Biotech Beef and Cloned Cows: Progress in Translational Genomics Alison Van Eenennaam, Ph.D.

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1 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 (530) animalscience.ucdavis.edu/animalbiotech Animal Genomics and Biotechnology Education

2 Translational genomics is defined as the adaptation of information derived from genome technologies for animal improvement

3 SNP (Single Nucleotide Polymorphism) A DNA sequence variation that varies sufficiently between individuals that its inheritance can be tracked through families

4 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

5 This is a picture of D _ A. 1. B 2. N 3. C 4. L 0% 0% 0% 0% B N C L

6 Given this information

7 Which do you think is my dog? % 0% 0% 0%

8 1. Using DNA information to identify carriers of recessive traits Images from an article by David S. Buchanan, NDSU

9 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

10 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

11 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

12 From September 8 December, 2008 identified genetic problem, developed test, and released carrier status of 736 bulls! 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. From: Buchanan, D.S. Genetic Defects in Cattle.

13 Early extension education about dwarfism explaining carriers and inheritance Image from Special CollectionsUniversity Libraries, Virginia Tech:

14 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? ¼ (25%) 3. ½ (50%) 4. 2/3 (66%) 5. ¾ (75%) 6. 1 (100%) 0 0% 0% 0% 0% 0% 0% ¼ (25%) ½ (50%) 2/3 (66%) ¾ (75%) 1 (100%)

15 2. There are various companies offering DNA tests for markerassisted selection in beef cattle

16 Tests for quantitative traits before SNPs Meat Tenderness Quality Grade (Marbling) Beef Cattle Feed Efficiency Meat Yield Disease Resistance Dairy Form Milk and Milk Component Yield

17 Which would you rather have??? 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 ** 0% 0% 1 2

18 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

19 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!

20 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

21 3. Mooving onto Genomic Selection r 0 Validation: New Progeny Tested Bulls Training 1: Old Progeny Tested Bulls Training 2: Old & New Progeny Tested Bulls Degree of genetic relationship between populations (ideally similar) r 1 Application: New Sire Candidates Slide courtesy of Marc Thallman, US MARC

22 Breeding value prediction in Dairy Sires Young sire Parent Average x Young sire Progeny Test x Young sire Genomic Selection x Birth 5 years; >>>> cost Birth; <<<< cost A S A D A S A D A S A D Mendelian Sampling? Accuracy 0.20 Mendelian Sampling Accuracy 0.80 Mendelian Sampling? Accuracy 0.65 Slide courtesy of Gonzalo Rincon, UC Davis

23 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) Animal Genomics and Biotechnology Education

24 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

25 Genomic selection can double rate of genetic gain Rate of genetic gain ΔG ΔG = (i m r m +i f r f )/ (L m + L f ) genetic standard deviation/year = (2* )/ (6+2) = 0.2 s.d./year (progeny test) = (2* *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

26 Velogenetics (Georges and Massey (1991) Theriogenology 35: ) 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)

27 Velogenetics could increase rate of genetic gain 8X Rate of genetic gain ΔG ΔG = (i m r m +i f r f )/ (L m + L f ) genetic standard deviation/year = (2* )/ (6+2) = 0.2 (progeny test) = (2* *0.6)/ (2+2) = 0.42 (genomic selection) = (2* *0.6)/ (.5+.5) = 1.68 (velogenetics) i.e. 8X

28 4. Onto cloning!!

29 Have you ever eaten a clone? Yes 2. No 0% 0% 0 Yes No

30 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.

31 Have you ever eaten milk or meat from a cloned animal? Yes 2. No 0% 0% 0 Yes No

32 Have I ever eaten products from a cloned animal? YES!! Holstein Association USA (Brattleboro, VT) first registered clones from embryo splitting (ETS) in 1982 and clones from embryo nuclear transfer (ETN) in 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.

33 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.

34 Dolly (1996), the first adult SCNT clone

35 Dolly rapidly became entangled with the debate over human cloning Ensuing discussion failed to elaborate on the reasons as to why cloning was developed

36

37 Who s Buying?

38 Are the milk and meat from SCNT clones safe for human consumption? 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

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40 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.

41 Do you oppose the genetic modification of animals? Yes 2. No 0% 0% 0 Yes No

42 56% of Americans oppose scientific research into the genetic modification of animals

43 No one seem to get too upset about the genetic modifications made by traditional animal breeders.

44 But they do get VERY upset about genetic modifications made by the process of genetic engineering.

45 ESPECIALLY geneticallyengineered food animals

46 Aqua bounty growth-enhanced salmon

47 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. Claim 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. Alison Van Eenennaam, Ph.D., UC Davis

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49 Retrieved from AquAdvantage image search on web

50 CASE STUDY: MASTITIS inflammation of the mammary gland

51 1. Conventional: Antibiotic therapy

52 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.

53 3. Genomic Selection (DNA-informed selective breeding on a grand scale) The use of 50,000 or more SNP markers across the entire genome enables an estimation of genetic merit Can be used to predict genetic merit for mastitis resistance

54 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, (2005).

55 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.

56 Which Animal Biotechnology would you use to combat mastitis? Conventional Treatment 2. Natural Therapy 3. Genomic Selection 4. Genetic Engineering 5. Clone a Resistant Bull Conventional Treatment Natural Therapy 0% 0% 0% 0% 0% Genomic Selection Genetic Engineering Clone a Resistant Bull

57 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.

58 to fail to apply the best available technologies to the solution of contemporary and future food shortages would be morally reprehensible. Fahrenkrug et al Precision Genetics for Complex Objectives in Animal Agriculture. J. Anim Sci. 88 (7):

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