Can Genomics of Dry Matter Intake in Transition Cows Improve Health and Fertility?

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1 Can Genomics of Dry Matter Intake in Transition Cows Improve Health and Fertility? W. Ron Butler Department of Animal Science Cornell University Periparturient transition period Cascade of metabolic and physiological changes important for milk production, health and future reproductive performance Nutrient accrual body reserves and fetus Calving Rapid mobilization of lipid & protein stores for energy metabolism-lactation -3 weeks weeks Feed intake (DMI) and energy balance may begin decreasing prepartum Dietary energy intake relative to requirements both in far-off and close-up dry periods affect feed intake in early lactation cows. Lower pre-calving feed intake (dry matter intake-dmi) is risk factor for metritis and ketosis after calving. Health Lower pre-calving feed intake/dmi is associated with delayed resumption of normal ovarian activity after calving. Reproduction Onset of lactation -- prolonged negative energy balance (NEB). Adoption of genomic selection has markedly accelerated genetic gains for milk production & created interest in genomics of DMI. Identify Genes associated with DMI The importance of energy metabolism in the lactating dairy cow Health -Liver (Trigs, inflammation) -Uterus (infection) Milk Production Energy Metabolism Reproduction/fertility during Lactation Ovarian Function - early Ovulation

2 + Negative Energy Balance - NEB Feed energy intake is less than the energy required for milk production plus maintenance and the balance is mobilized from reserves of body fat. During early lactation, cows vary widely in NEB largely due to differences in DMI. Feed intake (DMI) and energy balance may begin decreasing prepartum Lower pre-calving feed intake (dry matter intake-dmi) is risk factor for metritis and ketosis after calving. Prepartum differences in DMI associated with cow health. Prepartum DMI Day -7 to -9 before calving Health disorders Retained placenta Fever SC endometritis Reduced Fertility During uterine inflammation post-calving, cytokines secreted by white blood cells promote liver acute phase response - Acute phase proteins (+/-) e.g. Haptoglobin & Albumin Prepartum DMI and Uterine Health- metritis Last 2 weeks pre-calving Following fresh feed Time feeding DMI 1 kg = 3X risk Huzzey et al., JDS 2007 Post-calving- cows diagnosed with metritis had increased plasma Haptoglobin, + acute phase protein and a marker of liver response to an inflammatory state in the uterus (infection). Haptoglobin peaks d 6-7 postpartum in metritic cows. Huzzey et al., JDS 2009

3 Inflammation is common in transition cows Liver metabolism is altered during transition period Uterus Decreased glucose, glycogen, albumin Inflammation is normal for labor and delivery Infection Liver Increased lipid oxidation, ROS, peroxides, stress, haptoglobin Feed Intake NEFA Decreased insulin response of adipose tissue Mammary Gland Mastitis Liver adaptation to increased availability of NEFA is increased lipid oxidation for energy. First step produces reactive oxygen species (ROS) that can form lipid peroxide. Perhaps via oxidative stress, peroxides can trigger liver inflammation, decreased DMI and shifts in liver metabolism of carbohydrates and lipids that may lead to metabolic disorders. Healthy liver increased glucose (gluconeogenesis), glycogen and albumin (-APP). with inflammation, decreases in these, increased +APP and accumulation of triglycerides. Feed intake (DMI) and energy balance may begin decreasing prepartum Prepartum differences in DMI associated with cow health. Peripartum changes in DMI associated with reproductive performance. Dry Matter Intake (kg/day) Day relative to parturition OV NOV As early as 3 weeks prepartum, differences in DMI and EBAL are apparent in cows that develop OV vs. NOV follicles during first 3 weeks postpartum.

4 As early as 4 weeks prepartum, differences in DMI and NEB ( NEFA) are apparent in cows that develop OV vs. NOV follicles during first 3 weeks postpartum. Why is this important?? Early ovulation during lactation is associated with higher fertility later during the breeding period. Positive association between early ovulation postpartum and pregnancy during lactation Percent not pregnant DIM; n= DIM; n=89 Open 35% DIM; n=114 15% Time to pregnancy, d This important relationship has focused research attention on the regulation and re-initiation of postpartum ovarian activity. Galvao et al., Reprod. Dom. Anim. 45:e207-e211, 2010 Peripartum changes in DMI associated with reproductive performance DMI NEB/NEFA Hepatic acute phase response Haptoglobin Ovulatory vs. Nonovulatory follicles Stronger acute phase response(apr), Haptoglobin level, in clinically healthy lactating cows (2-8 DIM) impacts days to conception High APR and haptoglobin level group had an activated innate immune system and cytokine response (TNFα). Nightingale et al., Vet.Immunol.Immunopath. 2015

5 How might postpartum inflammatory conditions during NEB exert carryover effects on fertility in dairy cows? Comprehensive study of >5000 cows on effects of inflammatory disease between parturition and first AI. (Ribeiro et al., JDS 2016) As expected early uterine disease reduced pregnancy rate/ai. Most interestingly, non-uterine disease (NUTD) at either preantral or antral follicle stage pregnancy rate. How might postpartum inflammatory conditions during NEB exert carryover effects on fertility in dairy cows? Blood born factors can transfer into preantral or antral follicles to disturb follicle growth and development - oocyte viability. The carry-over effects of postpartum inflammation can last 3 months i.e. the estimated time required to complete ovulatory follicle development in cows -suggests reduced oocyte competence and embryo survival Feed intake (DMI) and energy balance may begin decreasing prepartum Prepartum differences in DMI associated with cow health. Peripartum changes in DMI associated with reproductive performance. Genomic analyses for associations with DMI in lactating dairy cows. Genetics to Genomics DMI in dairy cows has moderate heritability target for genetic selection. Identifying genetically superior animals for DMI requires having many animals with phenotypic and genotypic data. Identify areas on chromosomes significantly associated with DMI

