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In Male Reproductive Biology PATRÍCIA ISABEL FERREIRA MARQUES AN EVOLUTIONARY PERSPECTIVE INTO THE ROLE OF KALLIKREINS (KLKs) IN MALE REPRODUCTIVE BIOLOGY Tese de Candidatura ao grau de Doutor em Ciências Biomédicas submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto. Orientador – Doutora Susana Seixas Categoria – Investigadora Afiliação – Instituto de Investigação e Inovação em Saúde, Universidade do Porto (I3S); Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup). Coorientador – Doutor Victor Quesada Categoria – Investigador Afiliação – Departamento de Bioquímica y Biología Molecular de la Universidad de Oviedo Coorientador – Maria de Fátima Gärtner Categoria – Professora Catedrática Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto. Research work coordinated by: iii Financiamento: Este trabalho foi financiado por Fundos FEDER através do Programa Operacional Factores de Competitividade – COMPETE e por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia no âmbito do projeto FCOMP-01-0124-FEDER-028251 (Refª FCT: PTDC/BEX-GMG/0242/2012). Este trabalho foi ainda financiado pela FCT através da atribuição de uma bolsa individual de doutoramento (SFRH/BD/68940/2010). v Ao abrigo do art.º 8º do Decreto-Lei n.º 388/70, fazem parte integrante desta dissertação os seguintes manuscritos já publicados, aceites para publicação ou em preparação: Marques PI, Bernardino R, Fernandes T. Nisc Comparative Sequencing Program, Green ED, Hurle B, Quesada V, Seixas S. 2012. Birth-and-Death of KLK3 and KLK2 in primates: evolution driven by reproductive biology. Genome Biol Evol. 4(12): 1331-8. Marques PI, Fonseca F, Sousa T, Santos P, Camilo V, Ferreira Z, Quesada V, Seixas S. 2015. Adaptive Evolution Favoring KLK4 Downregulation in East Asians. Mol Biol Evol. Epub ahead of print (DOI: 10.1093/molbev/msv199). Marques PI, Fonseca F, Carvalho AS, Puente DA, Damião I, Almeida V, Barros N, Barros A, Carvalho F, Mathiesen R, Quesada V, Seixas S. Rare and common variants in KLK and WFDC gene families and their implications into male infertility phenotypes. In preparation. Em cumprimento do disposto no referido Decreto-Lei, a candidata declara que participou na obtenção, análise e discussão dos resultados, bem como na elaboração das publicações, sob o nome Marques PI. vii “It is not our differences that divide us. It is our inability to recognize, accept, and celebrate those differences.” Audra Lorde Acknowledgments Agradecimentos In all these years, many people were directly or indirectly involved in shaping up my academic career. It would have not been possible for me to thrive in my doctoral work without their precious support. Gostaria de agradecer à minha orientadora, Doutora Susana Seixas, por todo o apoio, entusiasmo e dedicação, não só neste desafio, mas também ao longo de todos estes anos que trabalhamos juntas. Sem dúvida, contribuiu para o meu crescimento profissional e pessoal. Por isso, por todos estes “atribulados” mas gratificantes anos, um grande obrigado! To my co-supervisor, Doctor Victor Quesada, for accepting me as his student and for believing in me and in my work. Thank you for all the scientific discussions and the patience while teaching me bioinformatics (I know sometimes I can be stubborn). I must also thank you for being an amazing host during my stays in Oviedo and for all of the rides from and to the airport. Gracias por todo! À Professora Doutora Fátima Gärtner, por ter aceite ser minha co-orientadora, por toda a ajuda e disponibilidade. À Fundação para a Ciência e a Tecnologia, agradeço a concessão da bolsa de doutoramento SFRH/BD/68940/2010 sem a qual a realização deste trabalho não teria sido possível. Ao Professor Doutor Eduardo Rocha, ao Doutoramento em Ciências Biomédicas e ao Instituto de Ciências Biomédicas Abel Salazar por me terem dado a oportunidade de realizar o Doutoramento numa área que me fascina. Ao Professor Doutor Sobrinho Simões agradeço a oportunidade de desenvolver o meu trabalho nas excelentes condições oferecidas pelo Ipatimup e de integrar nesta notável equipa de “Ipatimupianos”. xi To Professor Carlos López-Otín, for giving me the opportunity to join an incredible team that allowed me to grow up as a scientist. I’m also thankful for his enthusiasm in science that certainly has caught me! Gostaria também de agradecer ao Centro de Genética da Reprodução Prof. Alberto Barros (Professor Alberto Barros, à Dra. Joaquina e ao Dr. Nuno), ao Centro de Estudos de Infertilidade e Esterilidade (Professor Vasco Almeida e à Dra. Isabel Damião) e ao Jardim Zoológico de Lisboa (Dra. Teresa Fernandes e Dr. Rui Bernardino), pelo fornecimento de amostras sem as quais este trabalho não teria sido possível. I would like to acknowledge all of the co-authors of the publications presented in this thesis for their contribution. Ao grupo Genetic Diversity pela forma que me acolheu quando integrei no grupo e por terem criado um bom ambiente científico. Um especial obrigado à Ana Lima, Andreia B., Andreia S., Catarina, Filipa, Joana, Marisa, Natália, Sílvia, Sofia e Zélia pela partilha de experiências (dentro e