Evolutionary Medicine, Genetics, and Phenotypic Variation: Key Concepts and Frameworks

Evolutionary medicine (definition)

A discipline combining evolutionary biology and medicine to explain why the body remains vulnerable to disease, using evolutionary biology to inform medicine and disease patterns to advance evolutionary biology.

Proximate explanation

A "how" explanation for a trait.

Ultimate explanation

A "why" explanation for a trait.

Mechanism (Tinbergen, proximate)

The molecular, cellular, or biological mechanism underlying a trait.

Ontogeny (Tinbergen, proximate)

How a trait changes over an organism's lifetime, shaped by genes and experience.

Adaptive value (Tinbergen, ultimate)

Why a trait was built this way and selected for; how it increases fitness.

Phylogeny (Tinbergen's four questions)

The evolutionary history that produced a trait, and its vulnerabilities.

Tinbergen's Four Questions

A framework originally developed for ethology, adapted by evolutionary medicine into two proximate questions (mechanism, ontogeny) and two ultimate questions (adaptive value, phylogeny); complementary, not competing.

Fever - proximate question

How do immune signals alter hypothalamic temperature regulation?

Fever - ultimate question

Why did a costly rise in body temperature evolve, and when might it be protective?

Why fever may be protective

Higher body temperature speeds up white blood cell movement, lymphocyte activation, and cytokine production.

Founders of evolutionary medicine

George Williams (evolutionary biologist) and Randolph Nesse (physician), who formalized the field in the early 1990s.

"Nothing in biology makes sense except in the light of evolution."

Quote by Theodosius Dobzhansky (1973).

Key framework: what does natural selection maximize?

Reproductive success, NOT health.

Why the strength of selection declines with age

Older individuals contribute less to future generations, so selection is less effective at removing harmful variants that act late in life.

Nesse's quote on reproduction vs. health

"Where there is a conflict between reproductive success and health, reproduction always wins out."

Key framework: "evolution works with what it has"

New adaptations are built on top of ancient, already-constrained biological systems rather than starting from scratch.

Example: "ages of origin" of biological features

Metabolism arose ~3900-1600 Mya; bipedalism arose only ~6 Mya — illustrating how present-day traits are layered on top of ancient ones.

Key framework: disease vulnerability has a deep evolutionary history

Many genes/pathways underlying present-day disease trace back far earlier in the tree of life than the disease itself.

Mismatch hypothesis

Traits that evolved to be advantageous in ancestral environments may no longer be advantageous (or may be harmful) in modern environments.

Examples of proposed "mismatch" diseases

Acid reflux, metabolic syndrome, myopia, atherosclerosis, type 2 diabetes, gout, and osteoporosis (Gurven & Lieberman 2020).

Axial myopia

Nearsightedness caused by the eye growing too long during childhood, so the focal point of light falls in front of, rather than on, the retina.

Holm (1937) myopia study

Found myopia in only 0.4% of eyes examined among hunter-gatherers in Gabon.

Skeller (1954) myopia study

Found myopia in only 1.2% of eyes examined among Angmagssalik Inuit.

Modern myopia prevalence

The greatest cause of vision impairment globally; nearly half the world's population is projected to be nearsighted by 2050 (Holden et al. 2016).

Young et al. (1969) - pre-schooling generation

Alaskan Eskimos born 1880-1927 (before formal schooling) had only 1.5% myopia prevalence.

Young et al. (1969) - post-schooling generation

Alaskan Eskimos born after formal schools were established in 1932 had 51% myopia prevalence (ages 11-40) — same population, one generation later.

"Retina-defocus" hypothesis (myopia)

The eye grows to match the focal plane of images hitting the retina; defocused signals from near/close objects induce axial elongation via a feedback loop.

"Indoor light" hypothesis (myopia)

Reduced outdoor light exposure (more time indoors) promotes eye elongation and myopia; more outdoor light is protective.

Quiz: does natural selection eventually eliminate traits that harm health?

No — selection acts on reproductive fitness, not health, so a trait that hurts health can persist if it doesn't reduce reproduction.

Quiz: why does the rapid rise in myopia (to >50% within ~1 generation) support a mismatch explanation?

The increase happened far too quickly to be explained by genetic evolution, pointing to environmental/lifestyle change instead.

