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Identification and Characterization of Candidate Genes for Complex Traits in Cattle

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Identification and Characterization of Candidate Genes for Complex Traits in Cattle TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Tierzucht Identification and Characterization of Candidate Genes for Complex Traits in Cattle Xiaolong Wang Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. W. M. Windisch Prüfer der Dissertation: 1. Univ.-Prof. Dr. H.-R. Fries 2. Univ.-Prof. Dr. G. A. Thaller (Christian-Albrechts-Universität zu Kiel) Die Dissertation wurde am 30.05.2012 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum für Ernährung, Landnutzung und Umwelt am 09.11.2012 angenommen. Table of Contents Table of Contents Chapter Page Abbreviations iii List of tables v List of figures vi List of appendices vii Preface 1 1 General introduction 3 2 Study of candidate genes in a milk fat content QTL region on BTA5 in the German Hoslstein-Friesian population 12 3 Study of ambilateral circumocular pigmentation related genes in the German Fleckvieh population 37 4 General discussion 54 Summary 62 Zusammenfassung 64 Bibliography 66 Acknowledgements 79 Appendices 80 Curriculum vitae 111 ii Abbreviations Abbreviations °C Degrees celsius ACOP Ambilateral circumocular pigmentation ARHGDIB Rho GDP dissociation inhibitor (GDI) beta ART4 ADP-ribosyltransferase 4 ASIP Agouti ATF7IP Activating transcription factor 7 interacting protein BOSCC Bovine ocular squamous cell carcinoma bp Base pair BTA Bos taurus autosome CNV Copy number variation Ct Cycle threshold DERA Deoxyribose-phosphate aldolase (putative) DGAT1 Diacylglycerol O-acyltransferase 1 DMSO Dimethyl sulfid DNA Deoxyribonucleic acid dNTP Deoxynucleotides EBVs Estimated breeding values EDTA Ethylenediaminetetraacetic acid EGFR Epidermal growth factor receptor EPS8 Epidermal growth factor receptor pathway substrate 8 ERP27 Endoplasmic reticulum protein 27 FP Fat percentage FV German Fleckvieh GEBV Genetic estimated breeding value GHR Growth hormone receptor GPAT4 1-acylglycerol-3-phosphate O-acyltransferase 6 GRIN2B Glutamate receptor, ionotropic, N-methyl D-aspartate 2B GRM Genomic relationship matrix GSDMC Gasdermin C GUCY2C Guanylate cyclase 2C GWA Genome-wide association GWAS Genome-wide association studies H2AFJ H2A histone family, member J HF German Holstein-Friesian indel Insertion-deletion polymorphism KDR Kinase insert domain receptor KIT Tyrosine-protein kinase Kit iii Abbreviations LD Linkage disequilibrium LMO3 LIM domain only protein 3 MAF Minor allele frequency MAS Marker assisted selection Mb Mega base pairs MC1R Melanocortin 1 receptor MGP Matrix Gla protein MGST1 Microsomal glutathione S-transferase 1 miRNA micro-RNA MITF Microphthalmia-associated transcription factor mRNA Messenger ribonucleic acid mtDNA Mitochondrial DNA NCBI National center of biotechnology information NEFA Nonesterified fatty acids ng Nanogram PAX3 Paired box 3 PCR Polymerase chain reaction PDE6H Phosphodiesterase 6H, cGMP-specific, cone, gamma PTPRO Protein tyrosine phosphatase, receptor type, O QTL Quantitative trait loci QTG Quantitative trait genes QTN Quantitative trait nucleotides RACE Rapid amplification of cDNA ends RERG RAS-like, estrogen-regulated, growth inhibitor RFLP Restriction fragment length polymorphism RNA Ribonucleic acid RT-PCR Real-time polymerase chain reaction SNP Single nucleotide polymorphism SNP_id In-house single nucleotide polymorphism identification code STRAP Serine/threonine kinase receptor associated protein TBE Tris-borate-EDTA TE Tris EDTA buffer UTR Untranslated region UV Ultraviolet VNTR Variable number tandem repeat μL Micro litre iv List of tables List of tables Table 1-1. Candidate genes reported to affect milk fat traits in cattle. Table 1-2. Reported maJor candidate genes affecting coat colour in cattle. Table 2-1. Characteristics of the most significantly associated 50K Illumina BeadChip SNPs and additional polymorphisms for four maJor QTL for milk fat percentage in the German Holstein-Friesian population. Table 2-2. Localization of the identified sequence polymorphisms. Table 2-3. Amino acid substitutions caused by eleven non-synonymous SNPs found in the re-sequenced genes. Table 2-4. Association of the three non-synonymous SNPs with milk FP EBV in the HF population. Table 3-1. Localization of the identified sequence polymorphisms. Table 3-2. Amino acid substitutions caused by ten non-synonymous SNPs found in the re-sequenced genes. Table 3-3. Quantification of RNA from the bovine hair follicles. v List of figures List of figures Figure 1-1. Distribution of milk and mammary genes across all bovine chromosomes. Figure 1-2. Ambilateral circumocular pigmentation in the German