biotech beef and cloned cows: progress in translational … · 2012. 9. 5. · animal biotechnology...

Animal Genomics and Biotechnology Education

Biotech Beef and Cloned Cows:

Progress in Translational

Genomics Alison Van Eenennaam, Ph.D. Cooperative Extension Specialist

Animal Biotechnology and Genomics Department of Animal Science

University of California, Davis

alvaneenennaam@ucdavis.edu

(530) 752-7942

Twitter: @biobeef

animalscience.ucdavis.edu/animalbiotech

Animal Biotechnology and Genomics Education

“Translational genomics” is defined as the

adaptation of information derived from

genome technologies for animal improvement

Van Eenennaam CalPoly 3/10/11

SNP (Single Nucleotide Polymorphism)

A DNA sequence variation that

varies sufficiently between

individuals that its inheritance can be tracked

through families

Overview: A whirlwind tour of

translational genomics

1. Using DNA information to identify carriers of recessive traits (coat color, horns, disease)

2. Marker-assisted selection

3. Genome-enabled or genomic selection

4. Cloning

5. Genetic engineering

This is a picture

of D _ A.

B N C L

0% 0%0%0%

Given this information……

Which do you think is my dog?

1 2 3 4

0% 0%0%0%

1. Using DNA information to

identify carriers of recessive traits Images from an article by David S. Buchanan, NDSU http://www.ag.ndsu.edu/williamscountyextension/livestock/genetic-defects-in-cattle

Both are important!!

The ‘homozygous’ bull is a source of favorable form of the genetic variant. Can eventually be used to create homozygous calves

The other bull contributes other favorable genes, which will improve the other genes affecting the trait.

Breeding the marker-associated form of the gene into the bull that has no copies should improve the trait by combining all of the good forms of the genes together in one animal Van Eenennaam CalPoly 3/10/11

Compare dwarfism response in the 50s to the response to curly calf (AM)

An early '50's

advertisement that

superimposed a

measuring stick in the

picture of this bull

who was nick-named

"Short Snorter."

Based upon his height

and age, he was less

than a frame score 1.

Image from https://www.msu.edu/~ritchieh/historical/shortsnorter.jpg

Curly calf – Arthrogryposis multiplex

From a scientific standpoint,

AM is the complete deletion

of a segment of DNA that

encompasses two different genes

One of these genes is expressed at a crucial time in the development of nerve and muscle tissue. The mutation results in no protein being produced from this gene and therefore it is unable to carry out its normal function so homozygotes show phenotype

Dr. David Stefan of the University of Nebraska and Dr. Jon Beever of the University of Illinois worked to develop a genetic test from September – October, 2008

Animal Genomics and Biotechnology Education

From September 8 – December, 2008 identified genetic problem, developed test, and released carrier status of 736 bulls!

From: Buchanan, D.S. Genetic Defects in Cattle. http://www.ag.ndsu.edu/williamscountyextension/livestock/genetic-defects-in-cattle

In the 10 months following the release of the test, the AAA posted the results of tests for AM on about 90,000 cattle.

These AM test costs less than $30 (~2.7 million).

Of these, almost 5,000 bulls and more than 13,000 heifers have tested as carriers of AM. That leaves more than 22,000 bulls and more than 50,000 heifers which tested as free of AM.

Early extension education about dwarfism

explaining carriers and inheritance

Image from Special CollectionsUniversity Libraries, Virginia Tech: http://spec.lib.vt.edu/imagebase/agextension/boxseven/screen/AGR3618.jpg

If you breed a curly calf carrier cow (AMC) to an curly calf free bull (AMF), what is the chance that the offspring will be stillborn

as a result of being curly calf?

0% 0% 0%0%0%0%

2. ¼ (25%)

3. ½ (50%)

4. 2/3 (66%)

5. ¾ (75%)

6. 1 (100%) Van Eenennaam CalPoly 3/10/11

2. There are various companies offering DNA tests for marker-assisted selection in beef cattle

Meat Tenderness

Quality Grade (Marbling)

Beef Cattle Feed Efficiency

Meat Yield

Disease Resistance

Dairy Form

Milk and Milk Component Yield

Tests for quantitative traits – before 2010 10-100 SNPs

Which would you rather have???

