Tijmen Lourens Summary Evolutionary Medicine
Evolutionary Medicine
Lecture 1: Evolutionary Principles and Processes
Gene – a conceptual construct, a physical location in a chromosome where one or more
transcripts are produced, ‘locus’.
Allele – a real thing, a stretch of DNA located in some locus defined by its unique genetic
sequence.
Incomplete dominance – both alleles do not mask the other allele so it creates an
intermediate phenotype.
Codominance – incomplete dominance but both effects from alleles are present and there is
no intermediate phenotype.
Heterosis – phenomenon by which outbred organisms have better fitness than purebred
organisms. Has to do with heterozygosis.
- 50 – 70% of British Pakistani marriages are consanguineal. They have a lot higher
chance of marrying a first cousin.
Evolutionary Fitness:
- Concept used to express the degree to which a biological entity makes copies of itself
in the next generation
o Could be measured in terms of individuals (how many descendants an
individual has in the next generation – or in two generations). This would be a
measure of the fitness of an entire genotype.
o Could be measured in terms of alleles. (How many copies of an allele are
present in the next generation).
▪ Due to epistasis – measured as the average over all the genotypes
carrying the allele?
o Could even be measured in terms of culture. (how many people in the next
generation share an idea or a technological innovation.)
4 necessary conditions for natural selection to act:
1) Variation in the trait of interest
2) Variation is heritable
3) Variation in fitness (reproductive success)
4) A correlation between the trait and fitness
Assortative mating – the tendency of similar individuals to mate with each other. This will
drive a deviation from the Hardy-Weinberg equilibrium by preventing random association of
gametes and increasing the frequency of homozygotes above expected levels.
Natural selection will favour alleles that increase future reproductive output.
,Tijmen Lourens Summary Evolutionary Medicine
Genetic Drift:
- Population size is an important determinant of the strength of selection
- Random events (genetic drift) are less important, and selection is more efficient, in
large populations
Lecture 2: Evolutionary Thinking in Human Health
Evolutionary processes resulting in sub-optimal outcomes:
1) Selection is too slow
a. Mismatch between design and environment
i. Hunter-gatherers were exposed to periodic famines and food
shortages interspersed with periods of high food availability.
ii. This results in alleles maximizing metabolic efficiency, lipid storage and
highly motivated food-searching behaviours
iii. Now, with a chronic mild excess of calories, these alleles may be
maladaptive as they lead to diabetes, obesity and cardiovascular
disease
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
i. Genes promoting rapid growth and early reproductive activity in an
individual, will also promote poor old-age health and early death in
the same individual (in female macaques)
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
Lecture 3: More on Natural Selection
Types of selection:
- Advantageous – increases fitness of carriers
- Deleterious – reduces fitness of carriers
- Neutral – no effect on fitness
Positive selection = diversifying selection (allele spreads over population)
Negative selection = purifying selection (allele reduces over population)
Genetic drift = natural selection has no effect on the new mutant allele because it soes not
influence fitness.
,Tijmen Lourens Summary Evolutionary Medicine
Males seem to have a slightly lower recombination rate why?
Exam question: Selective sweep: a process by which a new advantageous mutation
eliminates or reduces variation in linked neutral sites as it increases in frequency in the
population.
Selective sweep = a method to detect natural selection.
- Gene region CPT1A is found all around the northern spheres (70% of the Inuit has it)
- Not found anywhere else in the world
- Really homologous for the Inuit (very little genetic diversity)
o CPT1A encodes the rate limiting gene for fatty oxidation in the liver, which
regulates energy balance and protects the liver during fasting
o Allele is associated with hypoketotic hypoglycaemia and high infant mortality
▪ The benefits in terms of metabolism outweigh the costs in terms of
infant mortality
▪ High levels of infant mortality are associated with adoption of a
western diet in this population but were originally absent (mismatch)
Genomic regions with suppressed genetic diversity due to selective sweeps are enriched
with deleterious (DEL) mutations in compared to neutral.
Detecting selection: nonsynonymous / synonymous substitution
- Mutations that result in a change to the amino acid produced
o Visible to natural selection
- Mutation that results in no change in the amino acid produced
o Invisible to natural selection
The rate of synonymous substitution (dS) tells us about the background rate of fixation of
mutants in the absence of natural selection. We can compare this with the rate of
nonsynonymous substitution to detect natural selection.
- If dN/dS > 1 = then natural selection must be favouring the spread of new variants in
the population → positive / diversifying selection
- If dN/dS < 1 then natural selection must be eliminating new variants in the
population → negative / purifying selection. Happens in most species.
