Evolutionary Medicine
Lecture 1 Introduction to Evolutionary Thinking Beukeboom
Genetic variation natural selection adaptation evolution
Natural selection = process by which individuals with certain heritable traits survive better and leave
more offspring than others.
Adaptation = trait that increases the ability of an organism to survive and reproduce in specific
environments (Darwinian fitness).
Evolution = a change over time in the genetic composition of a population.
Necessary conditions for natural selection:
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
The study of the evolutionary process entails:
• Analysis of factors that change the number of copies of a gene in a population as they are
passed on [population genetics]
• 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?)
Five agents of evolutionary change:
1. Mutation
2. Gene flow: the transfer of genetic variation from one population to another
3. Non-random mating: occurs when the probability that two individuals in a population will
mate is not the same for all possible pairs of individuals. It increases the degree of
homozygosity
4. Genetic drift: is the change in the frequency of an existing gene variant (allele) in a
population due to random sampling of organisms.
5. Selection
The evolution of lactose tolerance
Ability to digest milk at later age
LPH (breaks down lactose) is usually active during the first 2 years of life.
SNP in MCM6 in Europe, T-13910 in West-Afrika. SNP keeps LPH alive.
Evolution takes hundreds of generations to adjust traits to new conditions.
This lag produces serious mismatches in our reactions to novel conditions.
Evolutionary questions of HIV evolution
• Where did HIV come from?
• Why does HIV kill people?
• Wy are some people resistant to HIV?
• Why is it so difficult to develop a medicine against AIDS?
HIV: Human Immunodeficiency Virus Acquired Immune Deficiency Syndrome (AIDS).
First infection in USA – 1981
HIV is caused by an intracellular parasite of human macrophages and T-cells of immune system (uses
cells to copy itself and kill the host cell):
,HIV virion binds through CCR5 to the host cell membrane fusion with the membrane HIV
reverse transcriptase: RNA to DNA DNA is multiplied by host cell host cell gets killed.
Rapid evolution of resistance to azidothymidine (a drug used to combat HIV)
AZT = thymidine residue with N3 attached blocks mutation of HIV virus via reverse transcriptase.
There is more AZT needed in HIV patients after time, the HIV virus will evolve a reverse transcriptase
resistant to AZT.
Host-parasite interactions: virulence versus resistance
Coincidal hypothesis: virulence is a accidental by-product of selection on other traits (e.g. tetanus
bacteria)
Trade-off hypothesis: all pathogens evolve to lower virulence because damage to the host is
ultimately also detrimental to pathogen (e.g. flu virus).
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)
Why are some people resistant to HIV?
∆32 allele: a mutant form version of CCR5 encoded by the mutant allele fails to appear on the
surface of the cell virions of HIV cannot enter host cell.
∆32 allele confers strong protection against HIV.
This allele is more present in (the northern of) Europe than in Africa or Asia.
In Africa: strong selection pressure but low frequency of the allele (in homozygotes) no evolution
of resistance.
Where did HIV come from?
Phylogeny is used to reconstruct evolutionary history
As HIV moves from host to host, it diversifies inside each patient.
We got HIV from chimps, probably as a result of butchering them for food. Chimps got SIV from
monkeys.
,Virus was already present around 1920-1940 but only started affecting humans in the 1980s.
Lecture 2 Evolutionary thinking applied to human health Elliot
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.
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.
Naked mole-rat
Heterocephalus glaber
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 years (compared to 2
years for mouse).
• In this 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.
• Injection of induced pluripotent stem cells (iPSCs) into mouse testes results in tumour
formation within a few weeks.
• In this experiment, iPSCs derived from mouse, human and naked mole-rat were injected into
mouse testes.
• 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
Traits that were adaptive during evolution can become maladaptive after rapid
environmental change.
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. In modern environments, with a chronic mild excess of calories, these alleles
may be maladaptive as they lead to diabetes, obesity and cardiovascular disease.
Salt licks in past and present
One of our earliest hunting strategies was persistence hunting – run at a moderate pace for
many hours after a faster prey animal until it collapses from exhaustion. Prolonged moderate
exercise followed by days of rest. Our contemporary hunting strategies involve prolonged
immobility in a stress position followed by occasional bursts of intense activity (if we are
sporty). Results in chronic back pain and poor cardiovascular health.
If we examine the frequency of type II diabetes in modern human populations:
o It is those populations that have recently undergone nutritional transitions from
traditional diets to Western diets who exhibit the highest rates of diabetes (red
arrows)
o Populations who have experienced such diets for long periods of time (i.e.
Europeans) appear to exhibit lower rates of diabetes (green arrows) possibly
reflecting long term local evolutionary adaptation.
