Genetic Selection for Disease Resistance: Challenges and Opportunities

1. Genetic Selection for Disease Resistance: Challenges and Opportunities Gary Snowder Research Geneticist USDA, ARS, MARC

2. What is the Real Question? Can we select cattle to be disease resistant?

3. Maybe Sometimes Not in my lifetime Huh? Absolutely Not Sure Absolutely

4. Short Term: Overall, selection will probably be useful to reduce the incidence of microbial diseases.

5. Genetic research of human diseases is far ahead of livestock research.

6. bovine Animal disease research needs to catch up. Benefits from human and mouse disease research.

7. For Example: In mice, a gene known as Kif1C decreases susceptibility to Anthrax(Dietrich et al., 2001)

8. Outline • Current situation • Justification • Challenges • Immune System • Genetic Approaches

9. But First GENETIC DISEASE vs. GENETIC RESISTANCE

10. Genetic Disease (congenital) inherited disorder (conformation, metabolic, etc.) Genetic Resistance genetic component to resist pathogen infection

11. Dwarfism Syndactly (mulefoot) Bovine lymphocyte adhesion deficiency (BLAD) Complex Vertebral Malformation (CVM) Porphyria (pink tooth) Alopecia and Hypotrichosis (hairlessness) Beta-mannosidosis (Beta-man) Known Congenital Disorders in CattleApproximately 125 known genetic disorders

12. Current Situation of Microbial Diseases

13. Current Situation • Microbial resistance to antibiotics • No new class of antibiotic in over 30 years • Emergence of new diseases(BSE, CWD, Avian Flu) • Increase in disease transmission(Daszak et al., 2000) • Intensive mgmt • Wildlife to livestock transmission (Brucellosis, CWD, Avian Flu) • Therapeutic treatment costs are higher • Consumer expectations • Meat free of drug residue • Meat animals live a healthy and happy life

14. Breeding for societally important traits in pigs1 E. Kanis*,2, K. H. De Greef , A. Hiemstra*,3 and J. A. M. van Arendonk† *Animal Breeding and Genetics Group, Wageningen University, 6700 AH Wageningen, The Netherlands; and †Animal Sciences Group, 8200 AB Lelystad, The Netherlands 2 J. Anim. Sci. 2005, 83:948-957 • Consumers expect meat animals to be: • raised with better welfare, • produced in an environmentally friendly way, • fed without additives, and • not injected with antibiotics or vaccines.

15. “Good Milk comes from Happy Cows” Ad campaign - California Milk Advisory Board

16. “Good Milk comes from Happy Cows” Bad Mad

17. Justifications for Genetic Selection

18. Justifications: Genetic Selection for Reducing Disease • Cost or potential cost of disease is high • No available vaccine or antibiotic • Microbes are antibiotic resistance • A variety of pathogens infect the host in a similar manner or pathway. • Consumers shun the product because of health related fears • “Organic” labeled product

19. Justification: Genetic Variation for Disease Resistance • Rarely will all animals exhibit clinical symptoms. • Cattle breeds differ for disease related traits • Tick borne diseases (Wambura et al., 1998) • Pinkeye (Snowder et al., 2005a) • Bovine respiratory disease (Snowder et al., 2005b)

20. Disease Resistance is Heritable Mastitis .02 Somatic Cell Score .15 Pinkeye .22 Respiratory .11 to .48

21. Justification: Disease Liability Can Be Traced Back to Owner

22. Challenges

23. Challenges • What is the phenotype for disease resistance?

24. Important Note The success of selection for disease resistance is dependent on correctly identifying the phenotype. If it can’t be accurately measured, it’s not a useful trait.

25. Challenges • What is the phenotype for disease resistance? • Not all healthy animals are disease resistant. • Difficult to determine why some animals remain healthy.

26. Challenges • Many factors influence disease resistance. • Often these factors interact.

27. Disease expression can be confounded with similar diseases. Example: Pneumoniaor is it bronchitis, emphysema, pleuritis, pulmonary adenomatosis, etc.