Levels of selection: all suffice the requirements for selection
- Individuals
- Cells
- Genes
- Families
- Genomes
, Tijmen Lourens Summary Evolutionary Medicine
Lecture 4: Genetic Conflict
Conflict between mitochondrial and nuclear genomes:
Natural selection favours cells that maintain the integrity of their nuclear genome. But
natural selection also favours mitochondria that divide as rapidly as possible (because such
genes will be over-represented in the next generation of mitochondria). As we shall see, this
results in a conflict of interest!
Selection for rapid mitochondrial division has resulted in the mitochondrion shrinking over
time in all species.
- Original ancestor had 1000-10,000 genes, the largest mitochondrion has around 100
genes, and the human mitochondrion has just 37 genes.
- Many genes present in original endosymbiont were not relevant during symbiosis
since the needs of the mitochondrion are provided by the cell. These genes were lost
over evolutionary time.
- Some genes present in original endosymbiont were still necessary for mitochondrial
survival but occasional mutational events transferred these genes into the nuclear
genome.
- Once a mitochondrial gene is incorporated into nuclear genome, it’s no longer
required in mitochondrial genome → degrades by genetic drift and selection
favouring mitochondria that duplicate more rapidly.
- NUMT = Nuclear mitochondrial gene –
o NUMTs inserted into functional regions of the genome are known to be
associated with various genetic diseases.
Parent-offspring conflict: the larger you are at birth, the better your chances of surviving.
However, it is harder for your mom to give birth to you.
- To maximize fetal survival probability, mother invests 0.6 units of energy
- If a mother has 6 units of energy to invest in a brood, she could invest 0.6 each into a
total of 10 surviving offspring.
- But if she invests 0.2 units of energy per offspring, she could have 30 babies. Each
would have a 0.42 probability of survival, resulting in an expected 12.6 surviving
offspring!
Baby decides whether the pregnancy continues – Parent-offspring conflict.
1) Invasion of the placenta into the uterine wall
o Allows fetus to prevent cut-off of blood flow (modify spiral arteries), access
maternal blood efficiently
2) Fast food for baby
o Amount of food depends on glucose levels in maternal blood. You want more
than mom wants to give you. Insulin keeps blood sugar from getting
dangerously high. hPl (placental lactogen) blocks (bonds) maternal insulin.
o Mother seems to be partially diabetic during pregnancy
3) More blood please!
o Amount of food also depends on maternal blood pressure – you want mom’s
blood pressure to be higher.
Evolutionary Medicine
Lecture 1: Evolutionary Principles and Processes
Gene – a conceptual construct, a physical location in a chromosome where one or more
transcripts are produced, ‘locus’.
Allele – a real thing, a stretch of DNA located in some locus defined by its unique genetic
sequence.
Incomplete dominance – both alleles do not mask the other allele so it creates an
intermediate phenotype.
Codominance – incomplete dominance but both effects from alleles are present and there is
no intermediate phenotype.
Heterosis – phenomenon by which outbred organisms have better fitness than purebred
organisms. Has to do with heterozygosis.
- 50 – 70% of British Pakistani marriages are consanguineal. They have a lot higher
chance of marrying a first cousin.
Evolutionary Fitness:
- Concept used to express the degree to which a biological entity makes copies of itself
in the next generation
o Could be measured in terms of individuals (how many descendants an
individual has in the next generation – or in two generations). This would be a
measure of the fitness of an entire genotype.
o Could be measured in terms of alleles. (How many copies of an allele are
present in the next generation).
▪ Due to epistasis – measured as the average over all the genotypes
carrying the allele?
o Could even be measured in terms of culture. (how many people in the next
generation share an idea or a technological innovation.)
4 necessary conditions for natural selection to act:
1) Variation in the trait of interest
2) Variation is heritable
3) Variation in fitness (reproductive success)
4) A correlation between the trait and fitness
Assortative mating – the tendency of similar individuals to mate with each other. This will
drive a deviation from the Hardy-Weinberg equilibrium by preventing random association of
gametes and increasing the frequency of homozygotes above expected levels.
Natural selection will favour alleles that increase future reproductive output.
,Tijmen Lourens Summary Evolutionary Medicine
Genetic Drift:
- Population size is an important determinant of the strength of selection
- Random events (genetic drift) are less important, and selection is more efficient, in
large populations
Lecture 2: Evolutionary Thinking in Human Health
Evolutionary processes resulting in sub-optimal outcomes:
1) Selection is too slow
a. Mismatch between design and environment
i. Hunter-gatherers were exposed to periodic famines and food
shortages interspersed with periods of high food availability.
ii. This results in alleles maximizing metabolic efficiency, lipid storage and
highly motivated food-searching behaviours
iii. Now, with a chronic mild excess of calories, these alleles may be
maladaptive as they lead to diabetes, obesity and cardiovascular
disease
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
i. Genes promoting rapid growth and early reproductive activity in an
individual, will also promote poor old-age health and early death in
the same individual (in female macaques)
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
Lecture 3: More on Natural Selection
Types of selection:
- Advantageous – increases fitness of carriers
- Deleterious – reduces fitness of carriers
- Neutral – no effect on fitness
Positive selection = diversifying selection (allele spreads over population)
Negative selection = purifying selection (allele reduces over population)
Genetic drift = natural selection has no effect on the new mutant allele because it soes not
influence fitness.
