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Feinkartierung Und Kandidatengenanalyse Des Weaver-Syndroms Im Braunvieh

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Feinkartierung Und Kandidatengenanalyse Des Weaver-Syndroms Im Braunvieh Feinkartierung und Kandidatengenanalyse des Weaver-Syndroms im Braunvieh von Elisabeth Maria Kunz Inaugural-Dissertation zur Erlangung der Doktorwürde der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Feinkartierung und Kandidatengenanalyse des Weaver- Syndroms im Braunvieh von Elisabeth Maria Kunz aus Kaufbeuren München 2016 Aus dem Veterinärwissenschaftlichen Department der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Lehrstuhl für Tierzucht und Allgemeine Landwirtschaftslehre Arbeit angefertigt unter der Leitung von Priv.-Doz. Dr. Ivica Međugorac Mitbetreuung durch Dr. Sophie Rothammer Gedruckt mit Genehmigung der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Dekan: Univ.-Prof. Dr. Joachim Braun Berichterstatter: Priv.-Doz. Dr. Ivica Međugorac Korreferenten: Univ.-Prof. Dr. Bernhard Aigner Univ.-Prof. Dr. Gabriela Knubben-Schweizer Univ.-Prof. Dr. Kaspar Matiasek Univ.-Prof. Dr. Holm Zerbe Tag der Promotion: 16. Juli 2016 Meiner Familie, vor allem meinem Ururopa, der diesen Weg vor über einem Jahrhundert auch eingeschlagen hatte. Inhaltsverzeichnis I Inhaltsverzeichnis INHALTSVERZEICHNIS ................................................................................... I ABKÜRZUNGSVERZEICHNIS ....................................................................... VI ABBILDUNGSVERZEICHNIS/TABELLENVERZEICHNIS ............................... X ANHANGSÜBERSICHT ................................................................................. XII 1 EINLEITUNG ............................................................................................. 1 2 LITERATURÜBERSICHT .......................................................................... 3 2.1 Rassegeschichte Braunvieh ........................................................... 3 2.1.1 Charakteristika ...................................................................... 3 2.1.2 Anfänge der Rasse Braunvieh .............................................. 5 2.1.3 Brown Swiss ......................................................................... 5 2.1.4 Deutsches Braunvieh (Braunvieh × Brown Swiss) ................ 6 2.1.5 Original Braunvieh ................................................................ 8 2.2 Kartierung von Genen ................................................................... 10 2.2.1 Einteilung kartierter Merkmale ............................................ 10 2.2.2 Genetische Marker .............................................................. 10 2.2.2.1 Restriktionsfragment-Längenpolymorphismen ..... 11 2.2.2.2 Mikrosatelliten ...................................................... 12 2.2.2.3 Einzelbasenpolymorphismen ............................... 13 2.2.3 Genkarten ........................................................................... 15 2.2.3.1 Kopplung (Linkage) .............................................. 15 2.2.3.1.1 Kopplungsgleichgewicht und Kopplungsungleichgewicht .................. 16 2.2.3.2 Kopplungskartierungen (linkage mapping) ........... 17 Inhaltsverzeichnis II 2.2.3.3 Kopplungsungleichgewichts-Kartierungen (linkage disequilibrium mapping) .......................... 18 2.2.3.4 Kopplungsungleichgewichts- und Kopplungs- Kartierungen (linkage disequilibrium and linkage mapping) .................................................. 19 2.3 Das Weaver-Syndrom ................................................................... 21 2.3.1 Geschichte .......................................................................... 21 2.3.2 Symptome ........................................................................... 22 2.3.2.1 Frühstadium ......................................................... 23 2.3.2.2 Fortgeschrittenes Stadium ................................... 23 2.3.2.3 Endstadium .......................................................... 25 2.3.3 Pathologie ........................................................................... 26 2.3.3.1 Pathologisch-anatomische Untersuchung ............ 26 2.3.3.2 Pathologisch-histologische Untersuchung ........... 26 2.3.4 Diagnose ............................................................................. 27 2.3.5 Frequenz in der Braunvieh-/Brown Swiss-Population ......... 28 2.3.6 Bisher durchgeführte Studien.............................................. 30 2.3.6.1 Hoeschele und Meinert: Kopplung mit QTL für Milchmenge ..................................................... 30 2.3.6.2 Georges et al.: Kopplung des Weaver-Locus mit TGLA116 ........................................................ 30 2.3.6.3 Erweiterung des indirekten Gentests und Einengung des Weaver-Locus ............................. 