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High Density Mapping to Identify Genes Associated to Gastrointestinal Nematode Infections Resistance in Spanish Churra Sheep

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High Density Mapping to Identify Genes Associated to Gastrointestinal Nematode Infections Resistance in Spanish Churra Sheep Facultad de Veterinaria Departamento de Producción Animal HIGH DENSITY MAPPING TO IDENTIFY GENES ASSOCIATED TO GASTROINTESTINAL NEMATODE INFECTIONS RESISTANCE IN SPANISH CHURRA SHEEP (MAPEO DE ALTA DENSIDAD PARA LA IDENTIFICACIÓN DE GENES RELACIONADOS CON LA RESISTENCIA A LAS INFECCIONES GASTROINTESTINALES POR NEMATODOS EN EL GANADO OVINO DE RAZA CHURRA) Marina Atlija León, Mayo de 2016 Supervisors: Beatriz Gutiérrez-Gil1 María Martínez-Valladares2, 3 1 Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, León 24071, Spain. 2 Instituto de Ganadería de Montaña. CSIC-ULE. 24346. Grulleros. León. 3 Departamento de Sanidad Animal. Universidad de León. 24071. León. The research work included in this PhD Thesis memory has been supported by the European funded Initial Training Network (ITN) project NematodeSystemHealth ITN (FP7-PEOPLE-2010-ITN Ref. 264639), a competitive grant from the Castilla and León regional government (Junta de Castilla y León) (Ref. LE245A12-2) and a national project from the Spanish Ministry of Economy and Competitiveness (AGL2012-34437). Marina Atlija is a grateful grantee of a Marie Curie fellowship funded in the framework of the NematodeSystemHealth ITN (FP7-PEOPLE-2010-ITN Ref. 264639). “If all the matter in the universe except the nematodes were swept away, our world would still be dimly recognizable, and if, as disembodied spirits, we could then investigate it, we should find its mountains, hills, vales, rivers, lakes, and oceans represented by a film of nematodes. The location of towns would be decipherable, since for every massing of human beings there would be a corresponding massing of certain nematodes. Trees would still stand in ghostly rows representing our streets and highways. The location of the various plants and animals would still be decipherable, and, had we sufficient knowledge, in many cases even their species could be determined by an examination of their erstwhile nematode parasites.” N. A. Cobb, Yearbook of the United States Department of Agriculture (1914), page 472 Acknowledgements I would like to acknowledge Prof. Juan Jose Arranz for providing me the opportunity to conduct research in his group and for his advice and support throughout the entire course of my PhD. I am also grateful for the support and encouragement received from my supervisors, Dr. Beatriz Gutiérrez-Gil and Dr. María Martínez-Valladares, for their knowledge, their critiques, their guidance and their encouragement throughout the course of this study. I would like to extend my sincere thanks and appreciation to Prof. Francisco Antonio Rojo-Vázquez for his parasitological expertise and a huge amount of literature that helped me to understand these extraordinary organisms. I would also like to thank to Dr. Johannes Buitkamp to give me a opportunity to work with his group at the Institute for Animal Breeding in Germany, the Bayerische Landesanstalt für Landwirtschaft. Thank you so much for teaching me and introducing me to the complexity of the major histocompatibility complex immune genes. I had also oportunity to work with Prof. Mike Stear and Dr. Joaquin Prada at the University of Glasgow. I am really thankful for their understanding, disscusion and help which in the end had an impact on my understanding how to approach and deal with my data. Further, I wouId like to thank all my fellow graduate students and colleagues in the department at University of Leon for their freindship and assistance through these years. To all my friends, near by to me or far away, thank you so much for your understanding and encouragement in countless moments of crisis. I cannot list all the names here, but you are always on my mind. Your friendship makes my life a wonderful experience. There are no words to express my gratitude to my Mom, for your constant encouragement, support and for being so strict in terms of getting me to study properly from the very first days of my school. Finally, I must acknowledge with tremendous and deep thanks my boyfriend, Konrad Burnik. You were always there for me, even we were far away from each other, to give me possitive energy to go beyond my limits with your love, patience, support and unwavering belif in me what help me to complete this dissertation journey. Thank you! TABLE OF CONTENT Thesis proposal and objectives .............................................................................. 1 Literature review ................................................................................................... 7 1. Infection by GINs in sheep ........................................................................... 9 2. GINs in sheep ............................................................................................. 10 2.1.Taxonomy and life cycle of GINs ........................................................ 10 2.2. Most important ovine GINs and their pathogenesis and clinical signs 14 2.2.1. Teladorsagia circumcincta ....................................................... 14 2.2.2. Trichostrongylus spp ................................................................ 14 2.2.3. Haemonchus contortus ............................................................. 15 2.3. Interaction between host and parasite ................................................. 16 3. Control of GIN infections .......................................................................... 16 3.1. Antihelminthics ................................................................................... 16 3.2. Selection of resistant animals to GIN infection .................................. 18 4. Genetic studies about resistance to GIN infections in sheep ..................... 19 4.1. Indicator traits of parasite resistance and their heritabilities ............... 20 4.2. Methods to detect genes influencing GIN resistance in sheep ............ 22 4.2.1. The candidate gene approach ................................................... 23 4.2.2. Detection of QTL based on whole genome scans .................... 26 Materials and methods ......................................................................................... 35 1. Study area, resource population and sampling .......................................... 37 1.1. Faecal samples .................................................................................... 37 1.1.1. Faecal egg counts .................................................................... 37 1.1.2. Larval culture ........................................................................... 38 1.2.Blood samples ..................................................................................... 38 1.2.1. Estimation of IgA antibody titre in the serum (or Indirect ELISA for detection of parasite specific IgA) ......................... 38 1.2.2. DNA extraction ....................................................................... 38 2. Analyses related to Objective 1 .................................................................. 38 2.1. Resource population ........................................................................... 38 2.2. Statistical analyses .............................................................................. 39 2.3. Genotypes and physical map .............................................................. 39 2.4. QTL mapping analyses ....................................................................... 40 3. Analyses related to Objective 2 .................................................................. 42 3.1. Sequencing analysis of DRB1 exon 2 and study of the DRB1 microsatellite ....................................................................................... 42 3.2. Sequencing analysis of DQB exon 2 ................................................... 42 3.3. Description of obtained sequences of MHC class IIB genes ............. 43 4. Analyses related to Objective 3 .................................................................. 43 4.1. The Zero-Inflated Negative Binomial (ZINB) model ........................ 43 4.2. Estimation of zero-inflation ................................................................ 43 4.3. Extending the ZINB model ................................................................ 44 4.4. Correlations between phenotypes ....................................................... 45 Results .................................................................................................................. 47 1. Results of Objective 1 ................................................................................ 51 1.1. Detection and replication of QTL underlying resistance to gastrointestinal nematodes in adult sheep using the ovine 50 K SNP array. .................................................................................................... 51 1.2. Barrido genómico con el SNP-chip ovino 50K para la detección de QTL con influencia sobre la resistencia a nematodos intestinales en el ganado ovino de raza churra: análisis de ligamiento para el recuento de huevos en heces ............................................................................... 85 1.3. Search of genomic regions influencing faecal egg count, as an indicator of resistance to gastrointestinal nematode infections, based on the analysis of the OvineSNP50 BeadChip ............................... 91 2. Results of Objective 2 ................................................................................ 97 2.1. Short communication: Major Histocompatibility Complex Class IIB polymorphism in an ancient Spanish
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