1950s 1 st calf from surgical ET Frozen semen LN 2

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2 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN 2 Progestins used to synchronize estrus 2

3 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s PGF discovered Plastic straws replaced glass ampules 3

4 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s PGF discovered Plastic straws replaced glass ampules 1970s PGF approved for Dairy Cattle PRID developed 4

5 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s Pedometers (ED) Transrectal ultrasound Follicular Wave 1960s PGF discovered Plastic straws replaced glass ampules 1970s PGF approved for Dairy Cattle PRID developed 5

6 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s PGF discovered Plastic straws replaced glass ampules 1970s PGF approved for Dairy Cattle PRID developed 1990s TAI widely adopted Birth of Dolly 1 st cloned mammal 1980s Pedometers (ED) Transrectal ultrasound Follicular Wave 6

7 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s Sex Semen Genomics Resynchronization TAI Protocols 1960s PGF discovered Plastic straws replaced glass ampules 1990s TAI widely adopted Birth of Dolly 1 st cloned mammal 1970s PGF approved for Dairy Cattle PRID developed 1980s Pedometers ED Transrectal ultrasound Follicular Wave 7

8 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s Sex Semen Genomics Resynchronization TAI Protocols 2010s Ear Sensors for Health and Fertility Genetic selection for DPR, CCR, HCR 1960s PGF discovered Plastic straws replaced glass ampules 1990s TAI widely adopted Birth of Dolly 1 st cloned mammal 1970s PGF approved for Dairy Cattle PRID developed 1980s Pedometers (ED) Transrectal ultrasound Follicular Wave 8

9 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s Sex Semen Genomics Resynchronization TAI Protocols 2010s Ear Sensors for Health and Fertility Genetic selection for DPR, CCR, HCR 1960s PGF discovered Plastic straws replaced glass ampules 1990s TAI widely adopted Birth of Dolly 1 st cloned mammal 2020s Gene Editing Electronic Monitoring widely adopted Only X-bearing sperm 1970s PGF approved for Dairy Cattle PRID developed 1980s Pedometers estrus detection Transrectal ultrasound 9

10 Target Gene 8/24/2017 Protein engineering (gene editing) Horned Allele Horned Allele Gene Editing Polled Allele Polled Allele Excise old Insert new Paternal Maternal Chromosomes Paternal Maternal Chromosomes Paternal Maternal Chromosomes 10

11 Fertility and Reproduction Advances 1950s 1 st calf from surgical ET Frozen semen LN s Sex Semen Genomics Resynchronization TAI protocols 2010s Ear Sensors for Health and Fertility Genetic selection for DPR, CCR, HCR 1960s PGF discovered Plastic straws replaced glass ampules 1970s PGF approved for dairy cattle PRID developed 1990s TAI widely adopted Birth of Dolly 1 st cloned mammal 1980s Pedometers (ED) Transrectal ultrasound Follicular wave 2020s Gene Editing Electronic monitoring widely adopted Only X-bearing sperm???? 11

12 lbs per cow per year /24/2017 kg per cow per year Herds of the future: Experts forecast of milk yield in USA in ,000 70,000 3 Top USA Cow SD above national average 35,000 30,000 60,000 50,000 40,000 30,000 4 Top USA Herds 2017 Trend after Genomics Exponential ,000 20,000 15,000 20,000 Linear 10,000 10,000 0 Actual Yields 5,

13 Herds of the future: Integrated systems across farmsteads and beyond 2 Soils Crops Silo/bales Lagoon Natural areas Barns Milking center Personnel Equipment Commodities Robots Air Waterways Roads Vehicles 1 Integrated sensors & robotics 3 Cow friendly Reliable, Repeatable Precision, Accuracy Less labor 13

14 4 Shared Heifers Milk Cows 2 Herds of the future: Lateral integration of functions Milk Cows 1 Milk Cows Shared Transition Milk Cows Feed Center Milk Cows Shared Dry Milk Cows Milk Cows Milk Cows Milk Cows Milk Cows 3 Feed Center Shared Dairy Beef Milk Cows Milk Cows Shared Calves More Efficient Workforce Enhances labor efficiency Common protocols Driverless feed vehicles Identical robotics & barns Staff veterinarians 14

15 Herds of the future: Understanding the dairy herd as a SUPERORGANISM 1 We cannot learn about herds by studying these: Gene Cell 2 Organ Animal 15

