Transcript PowerPoint - Beef Improvement Federation

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?
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.
bovine
Animal disease
research needs to
catch up.
Benefits from
human and
mouse disease
research.
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
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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
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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
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.
“Good Milk comes from Happy Cows”
Ad campaign - California Milk Advisory Board
“Good Milk comes from Happy Cows”
Justifications for
Genetic Selection
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
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
Somatic Cell Score
Pinkeye
Respiratory
.02
.15
.22
.11 to .48
Justification:
Disease Liability Can Be Traced Back to Owner
Challenges
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.
nutrition
stress
pathogen(s)
immunological
background
age
genetics
mgmt system
biological status
season
immune system
epidemiology
preventative
measures
• Often these factors interact.
Disease expression can be confounded with
similar diseases.
Example: Pneumonia or is it bronchitis, emphysema,
pleuritis, pulmonary adenomatosis, etc.
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)
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
Consider the factors influencing disease.
Vaccination
Environment
Physiological State
Management
Nutrition
What is the genetic component?
Largely: Genotype by Environment
Interaction
Vaccination
Environment
Physiological State
Management
Nutrition
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)
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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
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?
Treatment Records
Host Immune Responses
Host Biological Responses
Pathogen 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
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.
Over 20 generations of divergent selection for immune
responsiveness to SRBC in White Leghorns
Negative correlation between growth and immune response.
Selection for Host Biological Response: Tumors
Selection for Host Biological Response:
Somatic Cell Score
Bovine Success Story
Selection for reduced somatic cell count in dairy cattle
decreased incidence of mastitis
(Shook and Schutz, 1992)
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)
Treatment Records
Ex.: Pinkeye
• Pros
– Often easy to measure
– Inexpensive
– Disease specific
• Cons
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Binomial
Incomplete exposure
Low heritability
Clustering
• Temporal, Spatial
– Error rate can be high
Host Biological Response
Ex.: Somatic Cell Score, Lung Lesions, To, Feed Intake
• 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
Pathogen’s Response
Ex.: Fecal egg count, fecal culture test, blood toxins
• Pros
– Quantitative
– Direct or indirect
response
– Disease specific
• Cons
– Often expensive
– Incomplete exposure
– Clustering
• Temporal, Spatial
– Error rate (moderate)
– Low to moderate
heritability
Immune Response
Ex.: Cell mediated, vaccine, base titers
• Pros
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Quantitative
Direct/Indirect
General disease
Possible to measure
on all animals
• Cons
– Often expensive
– Error rate (moderate)
– Low to moderate
heritability
– Autoimmunity
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?
Questions?