Quiz 3 (Lecture 10) Flashcards
Diseases have both ____ and ____ explanations
mechanistic and evolutionary
The mechanistic explanation of Crohns
mutations in NOD (Nucleotide-binding Oligomerization Domamaine) receptors
GWAS studies of NOD mutants
- homo 17 fold greater risk of Crohns
- hetero 2.5 fold greater risk
The evolutionary explanation of Crohns
there is an environmental interaction: the severity of Crohn’s disease depends on the state of the microbiome
Diseases can be placed into categories:
infectious- caused by pathogens
genetic- caused by genetic defects
degenerative- caused by the vulnerabilities of aging
Genetic Defects
are relatively rare, mutational catastrophes (trisomy 18-infants die shortly after birth)
Genetic Predispositions
are often polygenic and result from environmental mismatches- neutral or beneficial in some settings, detrimental in others
– genes interact together and with the environment causing disease
- some parts of our genome are most or less susceptible to disease
- more common
Catastrophes
include attacks by predators and parasites and accidents
- no variation, either has it or you do not
ex. contracting ebola or rabies
Accumulative effects
include smoking and lack of exercise
ex. the impact of lifestyle choices on the risk of heart disease, cancer, and type 2 diabetes
Catastrophe example
children born by c-section increased 20% risk of asthma
delivery of birth affects the microbiome and through its interactions with the immune system the risk of allergies, asthma, obesity, and autoimmune diseases
The gut is the largest
immune organ
The development of gut-associated lymphoid tissue is
triggered by signals produced by gut bacteria
*mammal genome has outsourced this essential function
Accumulative effects example
- the likelihood of suffering from peripheral artery disease increases as the exposure to secondhand smoke increases (measured as # of hours exposure per week)
- exposure to secondhand smoke varies across racial groups, ages, and socioeconomic status
Disease
a state that decreases survivability, increasing mortality
diseases have different causations
genetic interactions with environmental factors (GxE causations)
When a cause of the disease is an interaction, both
environmental and genotype factors must be accounted for.
ex. the environmental risks of cancer, such as tobacco and air pollution, depending on genotype
Genetic variation in N-acetyl transferase
1) Those with the combination of NAT2 slow acetylator, NAT1 fast acetylator, and current or ever cigarette smoking were 2.7 times more likely to get bladder cancer
2) NAT1 polymorphism interacts with dietary mutagen intake (bbq meat) to increase the risk of pancreatic cancer 2.5 times in men but not in women
Organs and tissues vary in their degrees of robustness, resilience, and vulnerability. This mosaic determines…
the spectrum of diseases, both in general and in particular environments
Not all organs and tissues are as robust and resilient as possible because of
tradeoffs- producing such structures and processes would cost more than it would pay
Tissues with high renewal rates and repair capacities are
relatively tolerant to damage–easily handled
ex. most epithelia
Tissues with low renewal rates and repair capacities are
not tolerant of damage–can be lethal
ex. neurons
Tissues with high energetic demands
rely exclusively on oxidative metabolism
ex. neurons and heart muscles
- this is why ischemia (lack of O2 and nutrients) rapidly and seriously damage brains, hearts, kidneys, often irreversibly or fatally
Tissues with low energetic demands
tolerate hypoxia relatively well because they can switch from oxidative to glycolytic metabolism
ex. adipocytes and fibroblasts
Tissues with high energetic demands
rely exclusively on oxidative metabolism
ex. neurons and heart muscles
- this is why ischemia (lack of O2 and nutrients) rapidly and seriously damages brains, hearts, and kidneys, often irreversibly or fatally
Protective structures have evolved
to shield vulnerable organs from frequently encountered threats
ex. skull protects brain
Some tissues and organs are
immune privileged– they do not permit immune responses that have damaging side effects (like inflammation)
ex. of organs: brain, eyes, gonads
- the price such tissues pay for avoiding the costs of inflammation is vulnerability to pathogens that gain access to them
Many structures are vulnerable because
of compromises imposed by tradeoffs
- Synovial joints (wrist, elbow, finger, shoulder, knee) have superior mobility but are vulnerable to arthritis
- Alveolar sacs have excellent gas exchange but are vulnerable to pneumonia when filled with inflammatory exudate
Constraints is that
other structures are vulnerable because of historical limitations which prevent further evolution and result in seemingly suboptimal structures
Choking
- an example of a constraint
- have a suboptimal design of throat because lungs evolved off of the esophagus
Pathologies can then result for two reasons
1) the mechanisms controlling the balance of the tradeoff are perturbed
2) the environment changes
1) the mechanisms controlling the balance of the tradeoff are perturbed examples
- the immune defense against infection brings with it the high cost of immunopathology and the risks of autoimmune disease
- the clotting system carries the risk of embolism and stroke
2) the environment changes examples
- if the environment changes, costs may exceed benefits until evolution catches up (can take a while)
- modern hygienic environments are abnormal: they elicit pathological immune responses (like asthma and allergies)
Some developmental and physiological processes are insensitive
to environmental change
ex. DNA replication
- robust to dysregulation but remain vulnerable to genetic defects
Some developmental and physiological processes are very
sensitive to environmental change
ex. glucose metabolism and blood pressure
- have flexibility at cost of vulnerability to dysregulation
Sensitive reactions evolve to be
adjustable
insensitive reactions evolve to be
fixed
Core biological processes are
fixed
ex. DNA replication, transcription of actin for the cytoskeleton
- major features of the body plan are fixed in developmental control (# of head, legs, arms, digits, eyes)
adjustable processes example
Glucose distribution is controlled by insulin
- insulin promotes the absorption of glucose from the blood to skeletal muscles and fat tissues by causing fat to be stored rather than used for energy
diseases of homeostasis: insulin resistance and type 2 diabetes
