Zehn Jahre genomische Selektion in der Schweiz...Bulldog, Doppellender Hornlos, Farbe. | 30 Erbfehler dank SNPs(Auszug) BH1 Embryonaler Fruchttod BS BH2 Lebensschwache Kälber BS,FV

www.qualitasag.ch | 1

Zehn Jahre genomische Selektionin der Schweiz

Plattform der Rassenclubs

Mutterkuh Schweiz

15. Dezember 2017

[email protected]

http://www.qualitasag.ch/


Ein zentrales Konzept in der Tierzucht...

Phänotyp Genotyp Umwelt

• Leistungen• Exterieur• Fitness• Verhalten

• Erbgut • Haltung• Fütterung

Grundlagen



Verbesserung der genetischen Veranlagung der Tiere für bestimmte Leistungs- und Fitnessmerkmale

Kenntnis des Erbgutes von Zuchttieren möglichst:• früh• genau• kostengünstig

?

?

Ziel der Tierzucht



Der „klassische“ Weg:

• Leistungsprüfung (Absetzgewicht, Schlachtdaten usw.)

• Herdebuchführung

• aufbauend darauf Zuchtwertschätzung

Der neue Weg:

• Leistungsprüfung (Absetzgewicht, Schlachtdaten usw.)

• Herdebuchführung

• aufbauend darauf Zuchtwertschätzung

• Informationen aus dem Erbgut

= genomische Selektion

Genetische VeranlagungWie beschaffen wir uns Kenntnis über das Erbgut?



• Direkt nur sehr schwer möglich– Quantitative Merkmale (viele Gene wirken auf ein

Merkmal)– wenig bekannt über Lage und Wirkung der Gene

• Genomische Selektion arbeitet mit SNP-Markern• SNP: Single Nucleotide Polymorphism

– punktuelle Veränderungen im Genom (1 bp lang)– kommen in sehr hoher Anzahl vor– nur je zwei Varianten

• Marker zeigen uns Genwirkungen aufgrund der physischen Nähe zu den Genen– Kopplungsungleichgewicht

Gene entdecken – WIE?



SNP1

CAGTATCGTAATAATAATAATAAGTCCTGGGCCTAAACCTGCAAGGTTTCGATATTGGCCCCCGG GTCATAGCATTATTATTATTATTCAGGACCCGGATTTGGACGTTCCAAAGCTATAACCGGGGGCC








AAABBB AAAB BBBB AA ABBB

SNP2

SNP3

SNP4

SNP5

SNP6

SNP7

SNP8

SNP10

SNP9

.........

Effektschätzung?



1) Vergleich von Zuchtwerten mit Genotypen

– Datengrundlage für die SNP-Effektschätzung bilden die SNP-Typisierungen und die konventionellen Zuchtwertevon Stieren* mit einem Nachzuchtprüfungsresultat

– Trainingsdatensatz (Referenzdatensatz, Kalibrierungsdatensatz, Lernstichprobe)

2) Schätzen der genomischen Zuchtwerte der anderen Tiere mit der Formel aus 1)

* teilweise werden auch Kühe im Trainingsdatensatz verwendet; diese sollten zufällig aus der Population ausgewählt werden

Effektschätzung - Prinzip



kg M

ilch

BBABAA

Beispiel mit einem SNP:

SNP-Effekt

Der Effekt eines zusätzlichen „B“-Allels beträgt +10kg

Effektschätzung



Die Berechnung der genomischen Zuchtwerte ist sehr einfach, denn man muss nur SNP-Effekte aufsummieren

SNP1









Kalb 1

AAABBB AAAB BBBB AA ABBB

SNP2

SNP3

SNP4

SNP5

SNP6

SNP7

SNP8

SNP10

SNP9

+1.3 -0.1 +0.5 +0 -0.4 +3.8 +38.3 +4.1 -5.7 +2.7

ZW = 2*(+1.3)+1*(-0.1)+1*(+0.5)+0*(0)+0*(-0.4)+ 2*(+3.8)+2*(+38.3)+0*(+4.1)+2*(-5.7)+1*(+2.7)

ZW = 81.2 = direkter genomischer Zuchtwert (DGZW)

Berechnung genomischer ZW



20152010200520001995

Trainingsstiere (nachzuchtgeprüfte Stiere)Selektions-Kandidaten

EffektschätzungSumme derSNP-Effekte

(DGZW)

