIENZE BIOMEDICHE CICLO XXIX COORDINATORE Prof. Persio dello Sbarba Genetic investigation in non-obstructive azoospermia: from the X chromosome to the whole exome Settore Scientifico Disciplinare MED/13 Dottorando Tutore Dott. Antoni Riera-Escamilla Prof. Csilla Gabriella Krausz _______________________________ _____________________________ (firma) (firma) Coordinatore Prof. Carlo Maria Rotella _______________________________ (firma) Anni 2014/2016 A la meva família Agraïments El resultat d’aquesta tesis és fruit d’un esforç i treball continu però no hauria estat el mateix sense la col·laboració i l’ajuda de molta gent. Segurament em deixaré molta gent a qui donar les gràcies però aquest són els que em venen a la ment ara mateix. En primer lloc voldria agrair a la Dra. Csilla Krausz por haberme acogido con los brazos abiertos desde el primer día que llegué a Florencia, por enseñarme, por su incansable ayuda y por contagiarme de esta pasión por la investigación que nunca se le apaga. Voldria agrair també al Dr. Rafael Oliva per haver fet possible el REPROTRAIN, per haver-me ensenyat moltíssim durant l’època del màster i per acceptar revisar aquesta tesis. Alhora voldria agrair a la Dra. Willy Baarends, thank you for your priceless help and for reviewing this thesis. També voldria donar les gràcies a la Dra. Elisabet Ars per acollir-me al seu laboratori a Barcelona, per ajudar-me sempre que en tot el què li he demanat i fer-me tocar de peus a terra. Ringrazio a tutto il gruppo di Firenze, che dal primo giorno mi sono trovato come a casa. Serena, grazie per il tuo affetto, per le rissatte, per darmi una mano sempre che avevo bisogno e per aiutarmi a integrarmi con la gente di Firenze e “Praho”. Elenina, grazie per le chiacherate, per le risste e per arrichire il mio vocabulario italiano con parole come “Abozzalla!”, “stai zitto” e “sei un deficiente”. Francesca, grazie per transmettere il tuo entusiasmo e positività. Fabrice, grazie per essere il mio maestro in bioiformatica e anche di bancone, pero soprattuto grazie per la tua amicizia. Marisa, Erminio, Emmanuele, Giulia, Elenona, grazie per il vostro tempo e per fare della mia stage un percorso pieno di felicità e comodità. Ringrazio anche al gruppo Baldi ed il gruppo Maggi, grazie per aver condiviso tanti belli momento con me. Ricardo, grazie per le conversazioni nel bar e per mettere da parte ogni mattina un cornetto con la marmellata di frutti di bosco. Mario, grazie per preparare la meglio verdura con ricotta condita con pepe di Firenze e farmi vedere che la Juve é la migliori squadra dell’Italia. A tutti voi, e a chi adesso dimentico: grazie di cuore! Voldria agrair també a la família d’acollida en el meu retorn a Catalunya, a la Fundació Puigvert. Luz, gràcies per estar sempre disposada a donar un cop de mà, per escoltar-me i aconsellar-me sempre que ho he necessitat i per aguantar les meves bromes que sé que són genials. Gemma, gràcies per les converses durant les tardes-vespres i pels consells de com poder enfocar els diferents reptes. Elena, gràcies pels consells i l’ajuda, tinguin o no, relació en aquesta tesis. Patricia i Laura, gràcies per apagar els “focs” que encenc al laboratori i per ajudar-me a solucionar qualsevol dubte, sempre amb un toc d’humor. Bea, Irene i Judith, gràcies pels bons moments i converses durant els dinars. Ivan, gràcies per rescatar-me mitja tesis d’un ordinador empapat d’aigua a dues setmanes d’entregar la tesis. Dani, gracias por tu ayuda y porque cada vez que vienes en el laboratorio traes el buen humor (y te llevas una cuantas galletas). Als antics companys de laboratori de l’IDIBAPS Judit, Xana, Carla, gràcies per ser una font de motivació constant (propera parada Berlín!). Chiara, gràcies perquè des del primer dia només he fet que rebre la teva ajuda. Gràcies per ser la meva mentora tant quan estaves a Itàlia com a la distància, perquè aquesta tesis també és teva. A tots el amics de tota la vida i els adquirits durant els darrers anys, a vosaltres també gràcies. A la meva família, gràcies per haver-me educat en la cultura del treball i l’esforç, pel vostre suport constant i per haver cregut en mi des del primer moment. Si ara sóc aquí, en gran part, és gràcies a vosaltres. A l’Helena, gràcies per ser com ets, per ser-hi sempre. Perquè els dies són millors si tu en formes part. Perquè amb tu sóc millor i perquè vull continuar acumulant mutacions al teu costat durant molt anys més. INDEX 1. SUMMARY ---------------------------------------------------------------------------------------------- 3 2. INTRODUCTION --------------------------------------------------------------------------------------- 6 2.1 MALE INFERTILITY ------------------------------------------------------------------------------------------ 6 2.1.1 Definition and prevalence --------------------------------------------------------------------------- 6 2.1.2 Classification and etiology --------------------------------------------------------------------------- 6 2.2 GENETICS OF MALE INFERTILITY ------------------------------------------------------------------------ 9 2.2.1 Genetic Diagnosis -------------------------------------------------------------------------------------- 9 2.2.2 Karyotype anomalies-------------------------------------------------------------------------------- 11 2.2.2.1 Numerical anomalies ---------------------------------------------------------------------------------------- 12 2.2.2.2 Structural anomalies ---------------------------------------------------------------------------------------- 13 2.2.3 Copy Number Variations (CNVs) ----------------------------------------------------------------- 16 2.2.3.1 Definition of CNVs ------------------------------------------------------------------------------------------- 16 2.2.3.2 Mechanisms of CNV Generation ------------------------------------------------------------------------- 19 2.2.3.3 Functional Consequences of CNVs ---------------------------------------------------------------------- 24 2.2.3.4 Y-linked CNVs ------------------------------------------------------------------------------------------------- 27 2.2.3.5 X-linked CNVs ------------------------------------------------------------------------------------------------- 33 2.3 THE X CHROMOSOME ----------------------------------------------------------------------------------- 35 2.3.1 General features and strucuture ----------------------------------------------------------------- 35 2.3.2 X-linked genes ---------------------------------------------------------------------------------------- 36 2.3.3 The importance of the X chromosome in male infertility --------------------------------- 39 2.4 DISCOVERY OF NOVEL CANDIDATE GENES IN THE ERA OF GENOMICS -------------------- 40 2.4.1 Tools for genomic studies ------------------------------------------------------------------------- 40 2.4.1.1 Microarray-based approaches ---------------------------------------------------------------------------- 40 2.4.1.2 Sequencing-based approach ------------------------------------------------------------------------------ 42 2.4.2 Application of genomic tools in the study of male infertility ---------------------------- 43 2.4.2.1 SNP based microarray and Genome Wide Association Studies (GWAS) ---------------------- 43 2.4.2.2 Comparative Genomic Hybridization (CGH) arrays. ------------------------------------------------ 45 2.4.2.3 Next Generation Sequencing- Whole Exome Sequencing: --------------------------------------- 46 3. AIMS OF THE THESIS ------------------------------------------------------------------------------- 48 4. RESULTS ----------------------------------------------------------------------------------------------- 49 1 4.1 Paper 1 ------------------------------------------------------------------------------------------------------- 52 4.2 Paper 2 ------------------------------------------------------------------------------------------------------- 76 4.3 Paper 3 ----------------------------------------------------------------------------------------------------- 106 5. DISCUSSION ----------------------------------------------------------------------------------------- 151 5.1 X-LINKED “AZF-LIKE” REGIONS ---------------------------------------------------------------------- 151 5.2 HIGH THROUGHPUT PLATFORMS AND MALE INFERTILITY ---------------------------------- 154 5.2.1 WES in NOA patients with consanguineous parents. ------------------------------------ 155 5.2.2 WES in sporadic NOA cases and normozoospermic controls. ------------------------- 158 6. CONCLUSIONS -------------------------------------------------------------------------------------- 163 7. BIBLIOGRAPHY ------------------------------------------------------------------------------------- 165 Annexes ------------------------------------------------------------------------------------------------- 177 2 1. SUMMARY The severest form of male factor infertility is non-obstructive azoospermia (NOA), which occurs in approximately 1% of all men in reproductive age. It is common knowledge that Klinefelter Syndrome (47, XXY) and Y-chromosome microdeletions are direct causes of NOA, but in the majority of patients the etiology of this spermatogenic alteration is still unknown. The global aim of the present thesis was to enhance our understanding on genetic factors involved in non-obstructive azoospermia. The first part of the thesis focuses on the search of X-linked “AZF-like” regions. The Y-linked AZF deletions, which arise through Non-Allelic
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