6 Genotype individual cows DNA samples from a cow can be genotyped using beadchips with 50k to 770k single nucleotide polymorphism (SNP) markers for comparison with their DMI phenotype data collected at specific stages of lactation. Genome-wide association studies (GWAS) are conducted to statistically link known markers on specific chromosomes with differences in DMI between animals (groups). GWAS results can be depicted in Manhattan plots showing markers or peaks of markers that meet or exceed the statistical criteria for significance. Results of genome-wide association studies (GWAS) for chromosomal markers associated with DMI A- data for primiparous cows 30 DIM (Tetens et al., 2014; B- data for multiparous cows first 2 weeks of lactation 90% cut-off for daily energy intake as % of requirement (Butler, unpublished). Genomic analysis for DMI - Candidate genes In previous studies of cattle with specific gene SNPs (e.g. AA,AB, or BB), differences in DMI may have been associated with the different alleles. Example: a SNP in growth hormone receptor (GHR) gene was linked to DMI in dairy cows along with SNPs in Leptin gene. (BTA 20 & 4) (Banos et al., JDS 2008) GWAS can also identify candidate genes -- SNP markers for DMI on chromosomes guide interrogation of bovine genomic databases for genes in close proximity. Known biological data for effects of these genes that may be related to the phenotype is assembled for further studies e.g. alleles in cows DMI. Genomic analysis for DMI - Candidate genes SNPs for DMI linked to genes on chromosome 27 in primiparous cows: IDO2 tryptophan metabolism; MEGF10 cellular growth factor activity; N-myc interactor. (Veerkamp, et al., Animal 2012) SNPs for feed efficiency in primiparous cows linked to genes on chromosome 27 & 4 : ADRB3 β adrenergic receptor and adipose mobilization; Leptin hormone from adipose tissue affects feeding and metabolism. (Hardie et al., JDS 2017) SNPs for DMI linked to genes on chromosomes 10, 25 & 26 in primiparous cows: Many candidate genes listed on each. (Hardie et al., JDS 2017)

7 Genomic analysis for DMI - Candidate genes Cornell U Genomic analysis for DMI - Candidate genes Cornell U Chr 19: TK1 - thymidine kinase 1, DNA replication & cell proliferation; BIRC5 - dual roles in promoting cell proliferation and preventing apoptosis; TMC6 - Transmembrane Channel Like 6 TTLL6 - tubulin polyglutamylase; Large area surrounding dense markers lack any genes annotated for bovine genome. Chr 26: CNNM1 - Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 1 Got1 - Glutamic-Oxaloacetic Transaminase 1 or Aspartate Aminotransferase 1; amino acid interconversion and glucose metabolism pathways; SLC25A28 - Solute Carrier Family 25 Member 28, metabolism Chr 1: SLC37A1 solute carrier translocates glucose-6-phosphate from the cytoplasm into the lumen of the ER for hydrolysis into glucose. Chr 19: TK1 - thymidine kinase 1, DNA replication & cell proliferation; BIRC5 - dual roles in promoting cell proliferation and preventing apoptosis; TMC6 - Transmembrane Channel Like 6 TTLL6 - tubulin polyglutamylase; Large area surrounding dense markers lack any genes annotated for bovine genome. Chr 26: CNNM1 - Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 1 Got1 - Glutamic-Oxaloacetic Transaminase 1 or Aspartate Aminotransferase 1; amino acid interconversion and glucose metabolism pathways; SLC25A28 - Solute Carrier Family 25 Member 28, metabolism Chr 1: SLC37A1 solute carrier translocates glucose-6-phosphate from the cytoplasm into the lumen of the ER for hydrolysis into glucose. Genomics of dietary energy utilization and Feed Efficiency Gross feed efficiency (GFE) = Total energy corrected milk/total DMI DMI and milk production during 150 DIM Spurlock et al., JDS Genetic correlation between GFE and energy balance (-0.73 to -0.99) Genetic selection for more energy efficient cows would favor lower energy status i.e. NEB High efficiency cows are deriving more of their energy requirement for milk production from body tissues. Cows with higher GFE during lactation had greater days open lower fertility; Genetic correlation between GFE and days open = 0.53 Vallimont et al., JDS 2013 Selection for improved feed efficiency should be carefully considered to avoid potential negative consequences on health and fertility via NEB Conclusions 1. During the periparturient period in cows, changes in DMI, health status, and re-initiation of ovarian activity are intertwined. 2. The periparturient period in cows is characterized by reduced DMI, increased mobilization of NEFA due to NEB, and a variable degree of liver metabolic disturbance/acute phase response. 3. Differences in peripartum DMI among cows are associated with differing effects on ovarian function and subsequent reproductive performance. 4. Genomic analysis has demonstrated that DMI is a complex trait associated with many genomic regions and individual genes. 5. Genomic tools hold promise for better genetic selection for DMI in dairy cows to improve health and reproduction by minimizing NEB.

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