Gene Editing in Cattle Can Increase Production and Sustainability

Animal Genomics and Biotechnology Education
Application of genome editing
in farm animals: Cattle
Alison Van Eenennaam, Ph.D.
Cooperative Extension Specialist
Animal Biotechnology and Genomics
Department of Animal Science
University of California, Davis, USA
Email: alvaneenennaam@ucdavis.edu
Twitter: @BioBeef BLOG: http://biobeef.faculty.ucdavis.edu
http://animalscience.ucdavis.edu/animalbiotech
Van Eenennaam 6/28/2018

Egg, beef, pork, chicken, fish and milk
production since 1980 and projected to 2050
(FAO 2018; Alexandratos and Bruinsma, 2012).
Van Eenennaam 6/28/2018 Animal Genomics and Biotechnology Education

Animal Biotechnology and Genomics Education
Demand for animal-derived food in 2050 could
be 70% higher than 2005 levels , & the demand
for beef could grow by as much as 66%
(Alexandratos and Bruinsma, 2012).
• Milk and meat from cattle & buffaloes contribute 45% of the global
animal protein supply [followed by chickens (31%), and pigs (20%)].
• In 2016, the global cattle population of 1.5 billion head produced
6.5 billion tons of cows’ milk, and 66 million tons of beef.
• In the past century, cattle breeding programs have greatly increased
the yield per animal with a resultant decrease in the emissions
intensity per unit of milk or beef, but not been true in all regions
We need to accelerate the rate of genetic
gain in global cattle breeding programs

Negative correlation between milk yield
(production) and carbon footprint/kg milk.
(Capper and Bowman, 2013 )

1988 Grand Champion Bull, National
Polled Hereford Show (frame 10).
1986. "Coblepond New Yorker"
weighed 2529 lbs and measured 65
inches tall at 35 mos. (Frame 10)
when he was Denver Champion.
1953. Grand Champion Angus
Female, International, 1953
1950. Grand Champion Steer,
International, weighing 1025 lbs
Images from Harlan Ritchie’s historical review of type
https://www.msu.edu/~ritchieh/historical/cattletype.html

US Cattle Inventory 1961 – 2015
Stocks Down (Million head; blue, left) vs.
Production Up (Million Tonnes; red, right)
USDA FAS Beef and Veal Production - Selected Countries Summary -
https://apps.fas.usda.gov/psdonline/app/index.html#/app/downloads

2016 Global Beef Production Numbers
Cattle numbers (Million Head; blue, left)
vs. Beef production (Million Tonnes; red, right)
FAOSTAT 2/28/2018

Genetic change per year =
(√Reliability x Intensity x Genetic Variation)
Generation Interval
reliability = how certain we are about our estimate
of an animal’s genetic merit
selection intensity = function of fraction selected
genetic variance = [can change using editing!]
generation interval = time between generations
The rate of genetic gain depends
upon the four components of the
breeders’ equation

Kasinathan, P. et al. 2015. Acceleration of genetic gain in cattle by
reduction of generation interval. Sci. Rep. 5, 8674; DOI:10.1038/srep08674

Approaches for genome editing cattle
Yum SY, Youn KY, Choi WJ, Jang G. 2018. Development of genome engineering
technologies in cattle: from random to specific. J Anim Sci Biotechnol. 9:16.
Somatic cell nuclear
transfer (SCNT)
Microinjection (MI)
into embryo

Van Eenennaam, A. L. 2017. Genetic Modification of Food Animals. Current Opinion in Biotechnology. 44:27-34.
How might gene editing be integrated with
genomic selection programs?

Editing is the Cherry on Top of Breeding Sundae
It will be able to introduce useful alleles without
linkage drag, and potentially bring in useful novel
genetic variation from other species
Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018
Artificial insemination
Performance recording
Development of breeding goals
Progeny testing
Somatic cell nuclear transfer cloning
Embryo Transfer
Genomic Selection
Genome Editing
Association of like minded breeders

Accelerated rate of gain when promoting
1-20 genome edits in genomic selection
Jenko, J. et a. 2015. Potential of promotion of alleles by genome editing to improve quantitative
traits in livestock breeding programs. Genetics Selection Evolution 47: 1-14.

How might gene editing be
used in cattle breeding?
Updated and modified from Van Eenennaam, A. L. 2017. Genetic Modification of Food Animals. Current Opinion in
Biotechnology. 44:27-34.
Target Targeted Trait/Goal Reference
Intraspecies POLLED allele substitution No horns/welfare trait Carlson et al., 2016
Intraspecies SLICK allele substitution Heat tolerance Sonstegard et al., 2017
Myostatin (MSTN) gene knockout Increased lean muscle yield Proudfoot et al., 2014
Beta-lactoglobulin gene knockout Elimination of milk allergen Yu et al., 2011
Prion protein (PRNP) knockout Elimination of prion protein Bevacqua et al., 2016
Intraspecies CALPAIN & CAPASTATIN allele
substitution
Improved meat tenderness Casas et al., 2006 (not
reduced to practice)
Insertion of lysostaphin/lysozyme transgene Resistance to mastitis Liu et al., 2013 &2014
CD18 gene edit Resistance to bovine respiratory
disease
Shanthalingam et al.,
2016
Insertion of SP110, NRAMP1 Resistance to tuberculosis Wu et al., 2015; Gao et
al., 2017
Intraspecies SRY translocation onto Y
chromosome
All male offspring Owen et al., 2018
NANOS gene knockout Infertile males (for gonial cell
transfer)
Ideta et al., 2016