16 Cows of the future: Genes and genomes of cows of the future 2 Epigenome including non-coding RNAs 1 Cow s DNA-sequence genome 3 Cow s microbiomes genomes 4 5 Gene editing to move genes within & among breeds Proprietary genes licensed in embryos 16

17 Cows of the future: Focus shifts to epigenome management Incidence, metritis Incidence, ketosis Incidence, RP Days to 1st AI First calving interval Incidence, mastitis SCC average Persistency of yield Productive life Lifetime protein Age first calving Lifetime fat Lifetime milk Days to 1st CL Energy balance Net income BCS Dry matter intake ME protein ME ME milk Lactose% Protein% Fat% 1 Genetic Epigenetic (broadly defined) 2 Temporal Relationships are Important to Note 19% 81% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Bennet Cassell, Using Heritability for Genetic Improvement 17

18 Managing the Epigenome Epigenomics changes in gene expression in somatic and germ cells without changing the genetic code Normal t a a a g c a t g c c g Relaxed DNA Helix Epigenetic a t t a g a c a c g g c Restrained DNA Helix 18

19 Activated Preantral Antral Ultrasound Ovulation 8/24/ Cows of past : 1992 model for Britt Hypothesis for epigenetic imprinting Bovine Practitioner 24: 39-43, Maintained = 62% CR Lost = 25% CR 2 Britt Hypothesis Our working hypothesis These conditions are somehow imprinted on follicles that begin development during the adversity. 3 Primordial -21 Epigenetic Imprinting Days Pre- or Post-partum 101 Days

20 Pregnancy per timed AI (%) at 40 d 8/24/2017 Cows of the present: The Britt Hypothesis in the present 90% 80% 70% 60% 1 Carvalho et al, J Dairy Science 97: , cows 84% 2 high fatty acids? 50% 40% 30% 789 cows 675 cows 38% low glucose? mediated by cumulus 20% 10% 25% embryo dies after fertilization 0% Lost Maintained Gained Body Condition Change During 3 Weeks Postpartum 20

21 Cows of the future: Less weight loss, metabolically robust 1 Consistent weight loss patterns 2 Sires differ in robustness of daughters M. Zachut and U. Moallem J. Dairy Sci. 100 (4) N.-T. Ha et al J. Dairy Sci. 100 (5)

22 Cows of the future: Examples of epigenetic management in cattle 1 4X Milking = Higher Yields for 2X Later 2 Antral Follicle Count Increases Fertility in Postpartum Dairy Cows Ultrasound of heifers Feeding before puberty Hale et al J.Dairy Sci :2061. Evans, AETA/CETA Joint Proceedings

23 Cows of the future: Managing the microbiome Microbiomics role of and relationships with microbes that live within animals, plants, soils and in all environments 23

24 Cows of the present: Rumen microbiome differences and relation to milk traits 2 F:B ratio differs among cows in same herd 1 Experimental approach Cows fed same TMR Individually sampled Analyzed multiple organisms Measured many milk traits F:B ratio correlated with milk fat yield 3 Jami, E., B. A. White, I. Mizrah Potential Role of the Bovine Rumen Microbiome in Modulating Milk Composition and Feed Efficiency. PLoS One 9:e

25 Cows of the present: Differences in uterine microbiome in diseased cattle 1 Monitor in heifers and cows 2 Inoculate at birth, weaning, puberty? Replace lowest prevalence? T.M.A. Santos and R.C. Bicalho. Diversity and Succession of Bacterial Communities in the Uterine Fluid of Postpartum Metritic, Endometritic and Healthy Dairy Cows. PLOS, December 27,

26 Future Microbiome management Herd & farm specific monitoring Agronomic Environmental Cow Specific Therapeutic Seeds Soils Crops Silages Forages Feeds Drinking water Waste water Irrigation water Manure Bedding Facilities Delivered by robotic feeders Sterile packs Intrauterine Intramammary Neonatal Some Rx 26

27 Accelerate innovation and applied research GENOMICS Expand to include animal and its microbiome Monitor herds average genomics by bulk milk or fecal samples MICROBIOMICS Launch genetic-based products that are effective for calves, then expand EPIGENETICS Capitalize on applied management opportunities related to reproduction and growth 27

28 Change in 21-day Pregnancy Rate 2012 t ,481 Holstein herds that process DHI records at DRMS, Raleigh, NC 28

29 Reaching for the Future Envision It and Create It 29