1. John B. Cole Animal Improvement Programs Laboratory Agricultural Research Service, USDA Beltsville, MD 20705-2350, USA john.cole@ars.usda.gov Applications of haplotypes in dairy farm management

2. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (2) Cole Introduction l Genomic selection increases selection response by reducing generation interval l Bulls were genotyped first due to cost l Now we have genotypes for many cows l What can we do with those data that we couldn’t do before?

3. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (3) Cole O-Style Haplotypes Chromosome 15

4. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (4) Cole Genetic merit of Jersey bulls Breeding Year Net Merit ($)

5. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (5) Cole Many cows have been genotyped Evaluation Date (YYMM) Genotypes

6. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (6) Cole Haplotypes for farm management l Many uses other than genetic evaluation w Culling decisions w Mating strategies w Identification of new recessive defects w Phenotypic prediction ARS Image Number K7964-1

7. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (7) Cole Input costs are rising quickly M:FP = price of 1 kg of milk / price of 1 kg of a 16% protein ration Month Milk:Feed Price Ratio July 2012 Grain Costs Soybeans: $15.60/bu (€0.46/kg) Corn: $ 7.36/bu (€0.23/kg)

8. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (8) Cole Optimal culling decisions l Low density genotypes on females can be used to guide early culling decisions w 165,526 genotyped cows in August 2012 l Sexed semen increases heifer population from which to select l What animals should be retained and what animals culled?

9. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (9) Cole Calves selected EBV selected calves (pre- ranked, 35% rel.) Optimal fraction calves tested with genomic test (65% rel.) EBV selected calves (after genomic testing) Cost of genomic testing per selected calf NPV of selected calves 100%€0-- 90%€3170-100€46€13€52 80%€6460-90€78€14€94 70%€8750-90€113€22€136 60%€11240-80€145€25€176 50%€13930-70€179€30€218 Testing and selecting heifer calves EBV = estimated breeding value, NPV = net present value

10. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (10) Cole Bottom line economics No sexed2x sexedNo sexed2x sexed Pre-ranking calf reliability0% 35% Genomic testing policy 1 20-1000-10070-9050-90 Statistics (€/cow/year): Profit without heifer calf value 381378381378 Heifer calves sold 14311431 NPV calves before pre-ranking 9910199101 NPV calves due to pre-ranking 003051 Added NPV from genomic testing 3871716 Cost of genomic testing 72349 Heifer calf value146180148191 Profit with heifer calf value527558529569 1 7K test (€36.50, 65% reliability)

11. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (11) Cole Farmers want new genomic tools

12. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (12) Cole New haplotype query Cole, J.B., and Null, D.J. 2012. AIPL Research Report GENOMIC2: Use of chromosomal predicted transmitting abilities. Available: http://aipl.arsusda.gov/reference/chromosomal_pta_query.html. http://aipl.arsusda.gov/reference/chromosomal_pta_query.html

13. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (13) Cole Simulated matings l Mated all genotyped Jersey bulls and cows in a fully cross-classified design w 5,877 bulls and 15,553 cows − 91,404,981 matings w Crossovers, independent assortment w 100 replicates per mate pair l Mean, variance, skewness, and kurtosis

14. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (14) Cole Distribution of progeny DGV Distribution of 6,000,000 randomly sampled simulated matings.

15. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (15) Cole Most extreme groups for progeny DGV

16. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (16) Cole Most extreme groups for DGV variance

17. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (17) Cole Most- and least-skewed progeny groups

18. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (18) Cole Most- and least-kurtotic progeny groups

19. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (19) Cole Within-herd analysis l Selected 3 Jersey herds w Ranked by number of genotyped animals and percentage of 50K genotypes l Compared actual with possible matings l Could the herd manager have selected better mate pairs?

20. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (20) Cole Comparison to actual matings l Simulated matings were compared to 220 actual matings from 142 mate pairs l Three strategies tested in simulation w Mating plans using traditional and genomic PTA as in Pryce et al. (2012) w Selection of mate pairs with greatest mean DGV w Bulls limited to 10 matings

21. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (21) Cole Sire portfolios Bulls used in herd Cows in herd Genotyped calves Consider each bull as a mate for each cow using different strategies. Actual calves born to these parents. Simulated calves

22. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (22) Cole Actual DGV and inbreeding Similar distribution of DGV Different distribution of relation- ships – different sire portfolios

23. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (23) Cole Herd 1 results Actual 1 Best PTA 2 Best gPTA 2 Best DGV 2 Genetic value416308446452 Difference−-108+28+36 SE(Genetic)1271112 Inbreeding0.0530.0750.0830.070 Min0.0100.0050.027<0.001 Max0.1100.2740.1450.112 Correlation−0.4430.2180.247 1 Results from 94 genotyped offspring of 62 cows. 2 Simulated matings of 62 cows to a portfolio of 54 bulls (n=3348 combinations).

24. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (24) Cole Herd 2 results Actual 1 Best PTA 2 Best gPTA 2 Best DGV 2 Genetic value468396534538 Difference−-726670 SE(Genetic)231413 Inbreeding0.0680.0510.077 Min0.0250.0010.021 Max0.0900.1200.1240.106 Correlation−0.5770.7350.745 1 Results from 31 genotyped offspring of 19 cows. 2 Simulated matings of 19 cows to a portfolio of 31 bulls (n=589 combinations).

25. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (25) Cole Herd 3 results Actual 1 Best PTA 2 Best gPTA 2 Best DGV 2 Genetic value480342505501 Difference−-1382521 SE(Genetic)1981210 Inbreeding0.0680.0760.0930.068 Min0.0150.0000.0450.015 Max0.1250.1830.1780.106 Correlation−0.6650.6820.495 1 Results from 95 genotyped offspring of 38 cows. 2 Simulated matings of 38 cows to a portfolio of 25 bulls (n=950 combinations).

26. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (26) Cole Specific combining ability l Quantitative model w Must solve equation for each mate pair l Genomic model w Compute dominance for each locus w Haplotype the population w Simulate matings and compute average dominance

27. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (27) Cole Inbreeding effects l Are inbreeding effects distributed uniformly across the genome? w Where are the recessives and the over- and under-dominant loci? l Inbreeding changes transcription levels and gene expression profiles in D. melanogaster (Kristensen et al., 2005)

28. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (28) Cole Precision inbreeding l Runs of homozygosity may indicate genomic regions where inbreeding is acceptable l Can we target those regions by selecting among haplotypes? Dominance Recessives Under-dominance

29. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (29) Cole Phenotypic prediction l Can haplotypes be used to improve phenotypic predictions? w Models with GxE are better predictors (Bryant et al., 2005) w Models with A+D better than records from relatives (Lee et al., 2008) w Disease risk can be predicted even if mechanisms unknown (Wray et al., 2005)

30. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (30) Cole Unknown phenotypes l Susceptibility to disease w e.g., Johne’s is difficult to diagnose l Differential response to management w e.g., Feed conversion efficiency l Can simulate more plausible outcomes with haplotypes than genotypes w Chromosome transmitted, not means

31. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (31) Cole Loss-of-function mutations l At least 100 LoF per human genome surveyed (MacArthur et al., 2010) w Of those genes ~20 are completely inactivated w Uncharacterized LoF variants likely to have phenotypic effects l How can mating programs deal with this?

32. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (32) Cole Novel haplotypes affecting fertility Name Chrom- osome Loca- tion Carrier Freq Earliest Known Ancestors HH1562-684.5Pawnee Farm Arlinda Chief HH2193-984.6Willowholme Mark Anthony HH3892-974.7Glendell Arlinda Chief, Gray View Skyliner JH11511-1623.4Observer Chocolate Soldier BH1742-4714.0West Lawn Stretch Improver

33. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (33) Cole Precision mating l Eliminate undesirable haplotypes w Detection at low allele frequencies l Avoid carrier-to-carrier matings w Easy with few recessives, difficult with many recessives l Include in selection indices w Requires many inputs

34. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (34) Cole Threats to continued progress Provisional US patent filed on 20 NOV 2010 after the 9WCGALP in Leipzig – no disclosure at that time! This MS with similar ideas was submitted 22 SEP 2010 and published on 12 APR 2011. Why share?

35. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (35) Cole Conclusions l Selecting calves based on genomic tests can increase farm profitability l Simple mate selection using haplotypes is as good or better than other strategies l We may be able to do interesting things with inbreeding and prediction l Tools for handling many new recessives in breeding programs are needed

36. 63 rd EAAP Meeting, Bratislava, Slovakia, 29 August 2012 (36) Cole Acknowledgments Paul VanRaden, Dan Null, and Tabatha Cooper Animal Improvement Programs Laboratory, ARS, USDA Beltsville, MD Albert De Vries Department of Animal Sciences University of Florida, Gainesville, FL David Galligan School of Veterinary Medicine University of Pennsylvania Kennett Square, PA