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Application of genome editing in farm animals: Cattle - Alison Van Eenennaam

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Application of genome editing in farm animals: Cattle - Alison Van Eenennaam

  1. 1. 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
  2. 2. 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
  3. 3. 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 Van Eenennaam 6/28/2018
  4. 4. Animal Biotechnology and Genomics Education Negative correlation between milk yield (production) and carbon footprint/kg milk. (Capper and Bowman, 2013 ) Van Eenennaam 6/28/2018
  5. 5. Animal Biotechnology and Genomics Education 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 Van Eenennaam 6/28/2018
  6. 6. Van Eenennaam 6/28/2018 US Cattle Inventory 1961 – 2015 Stocks Down (Million head; blue, left) vs. Production Up (Million Tonnes; red, right) Animal Genomics and Biotechnology Education USDA FAS Beef and Veal Production - Selected Countries Summary - https://apps.fas.usda.gov/psdonline/app/index.html#/app/downloads
  7. 7. Van Eenennaam 6/28/2018 2016 Global Beef Production Numbers Cattle numbers (Million Head; blue, left) vs. Beef production (Million Tonnes; red, right) Animal Genomics and Biotechnology Education FAOSTAT 2/28/2018
  8. 8. Animal Biotechnology and Genomics Education 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 Van Eenennaam 6/28/2018 The rate of genetic gain depends upon the four components of the breeders’ equation
  9. 9. Animal Biotechnology and Genomics Education Kasinathan, P. et al. 2015. Acceleration of genetic gain in cattle by reduction of generation interval. Sci. Rep. 5, 8674; DOI:10.1038/srep08674 Van Eenennaam 6/28/2018
  10. 10. Animal Biotechnology and Genomics Education Approaches for genome editing cattle Van Eenennaam 6/28/2018 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
  11. 11. Van Eenennaam 6/28/2018 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?
  12. 12. 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
  13. 13. Accelerated rate of gain when promoting 1-20 genome edits in genomic selection Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018 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.
  14. 14. Animal Biotechnology and Genomics Education 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 Van Eenennaam 6/28/2018
  15. 15. Animal Biotechnology and Genomics Education 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 Van Eenennaam 6/28/2018
  16. 16. Animal Biotechnology and Genomics Education https://www.youtube.com/watch?v=-Qks_LMmodw
  17. 17. 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 Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018 POLLED GENE
  18. 18. 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 Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018
  19. 19. 5 bull calves & 1 heifer calf were born in September, 2017 They are all hornless (heterozygous Pp for polled) Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018
  20. 20.  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 Van Eenennaam 6/28/2018 Animal Genomics and Biotechnology Education [Maci Mueller et al., 2018, Unpublished]
  21. 21. Gene editing of myostatin to obtain double muscle Nellore cattle Van Eenennaam 6/28/2018 Animal Genomics and Biotechnology Education 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.
  22. 22. Gene editing to knockout beta- lactoglobulin milk allergen Van Eenennaam 6/28/2018 Animal Genomics and Biotechnology Education 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.
  23. 23. Animal Biotechnology and Genomics Education Gene editing to produce cattle that are less susceptible to tuberculosis Van Eenennaam 6/28/2018 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.
  24. 24. Genetic improvement (permanent, cumulative) as a solution to animal disease rather than antibiotics/chemicals Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018
  25. 25. Animal Biotechnology and Genomics Education January 18th, 2017 FDA draft guidance considers all gene edited animals whose genomes have been “altered intentionally” to be drugs Van Eenennaam 6/28/2018 http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM113903.pdf Image by Aleksandra Domanović and Spencer Lowell
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. Animal Biotechnology and Genomics Education Does it make sense to regulate polled dairy calves differently to polled beef calves? Van Eenennaam 6/28/2018 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
  30. 30. Van Eenennaam 6/28/2018 Animal Genomics and Biotechnology Education 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
  31. 31. 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. Animal Genomics and Biotechnology EducationVan Eenennaam 6/28/2018

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