fora do Ipas), pelos bons momentos de descontração e por me terem ajudado (pelo menos tentaram) a manter a sanidade metal! Sem vocês não teria sido possível. To all members of the Lopez-Otin lab, especially Ceci, David and Yaiza, for welcome me and make me feel like home. À Tatiana, por tantos anos de amizade e por estar sempre presente quando precisei! Aos meus pais, à minha irmã e ao Fred, pelo carinho, apoio incondicional e compreensão em todos os momentos. xii Table of Contents Figures List xv Tables List xxv Abbreviations xxix Abstract 1 Resumo 3 Chapter 1 5 General Introduction 5 1. Genetic variation and natural selection 7 2. The Kallikrein (KLK) locus 13 2.1. Structure and organization 13 2.2. Phylogenetic evolution 16 2.3. Biological importance in human health and disease 18 2.3.1. Functions in reproductive biology 19 2.3.2. Functions in skin physiology 23 2.3.3. Functions in tooth enamel formation 25 2.4. Primate adaptive evolution 27 Chapter 2 29 Aims 29 Chapter 3 33 Papers 33 Paper I - Birth-and-Death of KLK3 and KLK2 in Primates: Evolution Driven by Reproductive Biology 35 Paper II - Adaptive Evolution Favoring KLK4 Downregulation 45 in East Asians 45 Paper III - Rare and common variants in KLK and WFDC gene families and their implications into semen hyperviscosity and other male infertility phenotypes 63 xiii Chapter 4 101 Final Discussion 101 1. Evolutionary history of KLKs 103 2. Implication of KLKs genetic variation in human health and disease 109 Chapter 5 113 Concluding Remarks 113 Chapter 6 117 References 117 Appendices 143 Appendix A - Supplementary Material Paper I 145 Appendix B - Supplementary Material Paper II 153 Appendix C - Supplementary Material Paper III 185 xiv Figures List Chapter 1 General Introduction Figure 1 – Different scenarios of natural selection. Each panel depicts changes in variant frequencies over time. Horizontal blocks represent chromosomes, neutral variants are shown as circles on the chromosomes and advantageous or deleterious variants are represented with a 12-point star. (A) Purifying selection - in which deleterious variants are removed from the population. (B) Balancing selection - in which the two alleles are maintained in the population as a result of heterozygote advantage over homozygous individuals. (C) Classic selective sweep - in which a novel advantageous variant arises in a population and increases in frequency over time until it approaches fixation. (D) Selection from standing variation - in which a variant that is already present in the population becomes advantageous in a new environment and increases in frequency over time until it approaches fixation. (E) Polygenic selection - involves multiple loci in different chromosomes (represented by different colors), when a complex trait becomes advantageous, it increases in frequency as do the set of variants contributing to it (adapted from Scheinfeldt and Tishkoff 2013). ........................................................ 9 Figure 2 – Genomic and proteomic structure of KLK proteases. (A) The human KLK gene cluster is located at chromosome 19q13.3-13.4. Arrows show the relative position and the transcription orientation for the 15 coding genes and expressed pseudogene. In the mRNA scheme, the boxes and lines represent exons and introns, respectively. KLK proteins are expressed as pre-pro-enzymes, in which the pre-domain is required for intracellular trafficking and the pro-domain must be cleaved in order to generate a mature KLK. (B) The structure of a mature KLK based on the crystal structure of KLK1. The catalytic triad residues are shown in green. The position of the kallikrein loop is also shown. The amino acids that are identical among all kallikreins are in red, whereas those that are conserved in at least eight kallikreins are in purple. Non-conserved amino acids are in blue (adapted from Lawrence, Lai, and Clements 2010 and Prassas et al. 2015). .........14 Figure 3 – Schematic representation of KLK genes in different species. The arrows specify the direction of transcription and known pseudogenes are indicated in red. Loci are not drawn to scale and bars do not represent chromosomes, as for many xv species the genomes are not yet fully assembled. On the left, a NCBI taxonomy- based dendrogram shows the taxonomic classes and the evolutionary relationship among taxa. Data compiled from Pavlopoulou et al. 2010, Koumandou and Scorilas 2013 and Lundwall 2013. .......................................................................................17 Figure 4 –KLKs expression patterns in adult tissues. mRNA concentration for each KLK (as indicated in top row) and tissue. The color code at the bottom shows the levels of expression (from Shaw and Diamandis 2007). .........................................19 Figure 5 - Schematic representation of the semen liquefaction proteolytic cascade. (A) In normal physiologic conditions, KLKs are activated in the prostate through a zymogen activation cascade. KLK activation by other KLK is represented by straight arrows and auto-activation ability is illustrated by curved arrows.
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