Fleckvieh breed. Figure 2-1. Association of 44,280 SNPs with the estimated breeding values for milk fat percentage in 2327 animals of the German Holstein-Friesian population. Figure 2-2. Detailed view of two genomic regions within known QTL for milk fat content in cattle. Figure 2-3. Schematic view of the BTA5 QTL region encompassing EPS8. Figure 2-4. Schematic view of the BTA27 QTL region encompassing GPAT4. Figure 2-5. The combined impact of the four identified QTL on BTA5, 14, 20 and 27 on the estimated breeding value for milk fat percentage in the German Holstein-Friesian population. Figure 2-6. Partitioning of the genetic variance onto 30 chromosomes and four identified QTL regions on BTA5, 14, 20 and 27. Figure 2-7. Prediction of regulatory sites for the polymorphisms in EPS8 and GPAT4. Figure 2-8. Multispecies protein sequence alignment for the three genotyped sequence variants. Figure 3-1. Schematic of the exonic structure and linkage disequilibrium plot of PAX3. Figure 3-2. The proportion of daughter with ACOP by genotypes for the ss475875642 (p.T424M) and UA-IFASA-5029. Figure 3-3. Domain structure and multispecies sequence alignment of the PAX3 protein. Figure 3-4. Evidence for the association of the p.T424M variant in the PAX3 locus. Figure 3-5. Differential expression of KIT in bovine hair follicles. Figure 4-1. Detailed evidence of the FP QTL region on BTA5 in the HF and FV breeds. Figure 4-2. FP EBVs by genotypes for the ss319604833 and Hapmap49734-BTA- 74577. vi List of appendices List of appendices Appendix 1. Exon/intron organization of the investigated bovine genes. Appendix 2. Primers used in candidate gene re-sequencing for sequence variant screening. Appendix 3. Sequence variants identified in the investigated bovine genes. Appendix 4. Primers and probes used for TaqMan genotyping. Appendix 5. Gene re-sequencing and SNP genotyping protocol. Appendix 6. DNA panels used for polymorphism screening. vii Preface Preface This PhD thesis concludes my three years research training within the field of animal genetics in the Chair of Animal Breeding, Technische Universität München. This dissertation is based on research results from two independent studies, all trying to identify QTN of two prototypical complex traits (milk fat content and ambilateral circumocular pigmentation) in cattle (Bos taurus). In order to achieve this, candidate genes were selected from QTL regions mapped by previous GWAS. Subsequently, candidate gene re-sequencing and mutation analyses were performed in order to refine these QTL regions. Chapter 1 provides an introduction to this thesis. It starts with a review of the conventional strategies to dissect candidate genes underlying complex traits, and mainly focuses on the methodology of GWAS, which is used to map the QTL regions in this dissertation. The procedures used to map the candidate genes for milk fat traits and coat colours in cattle are subsequently reviewed. Chapter 2 investigates the findings of a GWAS on milk fat content in 2435 German Holstein-Friesian bulls. The genetic associations between the EBVs for milk fat percentage of these bulls were analysed, and two novel QTL regions on BTA5 and BTA27 were discovered. The most significant QTL on BTA5 was chosen for further analysis. Sixteen positional candidate genes (LMO3, MGST1, DERA, STRAP, EPS8, PTPRO, RERG, ARHGDIB, PDE6H, ERP27, H2AFJ, MGP, ART4, GUCY2C, ATF7IP and GRIN2B) within the interval of this locus were re-sequenced and analysed in order to locate the causative variant. A promoter SNP that resides in an evolutionarily conserved site and 100 bp upstream of the EPS8 gene is highly associated with the EBVs of milk fat percentage. Chapter 3 refers to the results from a GWAS of ambilateral circumocular pigmentation in 3579 German Fleckvieh bulls. Five positional and functional genes (PAX3, KIT, KDR, GSDMC and MITF) underlying four QTL regions were chosen for re-sequencing and analysis. Expression of the KIT gene between the follicles from pigmented and unpigmented hair was also investigated. The general discussion in Chapter 4 starts with a strategy of selecting candidate genes 1 Preface derived from previous GWAS. This is followed by a discussion of genomic organization and characterization. Subsequently, the approaches of SNP detection, QTN validation and analysis of non-coding variants are discussed separately, and future perspectives for identification of QTN in farm animals conclude this thesis. 2 Chapter 1 General introduction 3 Chapter 1 Genetic evaluation using genome-wide information is an important milestone in the long- awaited application of molecular genetics technology to animal improvement. Certain genetic markers could improve estimates of the genetic potentials of animals as
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