Improving Fertility of Dairy Cattle Using Translational

GenomicsAFRI 2013-68004-20365

Tom Spencer, Holly Neibergs, Joe Dalton, Mirielle Chahine, Dale Moore, Pete

Hansen, John Cole, & Albert De Vries

Historical Changes in Estimated Breeding Value for DPR and Milk

Production

1957

1961

1965

1969

1973

1977

1981

1985

1989

1993

1997

2001

2005

2009

2013

-2-1012345678

-8000

-6000

-4000

-2000

0

2000

4000DPR Milk

Holstein year of birth

Dau

ghte

r Pr

egna

ncy

Rate

(D

PR)

Milk

DPR h2=0.04 DPR is the percentage of a bull’s daughter’s eligible for breeding thatbecome pregnant during each 21-day period

Genetics 101 What is a gene? What is a mutation? What are SNPs (single nucleotide

polymorphisms)? Genes are the blueprints that tell cells

how to make individual proteins – workhorse molecules of the body (muscle, enzymes, signaling molecules, etc.)

There are about 20,000 genes in cattle Mutations are a change in the blueprint –

usually bad but sometimes good A SNP is a specific type of mutation

caused by a single change in the DNA code – one base pair

Double-muscled Piedmontese bull caused by a single nucleotide

polymorphism mutation in a gene called myostatin (abbreviated MSTN)

limits muscle growth in fetal life

MSTNgene

Myostatininhibits muscle growth

Normal muscling Excessive muscling

Daughter Pregnancy Rate

Number of cows that became pregnant during a given 21-day periodNumber of cows that were eligible for breeding

A 1% increase in DPR =~ -4 days open

1% PR=400 lb milk

Welcome Super Petrone-ET

PR =

National average for PR ~16%DPR = PR of a bull’s daughters

PR (DPR) = 21/(days open – voluntary waiting period + 11)

(Dec 2014)+3.7 (-15 days open)

Many Factors Determine When a Cow Gets Pregnant – Low Heritability and

Many Genes

Walsh et al., Animal Reproduction Science, Volume 123, Issues 3–4, 2011, 127 - 138

Genetic Control of Reproduction

The heritability for reproduction is low (days open=0.04)

which means lots of variation in reproduction due to environment

which means identifying genetically-superior animals is difficult and progress is slow

which does not mean that it is futile to selectfor reproduction

Differences in fertility between high and low DPR groups

Trait NLSMEANS (%) (SEM)

P valueHigh DPR Low DPR

Preg. Rate, first service (Lact1) 2213 53.1 (1.69) 28.6 (2.32) <0.0001

Preg. Rate, first service (Lact2) 1969 43.9 (1.77) 23.0 (2.38) <0.0001

Preg. Rate, first service (Lact3) 1321 41.0 (1.88) 25.0 (2.53) <0.0001

Trait N LSMEANS (SEM) P valueHigh DPR Low DPRServices /conception (Lact1) 2213 1.93 (0.06) 3.26 (0.07) <0.0001

Services /conception (Lact2) 1969 2.09 (0.07) 3.30 (0.07) <0.0001

Services /conception (Lact3) 1321 2.20 (0.08) 3.20 (0.10) <0.0001

Days open (Lact 1) 2213 98 (2.59) 163 (2.94) <0.0001

Days open (Lact 2) 1969 112 (2.80) 167 (3.13) <0.0001

Days open (Lact 3) 1321 110 (3.24) 158 (3.81) <0.0001

There is a negative genetic correlation between fertility and milk production

Trait Correlation with DPR

Cow conception rate 0.61 Productive life 0.81Net merit 0.49Milk yield -0.45Fat yield -0.35Protein yield -0.34Somatic cell score -0.55

Trait

Milk yield Fertility Milk yieldFertility

Daughter Pregnancy Rate

Number of cows that became pregnant during a given 21-day periodNumber of cows that were eligible for breeding

A 1% increase in DPR =~ -4 days open

1% PR=400 lb milk

PR =

National average for PR ~16%DPR = PR of a bull’s daughters

PR (DPR) = 21/(days open – voluntary waiting period + 11)

Welcome Super Petrone-ET(Dec 2014)+3.7 (-15 days open)Milk +624 lb

Milk yield Fertility Milk yieldFertility

Petrone

Four obstacles to achieving optimal results for genetic selection for reproduction

Trait Reproductive traits routinely measured on cows are not very accurate

Heritability is low so we are not that good at identifying

genetically-superior bulls In general, animals that are genetically

superior for reproduction are genetically inferior for production Selection for fertility could reduce production

Reproductive traits are controlled by many genes and effects of one gene may depend on others Complicates the use of genomics

Approaches for overcoming obstacles to achieving optimal results for genetic selection for reproduction

Trait Find genetic mutations controlling reproduction Using routinely measured traits and those not routinely

measured In genes that control reproduction In parts of the DNA physically close to genes that control

reproduction (GWAS) Find how genes interact with each other to affect

reproduction (networks) Genes that have been copied where number of copies

are related to reproduction (copy number variants) Find genes related to reproduction that are

either not deleterious to production or are positively related to production

Fertility Milk yieldFertility

causativeSNP

Genetic Marker(GWAS)

Gene networksCopy number variants

Research: • Develop novel genetic markers of fertility in replacement heifers and

lactating cows, determine effects of specific single nucleotide polymorphisms (SNPs) on DPR and embryo development, and understand gene networks associated with DPR, fertilization and embryo development.