31 2.3.6.4 McClure et al.: weitere Einengung des Weaver-Locus, diagnostische SNPs und Weaver-Haplotyp ................................................. 31 Inhaltsverzeichnis III 3 MATERIAL UND METHODEN ................................................................ 33 3.1 Material ........................................................................................... 33 3.1.1 Zusammenstellung der Testpopulation ............................... 33 3.1.2 Zuteilung der Phänotypen ................................................... 33 3.1.3 Probenmaterial .................................................................... 35 3.1.4 Datenmaterial...................................................................... 35 3.2 Methoden ........................................................................................ 36 3.2.1 Verwendete Software .......................................................... 36 3.2.2 Verwendete Datenbanken .................................................. 36 3.2.3 Kombinierte Kopplungsungleichgewichts- und Kopplungs-Kartierung ......................................................... 37 3.2.3.1 Genotypisierung ................................................... 37 3.2.3.1.1 Auswahl der zu genotypisierenden Tiere .................................................... 37 3.2.3.1.2 Durchführung der Genotypisierung ..... 38 3.2.3.1.3 Qualitätskontrolle................................. 40 3.2.3.2 Haplotypisierung und Imputation .......................... 40 3.2.3.3 Korrektur auf Populationsstratifikation und Verwandtschaftsbeziehungen .............................. 42 3.2.3.4 Hauptkomponentenanalyse .................................. 43 3.2.3.5 Bestimmung der Locus IBD und Diplotypen- Verwandtschaftsmatrix ......................................... 44 3.2.3.6 Varianzkomponentenanalyse ............................... 45 3.2.3.7 Likelihood-Ratio Teststatistik ................................ 47 3.2.3.8 Festlegung der Signifikanzschwelle ..................... 47 3.2.3.9 Bestimmung der Konfidenzintervalle .................... 48 3.2.4 Vergleichende Kartierung per Fall-Kontroll- Assoziationsanalyse ........................................................... 48 Inhaltsverzeichnis IV 3.2.5 Ermittlung eines Weaver-Haplotypen auf BTA4 .................. 49 3.2.6 Nutzung von Sequenzdaten aus dem 1000 Bull Genomes Project ................................................................ 49 3.2.7 Überprüfung von Kandidatenmutationen durch gezielte Genotypisierungen ................................................ 50 3.2.7.1 Gezielte Genotypisierungen des SNP an Position 49 878 773 bp ........................................ 50 3.2.7.2 Gezielte Genotypisierungen des SNP an Position 50 858 538 bp ........................................ 52 3.2.7.3 Überprüfung des Krankheitsstatus von Tieren mit abweichenden PCR-RFLP Genotypen ............................................................ 53 3.2.8 Schätzung der Frequenz der Kandidatenmutation an Position 49 878 773 bp in einer Stichprobe von Braunvieh-Tieren aus der genomischen Evaluation ............ 54 3.2.9 Schätzung der Frequenz des Weaver-Haplotypen in anderen Rassen .................................................................. 54 3.2.10 Überprüfung des Krankheitsstatus des kontroversen Anlageträgers W0277 ......................................................... 55 4 ERGEBNISSE ......................................................................................... 57 4.1 Allgemeine Übersicht ....................................................................... 57 4.2 Kombinierte Kopplungsungleichgewichts- und Kopplungs- Kartierung auf BTA4 ........................................................................ 58 4.3 Vergleichende Kartierung per Fall-Kontroll-Assoziationsanalyse .... 58 4.4 Identifizierung eines gemeinsamen Haplotypen auf BTA4 .............. 61 4.5 Nutzung von Sequenzdaten aus dem 1000 Bull Genomes Project ............................................................................................. 61 Inhaltsverzeichnis V 4.6 Gezielte Genotypisierungen für zwei Kandidaten-SNPs per PCR-RFLP ....................................................................................... 64 4.6.1 Überprüfung widersprüchlicher Ergebnisse bezüglich des SNP an Position 49 878 773 bp ................................... 65 4.6.2 Überprüfung widersprüchlicher Ergebnisse bezüglich des SNP an Position 50 858 538 bp ................................... 68 4.7 Schätzung der Frequenz der Kandidaten-Mutation in einer Stichprobe von Braunvieh-Tieren aus der genomischen Evaluation ........................................................................................ 68 4.8 Schätzung der Haplotypenfrequenz und Überprüfung der Kandidatenmutation in anderen Rassen .......................................... 69 4.9 Überprüfung des Anlageträgerstatus von Tier
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