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Evolutionary medicine course notes
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Lecture 1 – Introduction to evolutionary thinking – Beukeboom - 24-02-’20Natural selection and evolution:
• Genetic variation is present in order to evolution to take place. If there is no genetic
variation, there cannot be evolution.
• Genetic variation → natural selection → adaptation → evolution.
• Evolution = a change over time in the genetic composition of a
population.
• Adaptation = trait that increases the ability of an organism to survive
and reproduce in specific environments (Darwinian fitness).
• Natural selection = process by which individuals with certain
heritable traits survive better and leave more offspring than others.
Four necessary conditions for natural selection to act:
1. Variation in the trait of interest.
2. The trait is heritable.
3. Variation in reproductive success.
4. A non-zero correlation between the trait and reproductive success.
Natural selection and evolutionary thinking:
• Some (mis) conceptions…
o The structure, diversity and adaptation of life can be explained by processes we can
observe now (Darwin).
o The theory of evolution by natural selection is testable.
o Natural selection is not teleological (goal oriented) but tinkering.
The study of evolution:
• The study of the evolutionary process entails:
o analysis of factors that change the number of copies of a gene in a population as
they are passed on [population genetics]
o analysis of how genes produce traits that interact with the environment [genotype
to phenotype map]
→ the variants that persist are not necessarily the best possible (why not?)
• Fitness = relative reproductive success.
Five agents of evolutionary change:
• Mutation = een verandering in het genetische materiaal, waarbij het genotype wordt
veranderd. Door een mutatie kan er een nieuwe erfelijke eigenschap ontstaan.
• Gene flow = een populatie kan allelen verliezen of er nieuwe allelen bij krijgen, doordat er
voortdurend uitwisseling plaats vindt tussen leden van aangrenzende populaties.
• Nonrandom mating (niet willekeurig paren) → hogere rate of homozygote genen.
• Genetic drift = willekeurige verspreiding van genen bij de (a)seksuele voortplanting. Leidt tot
vernietigen of bewaren van genen zonder onderscheid (in tegenstelling tot natuurlijke
selectie) te maken tussen gunstig of ongunstig.
• Selection
Populations have histories → you need to know something about the history of populations to
understand differences between populations. We settled in different environments during our
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,migrations out of Africa. You can see grouping of populations and you can see differences between
continents.
The evolution of lactose tolerance:
• Ability to digest milk at later age:
o LPH is actief in de eerste 2 jaren van ons lichaam. Daarna is het enzym er niet meer
en dan krijg je last van je maag als je melk drinkt. Maar in verschillende delen van de
wereld, zoals in Europa en West-Afrika: frequentie van mensen die nog lactose
kunnen verteren zijn nog heel hoog. SNP in MCM6 is een factor die ervoor zorgt dat
LPH actief blijft en je kan melk blijven drinken.
• Evolution takes hundreds of generations to adjust traits to new conditions.
• This lag produces serious mismatches in our reactions to novel conditions.
Evolution of HIV:
• Human immunodeficiency virus → acquired immune deficiency syndrome (AIDS).
• Het virus dood geen mensen. Mensen met AIDS gaan dood van andere infecties omdat ze
geen immuunsysteem meer hebben. Het virus dood de cellen van het immuunsysteem.
• Intracellular parasite of human macrophages and T-cells of immune system (uses cells to
copy itself and kill the host cell). Er is een eiwit op het membraan van de T-cel dat herkend
worden door het virion en er is ook een co-receptor nodig (CCR5). Deze 2 worden herkend
door het virion. Virion gaat samen met membraan en dan laat het het RNA vrij. Host cel
maakt nieuwe virions die weer vrijgelaten worden in het lichaam. De host cel reproduceert
dus het virus en de cel gaat dan zelf dood.
• RNA transcriptase: RNA wordt omgezet in DNA.
• Rapid evolution of resistance to azidothymidine (AZT): AZT is een variant van thymine
(baseparen DNA). Het voorkomt dat er duplicaties van het virus plaatsvinden. Maar snel
bleek het dat we hogere concentraties van AZT nodig hebben over tijd. Er ontstond snel
resistentie tegen deze drugs. Kleine mutatie in reverse transcriptase enzym. Toen kon
reverse transcriptase AZT niet meer accepteren.
• Eerst een susceptible variant to AZT → variant door mutatie: partly resistant to AZT →
mutatie: highly resistant to AZT. Result: the composition of the population has changed over
time. The fitness van de laatste is dan hoger dan de eerste. En deze is dan meer aanwezig in
de populatie dan de eerste vorm. De evolutie van resistentie is hier dus weergegeven.
Host-parasite interactions: virulence versus resistance:
• Pathogen/parasite:
o Population size is large
o Generation time is short
o Mutation rate is high
• Host:
o Population size is small
o Generation time is long
o Mutation rate is low
• Twee hypotheses waarop mensen hier naar kijken:
o Trade-off hypothesis: all pathogens evolve to lower virulence because damage to
the host is ultimately also detrimental to pathogen (e.g. flu virus)
o Short-sighted hypothesis: traits that enhance the within-host fitness may gain high
frequency even if they reduce transmission to new hosts (e.g. HIV)
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,Evolution of resistance to HIV:
• Some people are resistant to HIV. Dit is zo omdat
ze het CCR5-delta32 gen dragen. CCR5-delta32
allele confers resistance.