0%0%**

1. A bull that is ‘homozygous’ or two stars for a trait who also has an EPD of +3, or

2. A bull carrying no copies of that genetic variant with an EPD of +3

Both are important!!

The ‘homozygous’ bull is a source of favorable form of the genetic variant. Can eventually be used to create homozygous calves

The other bull contributes other favorable genes, which will improve the other genes affecting the trait.

Breeding the marker-associated form of the gene into the bull that has no copies should improve the trait by combining all of the good forms of the genes together in one animal Van Eenennaam CalPoly 3/10/11

What is wrong with this model?

A few markers are not sufficient to account for much (>10%) of the additive genetic variation – so little obvious relationship between phenotype and DNA-test results and little genetic progress likely to result from MAS

Markers do not exist for many important traits

Early adopters of genotyping for MAS in livestock have not experienced sufficient value capture i.e. they are too expensive !

Challenge for breeders is to identify those individuals that have the best

true breeding values

ΔG (rate of genetic gain)

= intensity of selection X

accuracy of selection X

genetic standard deviation

generation interval

3. Mooving onto Genomic Selection

Training 1: Old Progeny Tested Bulls

Validation: New Progeny Tested Bulls

Application: New Sire Candidates

Training 2: Old & New Progeny Tested Bulls

Slide courtesy of Marc Thallman, US MARC

Degree of genetic relationship between

populations (ideally similar)

Young sire Parent Average

Mendelian Sampling ?

Accuracy 0.20

Breeding value prediction in Dairy Sires

5 years; >>>> cost

Mendelian Sampling

Young sire Progeny Test

Accuracy 0.80

Mendelian Sampling

Accuracy 0.65

Young sire Genomic Selection

Birth Birth; <<<< cost

Slide courtesy of Gonzalo Rincon, UC Davis

Genomic selection can help breeders identify animals with superior

breeding values at a young age

ΔG = intensity of selection X

accuracy of selection X

genetic variation in the population /

generation interval)

Van Eenennaam CalPoly 3/10/11 Animal Genomics and Biotechnology Education

Dairy industry suited to WGS

• High use of AI

• Clear selection goal

• One breed used extensively

• Large number of high accuracy A.I. sires for training

• Extensive, uniform collection of data on traits

• Central evaluation (AIPL) receiving genotypes

• Obvious way to increase rate of genetic gain

• AI companies funding the genotyping because they

get a clear cost savings in terms of young sire

program

Genomic selection can double rate of genetic gain

Rate of genetic gain ΔG

ΔG = (im rm +if rf)/ (Lm + Lf) genetic standard deviation/year

= (2*0.8 + 0)/ (6+2) = 0.2 s.d./year (progeny test)

= (2*0.6 + 0.8*0.6)/ (2+2) = 0.42 (genomic selection)

i = intensity of selection

r = accuracy of selection

L = generation interval

Modified from Goddard. (2009) BIF Meeting

Velogenetics (Georges and Massey (1991) Theriogenology

35:151-159)

• Harvest oocytes from in-utero calves

• In-vitro

• maturation

• fertilization

• Selection based on genetic markers

• Implant in recipient cows

• L = 6 months (0.5 instead of 6 years)

Velogenetics could increase rate of genetic gain 8X

Rate of genetic gain ΔG

ΔG = (im rm +if rf)/ (Lm + Lf) genetic standard deviation/year

= (2*0.8 + 0)/ (6+2) = 0.2 (progeny test)

= (2*0.6 + 0.8*0.6)/ (2+2) = 0.42 (genomic selection)

= (2*0.6 + 0.8*0.6)/ (.5+.5) = 1.68 (velogenetics) i.e. 8X

4. Onto cloning!!

Have you ever eaten a

clone?

1. Yes

What is a clone ?

• Cloning, in horticulture and biology, any

organism whose genetic information is

identical to that of a "mother organism"

from which it was created.

• Food from clones has been a part of our

diet for years. Many common fruits (e.g.,

pears, apples, oranges and lemons) and

several vegetables (e.g., potatoes and

truffles) are clones. Van Eenennaam CalPoly 3/10/11

Have you ever eaten milk or

meat from a cloned animal?

1. Yes

Holstein Association USA (Brattleboro, VT)

first registered clones from embryo splitting

(ETS) in 1982 and clones from embryo

nuclear transfer (ETN) in 1989.