What is the problem we are trying to solve?
Carlson DF, Lancto CA, Zang B, Kim E-S, Walton M, et al. 2016. Production of hornless dairy cattle
from genome-edited cell lines. Nat Biotech 34: 479-81
Need to manually remove horns from dairy calves
to protect human handlers and other animals

https://www.youtube.com/watch?v=-Qks_LMmodw

Celtic allele (PC) corresponding to a duplication of 212 bp
(chromosome 1 position 1705834–1706045) in place of a
10-bp sequence = horned (1706051–1706060) at POLLED
TALENs introgress
Pc Polled allele
bovine fibroblast
Cell line
Somatic Cell
Nuclear Transfer
(SCNT) cloning
Embryo transfer2 bull calves
10 bp
212 bp
Born April 2015
POLLED
GENE

Purified DNA
= homozygous
polled
In vitro fertilization
(in the lab)
Frozen Semen
Semen from one of the bulls (Buri) was collected and
confirmed he was homozygous polled (PP), fertile in vitro,
and straws were frozen for artificial insemination in vivo

5 bull calves & 1 heifer calf were born in September, 2017
They are all hornless (heterozygous Pp for polled)

 Daughters of polled
Holstein sires will earn
less over their lifetimes
[Spurlock et al., 2014]
 Polled allele frequency
is 0.0071 [Null, 2015]
 Adding polled to
selection indices is not
effective [Cole, 2015]
 If used exclusively
polled sires would
increase inbreeding &
decrease genetic gain
[Mueller et al., 2018]
Current polled dairy sires
have inferior genetic merit
Maci
Mueller
[Maci Mueller et al., 2018, Unpublished]

Gene editing of myostatin to obtain
double muscle Nellore cattle
Proudfoot C, Carlson DF, Huddart R, Long CR, Pryor JH, King TJ, Lillico SG,
Mileham AJ, McLaren DG, Whitelaw CB, Fahrenkrug SC. 2015. Genome edited sheep and cattle.
Transgenic Res. 24:147-53.

Gene editing to knockout beta-
lactoglobulin milk allergen
Wei J, Wagner S, Maclean P, Brophy B, Cole S, Smolenski G, Carlson DF, Fahrenkrug SC, Wells
DN, Laible G. 2018. Cattle with a precise, zygote-mediated deletion safely eliminate the major milk
allergen beta-lactoglobulin. Sci Rep. 8:7661.

Gene editing to produce cattle that are
less susceptible to tuberculosis
Gao et al. 2017. Single Cas9 nickase induced
generation of NRAMP1 knockin cattle with reduced
off-target effects. Genome Biol. Feb 1;18(1):13.

Genetic improvement (permanent,
cumulative) as a solution to animal
disease rather than antibiotics/chemicals

January 18th, 2017 FDA draft guidance
considers all gene edited animals whose
genomes have been “altered intentionally” to
be drugs
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM113903.pdf
Image by Aleksandra Domanović and Spencer Lowell

2703 Sequenced Animals, 11x
~55 Breeds: Dairy, Beef, Dual Purpose, Crosses, Composites
1000 Bull Genomes Run 6
CRV CRV
2703 x 11 x 3 billion= 90,000,000,000,000
Slide courtesy Ben Hayes, QAAFI, Australia
Van Eenennaam 6/28/2018 Animal Biotechnology and Genomics Education

Run 6 – Taurus only
44.7 million filtered variants
43 million SNP, 1.7 million Indel
Run 6 – Taurus Indicus
86.5 million filtered variants
84 million SNP, 2.5 million Indel
1000 Bull Genomes Run 6
Slide courtesy Ben Hayes, QAAFI, Australia
Van Eenennaam 6/28/2018 Animal Biotechnology and Genomics Education

Animal Biotechnology and Genomics EducationVan Eenennaam 6/28/2018
Van Eenennaam Alison L. 2018. The Importance of a Novel Product Risk-Based Trigger for Gene-
Editing Regulation in Food Animal Species. The CRISPR Journal. 1.
https://doi.org/10.1089/crispr.2017.0023
Are Gene Edited Horn-less calves a drug?
Naturally-occurring bovine allele at Polled locus
What is the “new animal drug” in this case?
I am not a
drug

Does it make sense to regulate
polled dairy calves differently to
polled beef calves?
Carroll D, Van Eenennaam AL, Taylor JF, Seger J, Voytas DF. 2016. Regulate genome-
edited products, not genome editing itself. Nat Biotech 34: 477-9 rdcu.be/hUVn

May 29, 2018
Recombinetics formed an
alliance with Semex, a
Canadian-based, farmer-
owned cattle genetics
organization to
implement a precision
breeding program to
introduce hornless into
elite dairy cattle genetics
using genome editing
Canada has novel product based regulations

Thanks for inviting me!
My laboratory receives public funding support from the
National Institute of Food and Agriculture and the
Biotechnology Risk Assessment Grant (BRAG)
program, U.S. Department of Agriculture, under award
numbers 2013-68004-20364, 2015-67015-23316,
2015-33522-24106 and 2017-33522-27097.

Gene Editing in Cattle Can Increase Production and Sustainability

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Gene Editing in Cattle Can Increase Production and Sustainability