Quiz: which fever question is "ultimate"?

"Why did a costly increase in body temperature evolve, and under what conditions might it be beneficial?" (the "how do immune signals raise temperature" question is proximate).

Phenotype

An observable or measurable characteristic of an organism.

Health and disease as phenotypes

Health and disease are themselves phenotypes, which is why evolutionary medicine needs to explain why phenotypic variation exists.

Quantitative genetics

The study of how genetic and environmental variation contribute to variation in phenotypes within populations.

Molecular genetics

The study of the specific genes, genetic variants, and molecular mechanisms that produce phenotypes.

Mendelian trait

A trait controlled by one or a few genetic loci with dominant and recessive alleles, where the dominant allele masks the recessive allele's effect.

Additive genetic effect

Each allele contributes independently to a phenotype; the heterozygote is typically intermediate between the two homozygotes.

Genetic architecture of most human phenotypes

Quantitative, continuous, complex, and largely additive/polygenic (not simple Mendelian traits).

Francis Galton - contributions

Studied continuous traits like height using resemblance among relatives; pioneered correlation and regression toward the mean; helped found quantitative genetics.

Francis Galton - eugenics

Also founded the eugenics movement, applying ideas about heredity to selective human reproduction, with major harmful scientific and social consequences.

Genetic determinism

The idea that a person's life situation is determined by genetics rather than environment/experience/social inequity — historically used to justify slavery, colonialism, and racism.

R.A. Fisher's variance equation

Vp = Vg + Ve

Vp (Fisher's equation)

Phenotypic variance; the total variation observed in a trait.

Vg (Fisher's equation)

Genetic variance; differences caused by genetic variation between individuals.

Ve (Fisher's equation)

Environmental variance; differences caused by environment (nutrition, stress, disease, education, climate, etc.).

R.A. Fisher - eugenics

Like Galton, Fisher was also a prominent supporter of eugenics.

Broad-sense heritability (H²)

The proportion of phenotypic variance due to ALL genetic variance combined.

Components of broad-sense heritability

Additive effects (alleles add independently), dominance (effects depend on allele combos at the same locus), and epistasis (effects depend on interactions between different loci).

Narrow-sense heritability (h²)

The proportion of phenotypic variance due specifically to ADDITIVE genetic variance (VA).

What narrow-sense heritability predicts

How well offspring resemble their parents, and how a population will respond to selection.

Why narrow-sense heritability matters for disease evolution

Disease-related traits can evolve only to the extent that relevant phenotypic differences have a heritable (additive genetic) component AND affect fitness.

Estimating heritability with twins

Monozygotic (MZ) twins share ~100% of genetic variation; dizygotic (DZ) twins share ~50% on average; greater similarity in MZ vs. DZ twins is evidence of genetic variance.

Estimating heritability with parent-offspring regression

Comparing average parent phenotype to offspring phenotype; a strong correlation indicates high heritability.

Misconception: heritability = "caused by genes"

False — heritability is a population-level statistic about variance in a specific population/environment, NOT a statement about what fraction of one person's phenotype is "caused by genes."

Misconception: high heritability means environment doesn't matter

False — high heritability does NOT mean the environment is unimportant.

Misconception: low heritability means genes don't matter

False — low heritability does NOT mean genes are biologically unimportant.

Heritability is population/environment-specific

Heritability estimates for the same trait can vary across time and across populations (e.g., shown in millions of Danish twins, Auning et al. 2026); it is not a fixed, universal number.

Genotype × Environment (GxE) interaction

When the effect of a genotype on a phenotype depends on the environment in which it is expressed.

Reaction norm

Describes how a single genotype expresses different phenotypes across varying environmental conditions.

When do reaction norms indicate GxE?

When reaction norms for different genotypes cross (are not parallel).

Phenotypic plasticity

The ability of a single genotype to produce different phenotypes in different environments.

Quantitative trait locus (QTL)

A stretch of DNA statistically associated with differences in a phenotype (e.g., height, blood pressure, disease risk).

Genetic architecture (definition)

The underlying genetic basis of a trait: how many variants affect it, how large their effects are, and how those variants interact.

Monogenic trait

Variation at one gene has a major effect.

Oligogenic trait

A relatively small number of loci contribute important effects.