Effektschätzung



2005

Trainings-Stiere

EffektschätzungSumme der

SNP-Effekte (DGZW)

Validierungs-Stiere

Validierung:

Korrelation zwischen DGZW

und trad. ZW

2015201020001995

Sicherheit genomischer ZW: Validierung



Merkmal BV RH/HO

Produktion (Ekg) 49 % 56 %

Zellzahl 43 % 44 %

LBE 43 %

(25 - 56) 43 % (21 - 61)

Fruchtbarkeit 38 % 35 %

Nutzungsdauer 27 % 42 %

Sicherheit (B%) der DGZW



Zuchtwert (ZW): „konventionell“ geschätzt, ohne Einbezug von Markerinformation

Direkter genomischer Zuchtwert (DGZW): Zuchtwert geschätzt allein aufgrund von Markerinformationen

Genomisch optimierter Zuchtwert (GOZW): Zuchtwert geschätzt auf Grund von traditionellen Daten und Markerinformationen(Kombination von ZW und DGZW).

Begriffe

ZW-Typ traditionell Deklaration GOZW Tiergruppe

Abstammungs-ZW+ DGZW

GA Jungtiere

CH-Zuchtwert G Kühe, Stiere

Interbull-Zuchtwert GI Stiere



−20 0 20 40 60 80

−20

020

40

60

80

konv. ZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.54

−20 0 20 40 60 80

−20

020

40

60

80

DGZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.7

−20 0 20 40 60 80

−20

020

40

60

80

GOZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.72

Genauigkeit genomischer Zuchtwerte

Vergleich ZW Eiweiss kg 2012 - 2016

−20 0 20 40 60 80

−20

020

40

60

80

konv. ZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.54

−20 0 20 40 60 80

−20

020

40

60

80

DGZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.7

−20 0 20 40 60 80

−20

020

40

60

80

GOZW Eiweiss kg 2012

konv.

ZW

Eiw

eis

s k

g 2

016

Korrelation: 0.72

Abstammungs-ZW GOZW

kon

v. Z

W m

it N

ach

kom

me

n r = 0.54 r = 0.72



Anzahl Trainingsstiere Braunvieh

• Je grösser der Trainingsdatensatz desto genauer die genomischen Zuchtwerte

• Kühe im Trainingsdatensatz?• Heute ziemlich vollständiger Trainingsdatensatz bei

Braunvieh (Projekt Intergenomics): ca. 6‘500 Stiere Ekg

Aug 2011 Dez 2011

n Training corr(DGZW,CHZW)n = 250

n Training corr(DGZW,CHZW)n = 360

Veränderung (%)

Mkg 2471 0.60 3300 0.65 + 4.7

Fkg 2162 0.60 3202 0.70 + 10.6

Ekg 1710 0.53 3254 0.65 + 11.2

ZZ 2188 0.70 2896 0.70 ± 0.0



Anzahl Trainingsstiere Holsteinweltweit 2 grosse „Blöcke“

Warum hatte Schweiz lange keinen Zugang?

• kleine Populationen sind nicht sehr interessant

• Offener Zugang zu Typisierung von Stieren war hinderlich

CDDR (erweitert) EuroGenomics

USA Frankreich

Kanada Deutschland

Italien Die Niederlande

Grossbritannien Nordische Staaten

Schweiz (seit 2016) Spanien

Polen



• CDDR (Cooperative Dairy DNA Repository)

– Genotypen-Pool von KBO aus USA & CAN

• Erster Austausch im Februar 2016

– SNPs von 125‘000 HOL-Stieren erhalten

– 260‘000 Tiere im Pedigree erfasst

– 14 verschiedene SNP-Chips

– SNPs von 6000 HO/RH-Stieren geliefert

• Monatliche Updates

– Neu typisierte Stiere

Genotypenaustausch Holstein



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−40 −20 0 20 40 60 80

−40

−2

00

20

40

60

80

DGZW ORG vs Wonderment

DGZWs ORG

DG

ZW

s W

on

derm

en

t

Mean24.82

Stdv

15.41

Mean

24.69

Stdv

15.4

Korrelation: 1Rangkorrelation: 1

DGZW (Effektschätzung OHNE Stier XY)

DG

ZW

(E

ffe

ktsc

hät

zun

g M

ITS

tie

r X

Y)

Stier XY selbstNachkommen

Enkel

Zusammensetzung Trainingsstiere (Bsp. BV Training mit / ohne Stier XY)

Enger Bezug zwischen Trainingsdatensatz und Selektionskandidaten!