Most of us have probably ingested meat and

dairy products from livestock cloned by

natural reproduction (monozygotic siblings),

mechanical embryo-splitting, or even nuclear

transfer from an embryonic donor cell into an

enucleated oocyte.

Have I ever eaten products

from a cloned animal? YES!!

Mechanical embryo splitting

The Holstein association of America has registered 2319 embryo split clones (ETS) through October 2002 – probably

the most widely recognized were DUPLICATE and DIVIDE.

Dolly (1996), the first

adult SCNT clone

Dolly rapidly became entangled with the debate over human cloning

Ensuing discussion failed to elaborate on the reasons as to why cloning was developed

Who’s Buying?

On January 15th, 2008 the FDA published its final 968-page risk assessment on animal cloning. This report, which summarizes all available data on clones and their progeny are as safe to eat as food from conventionally bred animals

Are the milk and meat from SCNT clones safe for human

consumption?

Animal Biotechnology and Genomics Education Van Eenennaam CalPoly 3/10/11

Animal cloning regulations in Denmark and Norway

prohibit cloning for food and agricultural purposes.

January 2007: The European Food Standards Agency is seeking urgent legal advice after farmers announced the birth of a calf whose genetic mother is the clone of an American prizewinning dairy cow.

Do you oppose the genetic

modification of animals?

1. Yes

56% of Americans oppose scientific research

into the genetic modification of animals http://pewagbiotech.org/research/2005update/2005summary.pdf

No one seem to get too upset about the

genetic modifications made by traditional

animal breeders ……….

But they do get VERY upset about genetic

modifications made by the process of genetic

engineering…….

ESPECIALLY genetically-

engineered food animals

Aqua bounty growth-enhanced salmon

http://www.aquabounty.com/

Product Definition for the

AquAdvantage Salmon

Product Identity

Triploid hemizygous, all-female Atlantic salmon (Salmo salar)

bearing a single copy of the α-form of the opAFP-GHc2 rDNA

construct at the α-locus in the EO-1α lineage.

Significantly more of these Atlantic salmon grow to at least 100 g

within 2700 deg C days than their comparators.

Limitations for Use

These Atlantic salmon are produced as eyed-eggs for grow-out only

in the FDA-approved physically-contained fresh water culture facility.

Van Eenennaam CalPoly 3/10/11 Alison Van Eenennaam , Ph.D., UC Davis

Retrieved from “AquAdvantage” image search on web

CASE STUDY: MASTITIS

inflammation of the mammary gland

1. Conventional: Antibiotic therapy

2. Natural: alternative therapy

“An infected cow should be given an extra tablespoon of dolomite night and morning until the infection clears. Hydrogen peroxide; 10 ml squirted straight into the affected quarter has cured black mastitis in hours.”

The use of 50,000 or more SNP markers across the entire genome enables an estimation of genetic merit

3. Genomic Selection (DNA-informed

selective breeding on a grand scale)

Can be used to predict genetic merit for mastitis resistance

4. Genetic Engineering: Transgenic

cows show resistance to mastitis.

Wall,R.J. et al. Genetically enhanced cows resist intramammary Staphylococcus aureus infection. Nature Biotechnology 23, 445-451 (2005).

5. Clone a bull whose daughters are very

mastitis resistant (ie high accuracy EPD for

disease resistance) and use these bulls as

sires for mastitis resistance.

Which Animal Biotechnology

would you use to combat mastitis?

ntiona

ural T

nt Bull

0% 0%0%0%0%

1. Conventional Treatment

2. Natural Therapy

3. Genomic Selection

4. Genetic Engineering

5. Clone a Resistant Bull

“We have recently advanced our knowledge of genetics to the point where we can manipulate life in a way never intended by nature. We must proceed with the utmost caution in the application of this new found knowledge.”

LUTHER BURBANK, 1906 Creator of over 800 new plant varieties through plant breeding.

“to fail to apply the best available technologies to the

solution of contemporary and future food shortages

would be morally reprehensible.”

Fahrenkrug et al. 2010. Precision Genetics for Complex Objectives in Animal Agriculture. J. Anim Sci. 88 (7): 2530-2539.

biotech beef and cloned cows: progress in translational … · 2012. 9. 5. · animal biotechnology...

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