genetic selection for disease resistance: challenges and opportunities gary snowder research...
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Genetic Selection for Disease
Resistance:
Challenges and Opportunities
Gary Snowder
Research Geneticist
USDA, ARS, MARC
Short Term: Overall, selection will Short Term: Overall, selection will probably be useful to probably be useful to reduce the reduce the incidence of microbial diseases.incidence of microbial diseases.
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
Genetic Disease (congenital)
inherited disorder (conformation, metabolic, etc.)
Genetic Resistance
genetic component to resist pathogen infection
Known Congenital Disorders in CattleApproximately 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• 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 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
Cost or potential cost of disease is highNo available vaccine or antibiotic Microbes are antibiotic resistanceA 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)
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.
nutrition age genetics
stress mgmt systembiological
status
pathogen(s) seasonimmune system
immunological background
epidemiologypreventative
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.
WARNINGMicrobes 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.
Immune System
• Natural (barriers, secretions, etc.)
• Innate (born with)
• Acquired (memory)– Cell mediated (immune cells)
– Humoral (antibodies)
Management
Nutrition
Physiological State
EnvironmentVaccination
Consider the factors influencing disease.
Management
Nutrition
Physiological State
EnvironmentVaccination
What is the genetic component?Largely: Genotype by Environment Largely: Genotype by Environment
InteractionInteraction
Consider the animal responses to pathogen infection
• Subclinical (May not detect)
Difficulty to differentiate phenotypes Difficulty to differentiate phenotypes (Subclinical vs Disease Resistant)(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 To, Heart and Respiration Rate– Reduce Production or Recovery or Culling or Death– Etc.
• Healthy
So what do we select for?
Host Immune Responses
Pathogen Responses
Treatment Records
Host Biological Responses
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)
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):1007-1010.
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)
• Pros– Often easy to measure
– Inexpensive
– Disease specific
• Cons– Binomial
– Incomplete exposure
– Low heritability
– Clustering• Temporal, Spatial
– Error rate can be high
Treatment RecordsEx.: 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 ResponseEx.: Somatic Cell Score, Lung Lesions, To, 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 ResponseEx.: 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.
Long Term – Microbial Diseases
– Marker Assisted Selection for microbial diseases
– Few major genes discoveries– Focus on general immunity response