Training - Selektion



Fazit:Genotypen sind Spiegel-bild der Population

Simmental hat kaum genetische Verknüpfung zum Trainingsdatensatz:Validierung für viele Merkmale ungenügend

Struktur Trainingsstiere (HO/SI)



• Original Braunvieh funktioniert mit gemischtem Trainingsdatensatz (mit BV/BS)

– Stiere max. 95% BS

– Kühe mit OB-Anteil > 50% erhöhen Genauigkeit

• Simmental: nur Milch + Zellzahl (ITB-ZW), übrige Merkmale/Fleisch in Entwicklung

• Erhöhung der Anzahl SNP‘s (50‘000 800‘000) verbessert die Genauigkeit nicht

Genomische Selektion für kleine Populationen



X X XMachbarkeit Limousin

Aktuelle Anzahl Limousin-Stiere mit Sicherheit Zuchtwert > 50% und DNA

• Qualität der DNA muss in Ordnung sein• Trainingsdatensatz mit 1’500 Stiere = Investition CHF 150’000.-



Machbarkeit Angus

X X XXX

Aktuelle Anzahl Angus-Stiere mit Sicherheit Zuchtwert > 50%



Internationale Zusammenarbeit

• Nur mit Win – Win - Modell• Internationale Kooperation wichtig

(Interbeef, Genotypenaustausch)• Länder-/Populationsspezifische

Anpassungen/Entwicklungen notwendig• Herausforderung: Neue Methoden für

kleine Rassen nutzbar machen• Kommerzialisierung von Phänotypen,

Genotypen und Methoden• je mehr „nicht-öffentliche“ Investitionen in

Zuchtprogramme erfolgen, desto grösser wird das Interesse der Investoren kommerzielle Zuchtunternehmen



Höherer Zuchtfortschritt ...

• dank genaueren Zuchtwerten (v.a. Jungtiere) und kürzerem Generationenintervall

• weil „schwierige“ Merkmale besser züchterisch bearbeitet werden können (z.B. Fruchtbarkeit)

• weil neue Merkmale züchterisch bearbeitet werden können (z.B. Gesundheitsdaten)

Zucht mit genomischer Selektion



Generationsintervall USA



Gesamtzuchtwert der Stiere aus Genotypenaustausch Holstein

- Gesamtzuchtwert ISET- Inzuchtgrad F



Inzucht

• Inzuchtdepression = verminderte Leistungsfähigkeit und Fitness

• Auftreten von Erbfehlern

• Verminderung der genetischen Varianz = Gefährdung zukünftiger Zuchterfolge



Optimum genetic contribution

• optimiert den Zuchtfortschritt bei definiertem Inzuchtanstieg

• Sucht Tiere mit hohen Zuchtwerten und tiefem durchschnittlichen Verwandtschaftsgrad zur Population



Zusatznutzen

• Abstammungskontrolle Mutterkuhrassen AN, BV, DR, LM und SM

• Erbfehler/ZusatztestsBulldog, DoppellenderHornlos, Farbe



Erbfehler dank SNP‘s (Auszug)

BH1 Embryonaler Fruchttod BS

BH2 Lebensschwache Kälber BS,FV

CD Durchfall HO

FH1 Zwergwuchs FV

FH2 Minderwuchs (Leberproblem) FV, OB

FH4 Embryonaler Fruchttod FV

FH5 Herzschwäche, Tod innert 48h pp FV

HH1 Embryonaler Fruchttod HO





JH1 Embryonaler Fruchttod JE

MH1 Embryonaler Fruchttod MO

MH2 Embryonaler Fruchttod MO



Erbfehlerstrategie

• Viele neue Erbfehler entdeckt

• Neue Strategien erforderlich

– Ausschluss von Trägertieren nicht mehr für alle Erbfehler sinnvoll

– Vermeidung von Träger x Träger Paarungen (Machbarkeit im Natursprung?)