Polygenic trait

Many loci each contribute small effects; most common complex diseases (blood pressure, obesity, type 2 diabetes, asthma, depression) are polygenic.

Type 1 vs. Type 2 diabetes (genetic architecture)

Type 1 involves fewer loci with relatively larger effects (more oligogenic); Type 2 involves many loci with individually small effects (highly polygenic).

Key takeaway: genes and environment don't simply "add up"

Disease risk is shaped by genetics, environment, AND their interaction (GxE) together; rapid environmental shifts can change disease patterns via plasticity without any genetic (evolutionary) change.

Quiz: what does a heritability of 0.70 mean?

70% of the phenotypic variation in that particular population, at that time, is associated with (additive) genetic differences among individuals — NOT that 70% of any one person's trait is genetic.

Quiz: GxE interaction example

Two genotypes have similar disease risk in environment A, but genotype 1 has substantially higher disease risk than genotype 2 in environment B.

Quiz: genetic architecture of most complex diseases

Most common, complex human diseases are influenced by many genetic variants, each with a relatively small effect (a polygenic architecture).

Evolution (Darwin's definition)

"Descent with modification": inherited traits change over time.

Darwin and the theory of evolution

Formally proposed by Charles Darwin in 1859, though he had been developing the idea since at least 1837.

Evolution (genetic definition)

A change in allele frequency in a population over time.

Hardy-Weinberg equilibrium

A principle stating that allele and genotype frequencies in a population will remain constant across generations if certain assumptions are met (no mutation, random mating, no gene flow, no drift, no selection).

Violating Hardy-Weinberg assumptions

Means the population may be evolving (allele frequencies may be changing).

Five evolutionary processes that change allele frequencies

Mutation, non-random mating, gene flow/migration, genetic drift, and natural selection.

Mutation (evolutionary process)

The generation of new alleles from one generation to the next (germline or de novo).

How many de novo mutations does each person have?

Roughly 60.

Why mutation changes allele frequencies only subtly

Mutations occur at low frequency, and most are neutral (no fitness effect) or only mildly deleterious, so they don't easily persist or spread.

Mutation and human disease

Most complex diseases are driven by common variants already circulating in the population (polygenic), not single de novo mutations, though de novo mutations can still cause rare disease.

Non-random mating

Individuals are more or less likely to mate with one another than expected by chance, based on their traits or genotype.

Effect of non-random mating

Often alters genotype distributions more than allele frequencies.

Assortative mating

A form of non-random mating in which individuals with similar phenotypes are more likely to mate with each other.

Assortative mating in humans

Weakly documented (e.g., some evidence for height; Robinson et al. 2017), not a major driver of allele frequency change.

Gene flow

Any movement of alleles into or out of a population, via migration or admixture.

Migration (as an evolutionary process)

The movement of individuals from one population to another.

Admixture (as an evolutionary process)

The mixing of previously differentiated populations, resulting in individuals with ancestry from multiple populations.

Effect of gene flow WITHIN a population

Can introduce or reintroduce alleles, increasing genetic variation.

Effect of gene flow BETWEEN populations

Makes distant populations more genetically similar to one another, reducing divergence.

Gene flow and human disease

Human populations are rarely completely isolated, so continual gene flow means there are very few population-specific disease alleles.

Genetic drift

Random changes in allele frequency due to chance ("sampling error") in which alleles are passed to the next generation.

Genetic drift and population size

Random fluctuations in allele frequency are greater in smaller populations.

What genetic drift does to genetic variation

Causes genetic variation to be lost, and can cause initially identical populations to become different from each other over time.

Founder effect

A type of genetic drift where a new colony is started by a few members of the original population, so the new population has only a sample of (reduced) genetic variation.

Serial founder effect in humans

As humans spread across the globe in successive waves, repeated founder events/bottlenecks made genetic drift an important force in human evolutionary history (Henn et al. 2011).

Natural selection (evolutionary process)

Differential survival/reproduction of individuals based on heritable trait differences.

What determines how much phenotypic change selection produces?

Both the strength of selection AND the heritability of the trait.

Selection differential (S)

The difference between the mean phenotype of the whole population and the mean phenotype of individuals who reproduce (e.g., S = 5 cm if population mean height is 170 cm and reproducing individuals' mean is 175 cm).