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

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

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

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

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

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

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

Outline I.Current situation II.Justification III.Challenges IV.Immune System V.Genetic Approaches

But First GENETIC DISEASE vs. GENETIC RESISTANCE

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

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

Current Situation of Microbial Diseases

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

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. Breeding for societally important traits in pigs 1 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:

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

“Good Milk comes from Happy Cows” Bad Mad

Justifications for Genetic Selection

 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 Justifications: Genetic Selection for Reducing Disease

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)

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

Justification: Disease Liability Can Be Traced Back to Owner

Challenges

What is the phenotype for disease resistance?

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.

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

Challenges Many factors influence disease resistance. nutritionagegenetics stressmgmt systembiological status pathogen(s)seasonimmune system immunological background epidemiology preventative measures Often these factors interact.

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

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) Challenges A variety of microbes may cause the same disease.

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.

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

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.

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

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.

The Immune System

A Very Simplistic Review

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

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

Genetic Approaches to Reduce Microbial Diseases

Management Nutrition Physiological State Environment Vaccination Consider the factors influencing disease.

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

Consider the animal responses to pathogen infection.

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

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 T o, Heart and Respiration Rate –Reduce Production or Recovery or Culling or Death –Etc. Healthy

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

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

Genetic Components Major genes Polygenic effects Host – Pathogen interaction

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

The Selection Trait will be Disease Dependent

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)

Selection for Immune Responsiveness

Findings: Selection for immune responsiveness to SRBC improves immune response to other diseases Negative genetic correlation between growth and immune response Environment by immune response interaction

Over 20 generations of divergent selection for immune responsiveness to SRBC in White Leghorns Negative correlation between growth and immune response. Selection for Immune Responsiveness Effects of genetic selection for high or low antibody response on resistance to a variety of disease challenges and the relationship of resource allocation. Gross WB, Siegel PB, Pierson EW. Avian Dis. 2002;46(4):

Selection for Host Biological Response: Tumors

Bovine Success Story Selection for reduced somatic cell count in dairy cattle decreased incidence of mastitis (Shook and Schutz, 1992) Selection for Host Biological Response: Somatic Cell Score

Selection based on Pathogen Response Ovine Success Story Selection for reduced fecal parasite egg count resulted in internal parasite “resistant” sheep (Woolaston et al., 1992)

Major Gene Swine Success Story Pigs fully resistant to bacteria-induced diarrhea (E. coli) (Gibbons et al., 1977)

Major Genes Sheep genotyped for resistance to scrapie (Belt et al., 1995)

Pros –Often easy to measure –Inexpensive –Disease specific Cons –Binomial –Incomplete exposure –Low heritability –Clustering Temporal, Spatial –Error rate can be high Treatment Records Ex.: Pinkeye

Pros –Quantitative –Direct or indirect response –May be disease specific Cons –Often expensive –Incomplete exposure –Clustering Temporal, Spatial –Error rate (moderate) –Low to moderate heritability –May not be disease specific Host Biological Response Ex.: Somatic Cell Score, Lung Lesions, T o, Feed Intake

Pros –Quantitative –Direct or indirect response –Disease specific Cons –Often expensive –Incomplete exposure –Clustering Temporal, Spatial –Error rate (moderate) –Low to moderate heritability Pathogen’s Response Ex.: Fecal egg count, fecal culture test, blood toxins

Pros –Quantitative –Direct/Indirect –General disease –Possible to measure on all animals Cons –Often expensive –Error rate (moderate) –Low to moderate heritability –Autoimmunity Immune Response Ex.: Cell mediated, vaccine, base titers

Immune Response Approach will probably be some sort of Selection Index that will include some combination of: Base immune measure Vaccine response Cell mediated response (SRBC) And some threshold for high responders (titers) to reduce effect on production traits.

The Future

Long Term – Microbial Diseases –Marker Assisted Selection for microbial diseases –Few major genes discoveries –Focus on general immunity response

Transgenic Animals

Questions?