• Frequency of this allele is the highest in North
Europe → mystery why???
• 20% aanwezigheid van het recessieve allel.
Alleen homozyt: 100%. Dan ben je helemaal
resistent tegen HIV. Het duurt 40 generaties
voordat iedereen dat heeft in de populatie.
• Wanneer de selection pressure hoog is en de initial frequency laag: maar 20% resistentie op
zowel recessief als homozygoot. Over 40 generaties nog steeds.
• Low initial frequency is low and the selection pressure is high → niemand heeft het allel. 0%
aanwezig.
• We moeten wat Europeanen naar Afrika sturen is de oplossing om het allel te krijgen.
Hierdoor verspreid je genen en je krijgt dan dit gen (dus hogere kans op HIV), maar mensen
in Afrika krijgen lagere kans op HIV omdat Europanen een hogere frequentie hebben van het
gen tegen HIV. Dus voor ons is het niet goed, maar daar wordt het probleem dan opgelost.
Origin of HIV:
• Phylogeny = reconstruction evolutionarry history.
• Molecular clock = base substitutions accumulate in populations with a constant rate.
Lecture 1 – evolutionary thinking in human health - Elliot - 24-02-’20
Traditional medicine – proximate mechanisms:
• Physical and biochemical mechanisms underlying the immediate causes of disease
• How does intermediary metabolism work?
• What causes appendicitis?
• How does the adaptive immune system recognize foreign material?
• What are the genetic bases of viral pandemics?
• How does HIV cause disease?
• How does it work/go wrong?
Evolutionary medicine – ultimate mechnisms:
• How natural selection, evolutionary conflicts and chance events shape diseases and disease
risk on a timescale of many generations
• Why do vertebrates have adaptive immunity?
• Why are humans so vulnerable to HIV?
• Why has fever evolved? Who does it benefit?
• Why do we cough?
• Why is it like this?
Why do we get sick?
• Natural selection is an optimizing process in which, on average, genes from the most fit
individuals increase in frequency in each successive generation.
• Dawkins: “Natural selection… is a non-random force, pushing towards improvement. …Every
generation has its Darwinian failures but every individual is descended only from previous
generations' successful minorities… There can be no going downhill - species can't get worse
as a prelude to getting better.”
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, • Yet in human health we see, everywhere, apparently suboptimal outcomes, such as illness
and death that reduce reproductive output.
• There is no biological requirement that we must suffer from cancer! It is not an inherent
characteristic of animal cells.
o Naked mole-rat: this unusual rodent is virtually immune to cancer in the wild. It is
the only eusocial rodent, is strongly resistant to pain, and lives for up to 30 ears
(compared to 2 years for mouse).
o In an experiment, mice (A) and blind mole-rats (B) were injected with a mutagen that
typically causes cancer in mammals.
▪ In mice, injection resulted in fibrosarcoma, a disorganized soft tumor with
haemorrhage and necrosis.
▪ In blind mole-rats, injection resulted in benign fibrosis creating a firm
harmless nodule.
• Cells from naked mole-rats cannot cause cancer in other species!
o Injection of induced pluripotent stem cells (iPSCs) into
mouse testes results in tumour formation within a few
weeks.
o In this experiment, iPSCs derived from mouse, human and
naked mole-rat were injected into mouse testes.
o Human and mouse iPSCs grew into tumours, while those
derived from naked mole-rat showed no tumor
development, indicating the existence of an inherent cancer-
suppressive mechanism in naked mole-rat cells.
Evolutionary processes resulting in sub-optimal outcomes:
1. Selection is too slow
a. Mismatch between design and environment
b. Accumulation of mutations
2. Selection is too fast
a. Competition with a pathogen or other organism
3. Selection cannot solve some problems irrespective of time
a. Trade-offs between different biological functions
b. Trade-offs between different times of life
c. Constraints on what is actually evolvable
4. We misunderstand what selection shapes
a. Natural selection does not necessarily favour being happy and healthy
b. Some diseases may actually be unpleasant adaptive responses
1. Selection is too slow:
A. Mismatch between design and environment:
o Traits that were adaptive during evolution can become maladaptive after rapid
environmental change. For example: Great barrier reef after several decades of: pH
decreased by 0.1; increased nutrient content of water; increased sedimentation. Alle
kleuren zijn weg.
o Hunter-gatherers were exposed to periodic famines and food shortages interspersed
with periods of high food availability (i.e., a successful hunt). This situation selected
for alleles maximizing metabolic efficiency, lipid storage and highly motivated food-
searching behaviours.
o In modern environments, with a chronic mild excess of calories, these alleles may be
maladaptive as they lead to diabetes, obesity and cardiovascular disease.
o Evolutionaire druk om te zoeken voor zout wordt een probleem om dat het zorgt
voor ziektes.
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