28. Challenges • A variety of microbes may cause the same disease. Bovine Respiratory Disease caused by: Viruses: (infectious bovine rhinotracheitis, bovine viral diarrhea, bovine respiratory syncytial, and parainfluenza type three), Bacteria (Mannheimia haemolytica, Pasteurella multocida, Haemophilus somnus) and Mycoplasmas(Ellis, 2001)

29. Challenges • Disease of interest is a secondary disease. • Determine optimal number of resistant animals necessary in a population to prevent epidemic. • Disease diagnosis is costly and time consuming.

30. Challenges • Select for resistance or tolerance? • RESISTANCE- ability to prevent the pathogen from entering its biological system. • Never infected (Bos indicus have high resistant to Pinkeye) • Never transmit pathogen (limited transfer, E. coli resistant pigs) • Epidemiologically, it is best to have RESISTANT animals. • TOLERANCE - ability of an infected animal not to express clinical symptoms. • Infected • Transmit pathogen (shedders) • Probably easier to select for • May have subclinical infection • May be practical when resistance not possible

31. Challenges • May not be ethical or practical to challenge animals with a pathogen. (Animal Care Issues) • Selection may disrupt the homeostasis of the immune system. • Selection against one pathogen may make the host more susceptible to a different pathogen. • Selection for animals resistant to a particular pathogen may result in indirect selection for a more virulent pathogen.

32. WARNING Microbes can change their genetic makeup much faster than we can change the host’s genetic ability to resist them.

33. Challenges • Genetic correlations between production and disease resistance traits are often antagonistic • Milk yield in dairy cattle has antagonistic correlations with metabolic, physiologic, and microbial disease traits(Simianer et al., 1991; van Dorp et al., 1998) • Selection for growth rate in turkeys increased susceptibility to Newcastle disease(Sacco et al., 1994) • Growth rate in mice is genetically associated with over 100 physiologic, metabolic, and microbial susceptible diseases(nih.gov) • In beef cattle, these correlations have not been defined.

34. The Immune System

35. A Very Simplistic Review

36. Except for the nervous system, the immune system is the most complex biological system.

37. Immune System • Natural (barriers, secretions, etc.) • Innate (born with) • Acquired (memory) • Cell mediated (immune cells) • Humoral (antibodies)

38. Genetic Approaches to Reduce Microbial Diseases

39. Consider the factors influencing disease. Vaccination Environment PhysiologicalState Management Nutrition

40. What is the genetic component? Largely: Genotype by Environment Interaction Vaccination Environment Physiological State Management Nutrition

41. Consider the animal responses to pathogen infection.

42. Consider the animal responses to pathogen infection • Subclinical (May not detect) Difficulty to differentiate phenotypes (Subclinical vs Disease Resistant)

43. Consider the animal responses to pathogen infection • Subclinical (May not detect) • Immune Response • Perhaps slight negative effect on production (measurable?) • Clinical (Measurable and Non-Measurable) • Lethargic and Decreased Feed Intake • Bleeding • Tumors, Lesions, etc, • Increased Body To, Heart and Respiration Rate • Reduce Production or Recovery or Culling or Death • Etc. • Healthy

44. Consider the pathogen’s responses in the host • Toxin • Reproductive rate • Invade other tissues

45. We are interested in the genetic component(s) influencing the host and/or pathogen responses.

46. Genetic Components • Major genes • Polygenic effects • Host – Pathogen interaction

47. So what do we select for? Treatment Records Host Immune Responses Host Biological Responses • Pathogen Responses

48. The Selection Trait will be Disease Dependent

49. Evaluation of Treatment Records led to Discovery Bovine Success Story Breeding a bull with a natural resistance to brucellosis to normal cows increased resistance to brucellosis in the calves to 59% compared to 20% in a control population. (Templeton et al., 1990)

50. Selection for Immune Responsiveness