Lecture 1 Introduction to Evolutionary Thinking Beukeboom
Genetic variation natural selection adaptation evolution
Natural selection = process by which individuals with certain heritable traits survive better and leave
more offspring than others.
Adaptation = trait that increases the ability of an organism to survive and reproduce in specific
environments (Darwinian fitness).
Evolution = a change over time in the genetic composition of a population.
Necessary conditions for natural selection:
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
The study of the evolutionary process entails:
• Analysis of factors that change the number of copies of a gene in a population as they are
passed on [population genetics]
• 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?)
Five agents of evolutionary change:
1. Mutation
2. Gene flow: the transfer of genetic variation from one population to another
3. Non-random mating: occurs when the probability that two individuals in a population will
mate is not the same for all possible pairs of individuals. It increases the degree of
homozygosity
4. Genetic drift: is the change in the frequency of an existing gene variant (allele) in a
population due to random sampling of organisms.
5. Selection
The evolution of lactose tolerance
Ability to digest milk at later age
LPH (breaks down lactose) is usually active during the first 2 years of life.
SNP in MCM6 in Europe, T-13910 in West-Afrika. SNP keeps LPH alive.
Evolution takes hundreds of generations to adjust traits to new conditions.
This lag produces serious mismatches in our reactions to novel conditions.
Evolutionary questions of HIV evolution
• Where did HIV come from?
• Why does HIV kill people?
• Wy are some people resistant to HIV?
• Why is it so difficult to develop a medicine against AIDS?
HIV: Human Immunodeficiency Virus Acquired Immune Deficiency Syndrome (AIDS).
First infection in USA – 1981
HIV is caused by an intracellular parasite of human macrophages and T-cells of immune system (uses
cells to copy itself and kill the host cell):
,HIV virion binds through CCR5 to the host cell membrane fusion with the membrane HIV
reverse transcriptase: RNA to DNA DNA is multiplied by host cell host cell gets killed.
Rapid evolution of resistance to azidothymidine (a drug used to combat HIV)
AZT = thymidine residue with N3 attached blocks mutation of HIV virus via reverse transcriptase.
There is more AZT needed in HIV patients after time, the HIV virus will evolve a reverse transcriptase
resistant to AZT.
Host-parasite interactions: virulence versus resistance
Coincidal hypothesis: virulence is a accidental by-product of selection on other traits (e.g. tetanus
bacteria)
Trade-off hypothesis: all pathogens evolve to lower virulence because damage to the host is
ultimately also detrimental to pathogen (e.g. flu virus).
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)
Why are some people resistant to HIV?
∆32 allele: a mutant form version of CCR5 encoded by the mutant allele fails to appear on the
surface of the cell virions of HIV cannot enter host cell.
∆32 allele confers strong protection against HIV.
This allele is more present in (the northern of) Europe than in Africa or Asia.
In Africa: strong selection pressure but low frequency of the allele (in homozygotes) no evolution
of resistance.
Where did HIV come from?
Phylogeny is used to reconstruct evolutionary history
As HIV moves from host to host, it diversifies inside each patient.
We got HIV from chimps, probably as a result of butchering them for food. Chimps got SIV from
monkeys.
,Virus was already present around 1920-1940 but only started affecting humans in the 1980s.
Lecture 2 Evolutionary thinking applied to human health Elliot
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.
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.
Naked mole-rat
Heterocephalus glaber
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 years (compared to 2
years for mouse).
• In this 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.
• Injection of induced pluripotent stem cells (iPSCs) into mouse testes results in tumour
formation within a few weeks.
• In this experiment, iPSCs derived from mouse, human and naked mole-rat were injected into
mouse testes.
• 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
Traits that were adaptive during evolution can become maladaptive after rapid
environmental change.
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. In modern environments, with a chronic mild excess of calories, these alleles
may be maladaptive as they lead to diabetes, obesity and cardiovascular disease.
Salt licks in past and present
One of our earliest hunting strategies was persistence hunting – run at a moderate pace for
many hours after a faster prey animal until it collapses from exhaustion. Prolonged moderate
exercise followed by days of rest. Our contemporary hunting strategies involve prolonged
immobility in a stress position followed by occasional bursts of intense activity (if we are
sporty). Results in chronic back pain and poor cardiovascular health.
If we examine the frequency of type II diabetes in modern human populations:
o It is those populations that have recently undergone nutritional transitions from
traditional diets to Western diets who exhibit the highest rates of diabetes (red
arrows)
o Populations who have experienced such diets for long periods of time (i.e.
Europeans) appear to exhibit lower rates of diabetes (green arrows) possibly
reflecting long term local evolutionary adaptation.