– Genetic Load Index (Frequenz, Schaden, Vererbung)



ChipName

GGPLD v2 (9K)

GGPLD v3 (26K)

GGPLDv4 (30K)

50Kv1 (54K)

50Kv2 (54K)

GGPHD (80K)

GGPHD (150K)

HD (850K)

GGPLD v2 (9K)

8.762 92.9% 92.9% 92.6% 92.3% 92.1% 93.6% 95.8%

GGPLD v3 (26K)

26.151 99.8% 32.1% 31.9% 36.3% 95.0% 98.8%

GGPLD v4 (30K)

30.125 34.1% 35.9% 95.1% 97.2%

50K v1 (54K)

54.001 96.6% 52.4% 77.2% 90.2%

50K v2 (54K)

54.609 51.7% 75.8% 90.5%

GGPHD (80K)

76.999 95.9% 96.8%

GGPHD(150K)

139.481 96.3%

HD(850K)

777.962

SNP Chip Modelle – Überlappung



IMPUTING = Auffüllen der fehlenden SNPs bei den LD TierenInformationsquellen:

– Pedigree

– Populationsinformation (Linkage Disequilibrium)

Imputing: Daten



durchschn.

% korrekt

durchschn.

% inkorrekt

durchschn.

Korrelation

imputiert-wahr

Beide Eltern 98,6 1,4 0,98

Vater + MGV 98,1 1,9 0,97

Vater 97,6 2,4 0,96

Andere 97,3 2,7 0,95

Imputing LD auf 50k

Daten: 3‘738 mit 50k typisierte BV-Tiere

Annahme: die 723 jüngsten Tiere sind mit LD Chip typisiert

Frage: wie gut werden fehlende SNPs geschätzt?



Logistik genomische Selektion



Entnahme einer Haarprobe





Typisierungen nach Auftraggeber

0

1000

2000

3000

4000

5000

BVCH SHZV shb weitere

2011 2012

2013 2014

2015 2016



Anzahl Typisierungen 2016

5679

1028 66

GGP LD

GGP HD

HD



Chip Laborpreise GeneSeek

• GGPLDv4 (30K) $ 38.00• 50Kv2 (54K) $ 85.00• GGPHD (150K) $ 85.00• HD (770K) $ 165.00

Preise für SNP-Typisierung inkl. DNA-Aufbereitung

• Probenhandling Qualitas CHF 5.- bis 17.-



Durch Wettbewerb / Konsumenten gefordert!

• Gesundheit, Immunität

• Futterverwertung, Effizienz, Treibhausgasemissionen

• Tierwohl, Tierverhalten

• Fleischqualität

Genomische Selektion ermöglicht schnellere Verfügbarkeit!

Genomische Selektion für neue Merkmale



• Neue Konzepte für die Leistungsprüfung

• Prüfbetriebe Vertragsbetriebe mit möglichst zuverlässiger Erfassung von züchterisch interessanten Merkmalen

• Genotypisierung von weiblichen Tieren

– Mehrere 1000 Kühe mit guten Phänotypen

• Hohe Investitionen für Züchter

– Internationale Kooperation

Genomische Selektion für neue Merkmale



Hohe Investitionen & zunehmende Kommerzialisierung

• Aufbau Trainingsdatensatz / Problem Populationsgrösse / Eigentum & Nutzung SNP-Daten

• Kombination genomische Selektion – Fortpflanzungs-technologien (ET-Stationen & Samensexing)

• Neue Technologien: Genom-Editierung

• Samen von Top-Stieren nur gesext verfügbar

• Weibliche Toptiere im Eigentum kommerzieller Firmen

• kommerzielle genomische Indexe (CLARIFIDE Plus; EvaLim)

Tendenzen Rindviehzucht



• Genomische Selektion funktioniert und ist fester Bestandteil der Schweizer Milchviehzucht-programme

• Entwicklung der genomischen Selektion geht weiter, es bleibt noch viel zu tun

• Neue Merkmale (Fitness, Gesundheit, Effizienz) gewinnen an Bedeutung

• Zunehmende Kommerzialisierung der Milchviehzucht

• Fleischrinderzucht kann von den Erfahrungen der Milchviehzucht profitieren

Schlussfolgerungen



Danke für Ihre Aufmerksamkeit!


Documents

Zehn Jahre genomische Selektion in der Schweiz...Bulldog, Doppellender Hornlos, Farbe. | 30 Erbfehler dank SNPs(Auszug) BH1 Embryonaler Fruchttod BS BH2 Lebensschwache Kälber BS,FV