,Tijmen Lourens Summary Evolutionary Medicine
Males seem to have a slightly lower recombination rate why?
Exam question: Selective sweep: a process by which a new advantageous mutation
eliminates or reduces variation in linked neutral sites as it increases in frequency in the
population.
Selective sweep = a method to detect natural selection.
- Gene region CPT1A is found all around the northern spheres (70% of the Inuit has it)
- Not found anywhere else in the world
- Really homologous for the Inuit (very little genetic diversity)
o CPT1A encodes the rate limiting gene for fatty oxidation in the liver, which
regulates energy balance and protects the liver during fasting
o Allele is associated with hypoketotic hypoglycaemia and high infant mortality
▪ The benefits in terms of metabolism outweigh the costs in terms of
infant mortality
▪ High levels of infant mortality are associated with adoption of a
western diet in this population but were originally absent (mismatch)
Genomic regions with suppressed genetic diversity due to selective sweeps are enriched
with deleterious (DEL) mutations in compared to neutral.
Detecting selection: nonsynonymous / synonymous substitution
- Mutations that result in a change to the amino acid produced
o Visible to natural selection
- Mutation that results in no change in the amino acid produced
o Invisible to natural selection
The rate of synonymous substitution (dS) tells us about the background rate of fixation of
mutants in the absence of natural selection. We can compare this with the rate of
nonsynonymous substitution to detect natural selection.
- If dN/dS > 1 = then natural selection must be favouring the spread of new variants in
the population → positive / diversifying selection
- If dN/dS < 1 then natural selection must be eliminating new variants in the
population → negative / purifying selection. Happens in most species.
Levels of selection: all suffice the requirements for selection
- Individuals
- Cells
- Genes
- Families
- Genomes
, Tijmen Lourens Summary Evolutionary Medicine
Lecture 4: Genetic Conflict
Conflict between mitochondrial and nuclear genomes:
Natural selection favours cells that maintain the integrity of their nuclear genome. But
natural selection also favours mitochondria that divide as rapidly as possible (because such
genes will be over-represented in the next generation of mitochondria). As we shall see, this
results in a conflict of interest!
Selection for rapid mitochondrial division has resulted in the mitochondrion shrinking over
time in all species.
- Original ancestor had 1000-10,000 genes, the largest mitochondrion has around 100
genes, and the human mitochondrion has just 37 genes.
- Many genes present in original endosymbiont were not relevant during symbiosis
since the needs of the mitochondrion are provided by the cell. These genes were lost
over evolutionary time.
- Some genes present in original endosymbiont were still necessary for mitochondrial
survival but occasional mutational events transferred these genes into the nuclear
genome.
- Once a mitochondrial gene is incorporated into nuclear genome, it’s no longer
required in mitochondrial genome → degrades by genetic drift and selection
favouring mitochondria that duplicate more rapidly.
- NUMT = Nuclear mitochondrial gene –
o NUMTs inserted into functional regions of the genome are known to be
associated with various genetic diseases.
Parent-offspring conflict: the larger you are at birth, the better your chances of surviving.
However, it is harder for your mom to give birth to you.
- To maximize fetal survival probability, mother invests 0.6 units of energy
- If a mother has 6 units of energy to invest in a brood, she could invest 0.6 each into a
total of 10 surviving offspring.
- But if she invests 0.2 units of energy per offspring, she could have 30 babies. Each
would have a 0.42 probability of survival, resulting in an expected 12.6 surviving
offspring!
Baby decides whether the pregnancy continues – Parent-offspring conflict.
1) Invasion of the placenta into the uterine wall
o Allows fetus to prevent cut-off of blood flow (modify spiral arteries), access
maternal blood efficiently
2) Fast food for baby
o Amount of food depends on glucose levels in maternal blood. You want more
than mom wants to give you. Insulin keeps blood sugar from getting
dangerously high. hPl (placental lactogen) blocks (bonds) maternal insulin.
o Mother seems to be partially diabetic during pregnancy
3) More blood please!
o Amount of food also depends on maternal blood pressure – you want mom’s
blood pressure to be higher.