Extension:

• Develop a sustained effort to disseminate, demonstrate, evaluate and document the impact of using genetic selection tools to increase fertility on herd management and profitability to producers and personnel involved in dairy cattle enterprises.

Agriculture and Food Research Initiative Grant 2013-68004-20365

Improving Fertility of Dairy Cattle Using

Translational Genomics

OBJECTIVES

Research Objectives and Goal• Develop novel genetic markers of fertility in replacement heifers

and lactating cows• Understand genetic variants that control fertility

– Identify causative SNPs in genes known to be involved in reproduction that are related to daughter pregnancy rate (DPR)

– Identify genetic markers for embryo cleavage rate and blastocyst development

– Identify genetic markers for uterine receptivity and capacity for early pregnancy

• Provide novel markers useful in genomic selection of sires and dams to improve fertility in dairy cattle

• Approach: Breeding records will be used to fertility classify replacement Holstein heifers and primiparous lactating cows based on pregnancy outcome to AI.

o Heifers must have a normal reproductive tract by palpation, no record of diseases, and display standing estrus before AI.

• Cows must have a normal reproductive tract, uncomplicated pregnancy, no records of diseases (mastitis, retained placenta, metritis or uterine infection, milk fever, displaced abomasum, clinical lameness) preceding or after AI, display standing estrus before AI, and average to high milk yields (>53 lb milk per day).

• Fertility phenotypes:o Highly fertile (pregnant on first AI)o Subfertile (pregnant after 4th AI)o Infertile (never pregnant to AI and culled)

Objective 1: Develop novel genetic markers of fertility in replacement heifers & lactating cows

Genome-wide Association Study (GWAS) of Fertility in Holstein Heifers

• Fertility phenotyped by artificial insemination (AI) breeding record analysis• 470 High Fertile (pregnant upon first AI)• 189 Infertile (never pregnant with no obvious physiological problems)

• Animals were genotyped using the Illumina BovineHD 777K BeadChip

• The blue line represents the Wellcome Trust threshold for moderate significance.

Objective 2: Identify SNPs in genes known to be involved in reproduction that are related to daughter pregnancy rate

Importance: Identification of mutations in genes

controlling fertility (causative mutations) rather than genetic markers near mutation

Genes associated with DPR in a population of 550 bulls

Cochran et al. 2013

434 SNPs550 bulls

40 SNPs associated with DPR12 SNPs associated with blastocyst development

Fat yield - 19

Milk yield - 23

Net merit - 34

Productive life -36

Cow conception rate - 33

Heifer conception rate - 22

Protein yield -19

Protein percent - 22

Fat percent - 13

Somatic cell score - 13

• Obtained semen from 550 bulls born between 1962 and 2010• High DPR Bulls (>1.7) (n=288)• Low DPR Bulls (<-2) (n=262)• Varying reliabilities (46-99%)

29 of 40 genes associated with DPRare not associated with production

Objective 3: Evaluate the efficiency and profitability of increasing fertility in dairy cattle using genetic selection tools. Studies will evaluate their added value in terms of efficiency of food production and profitability for dairy farmers through computer modeling. A Web-based decision support tool will be developed for producers.

Objective 4: Conduct a national effort to transfer science-

based information to dairy producers, managers, and allied industry personnel, complete with strategies to improve fertility using novel genomic information and tools from the first three parts.

Expected Outcomes of the Grant

Better Genomic Tools for Predicting Reproduction

More Reliable Estimates of Breeding Values for Reproductive Traits

More Rapid Progress in Improving Dairy Cow Fertility

Hearty Thanks!• M/M Feedlot (Idaho)

o Darin Mann• Ag Health Laboratories (Sunnyside, WA)

o Fred Mueller• Cow Palace Dairy (Washington)

o Levi Gassaway• DeRuyter Brothers Dairy (Washington)

o Kelly Reed• J&K Dairy (Washington)

o Jason Sheehan• George DeRuyter & Son Dairy

o Dan DeRuyter• Kevin Gavin & Joao Moraes (WSU)

Genasci Dairy

ShenandoahDairy