Evolutionary Medicine, Genetics, and Phenotypic Variation: Key Concepts for Biology and Medicine

Evolutionary medicine

Uses evolutionary biology to explain why humans remain vulnerable to disease and to complement proximate medical explanations.

Proximate explanation

Explains HOW a trait works through its immediate mechanism or development.

Ultimate explanation

Explains WHY a trait exists by considering its adaptive value and evolutionary history.

Mechanism

A proximate explanation describing the molecular, cellular, physiological, or biological processes underlying a trait.

Ontogeny

A proximate explanation describing how a trait develops or changes across an organism's lifetime through genes and experience.

Adaptive value

An ultimate explanation asking how a trait affected fitness and why natural selection may have favored it.

Phylogeny as an ultimate explanation

Explains how a trait and its vulnerabilities arose through evolutionary history.

Why are proximate and ultimate explanations complementary?

They answer different questions about the same phenotype; understanding mechanism does not explain why evolution produced that vulnerability.

Natural selection does not maximize health

Natural selection favors traits that increase reproductive success, even if they reduce health or survival in other ways.

Why does the strength of natural selection decline with age?

Effects occurring after most reproduction contribute less to differences in reproductive success and are therefore exposed to weaker selection.

Evolutionary mismatch hypothesis

Traits that were advantageous or neutral in past environments can become disadvantageous after environmental conditions change, especially when change is rapid.

Myopia

A condition in which images focus in front of the retina, usually because the eye is too long, causing distant objects to appear blurry.

Why is myopia consistent with evolutionary mismatch?

Its prevalence can rise dramatically within a generation after lifestyle change, too quickly to be explained by genetic evolution alone.

What does the myopia example show about genes versus environment?

A phenotype can be heritable while still changing greatly when the environment changes.

Phenotype

An observable or measurable characteristic of an organism; health and disease can both be phenotypes.

Phenotypic variation

Differences in observable or measurable traits among individuals.

Quantitative genetics

Study of how genetic and environmental variation contribute to phenotypic variation within populations.

Molecular genetics

Study of specific genes, genetic variants, and molecular mechanisms that produce phenotypes.

Mendelian trait

A trait largely controlled by one or a few loci, often involving dominant and recessive alleles.

Complex trait

A phenotype influenced by many genetic variants plus environmental factors, usually producing quantitative or continuous variation.

Polygenic trait

A trait influenced by many genetic loci.

Additive genetic effect

Each allele contributes independently to the phenotype, so effects can be summed across alleles.

Dominance

Genetic effects depend on which alleles occur together at the same locus.

Epistasis

Genetic effects depend on interactions among alleles at different loci.

Genetic determinism

The incorrect or oversimplified idea that genes rigidly determine an individual's phenotype independent of environment and experience.

Phenotypic plasticity

The ability of the same genotype to produce different phenotypes in different environments.

G×E interaction

A genotype-by-environment interaction in which the effect of genotype on phenotype depends on the environment.

Reaction norm

The pattern of phenotypes produced by a particular genotype across different environments.

How can reaction norms reveal G×E interaction?

Nonparallel or crossing reaction norms show that genotypes respond differently to environmental change.

Phenotypic variance

Total observed variation in a phenotype within a population.

Genetic variance

Phenotypic variation attributable to genetic differences among individuals.

Environmental variance

Phenotypic variation attributable to differences in individuals' environments.

Broad-sense heritability

The proportion of phenotypic variance attributable to all genetic variance, including additive, dominance, and epistatic effects.

Narrow-sense heritability

The proportion of phenotypic variance attributable specifically to additive genetic effects.

Why is narrow-sense heritability important for evolution?

Additive genetic effects are predictably inherited, so narrow-sense heritability helps determine a population's response to selection.

High heritability does NOT mean what?

It does not mean the environment is unimportant, the trait is genetically determined, or the phenotype cannot be changed.

Why is heritability population-specific?

It describes variation within a particular population and set of environments, so it can differ across populations, places, and times.

Genetic architecture

The underlying genetic basis of a trait, including how many variants affect it and their frequencies, effect sizes, and interactions.

Breeder's equation

R = h²S; evolutionary response to selection depends on narrow-sense heritability and the strength of selection.

Response to selection (R)

The expected change in a population's mean phenotype between generations due to selection.

Selection differential (S)

Difference between the mean phenotype of selected reproducing individuals and the original population mean.

Evolution

A change in allele frequencies in a population over time.

Hardy-Weinberg equilibrium

Genetic variation remains constant across generations when evolutionary forces such as selection, drift, mutation, migration, and nonrandom mating are absent.

Five major evolutionary processes

Mutation, nonrandom mating, gene flow, genetic drift, and natural selection.

Mutation

Generation of new alleles, including new germline or de novo variants.

Why is mutation usually a weak short-term force on allele frequencies?

New mutations are individually rare, and most are neutral or mildly deleterious rather than strongly beneficial.

Common versus rare genetic variation in disease

Most complex diseases are highly polygenic and influenced mainly by common existing variants, while rare de novo mutations can cause some rare diseases.

Nonrandom mating

Individuals mate more or less often than expected by chance based on phenotype or genotype.

Assortative mating

A form of nonrandom mating in which individuals with similar phenotypes are more likely to mate.

What does nonrandom mating often change most directly?

Genotype frequencies, although under some circumstances it can also contribute to evolutionary change.

Gene flow

Movement of alleles into or out of populations through movement and reproduction.

Migration

Movement of individuals from one population to another, which can cause gene flow if migrants reproduce.

Admixture

Genetic mixing between previously differentiated populations.

Effect of gene flow within a population

Can introduce or reintroduce alleles and increase genetic variation.

Effect of gene flow between populations

Tends to reduce genetic differentiation by moving alleles among populations.

Introgression

Movement of genetic variants from one species or differentiated lineage into another through interbreeding and subsequent reproduction.

Genetic drift

Random change in allele frequencies caused by chance rather than differences in fitness.

How does population size affect genetic drift?

Drift is stronger in small populations, causing larger random changes in allele frequency and faster loss or fixation of variation.

Founder effect

Genetic drift occurring when a new population is established by a small number of individuals carrying only a subset of the original population's variation.

Serial founder effect in human history

Repeated founder events during human expansion reduced genetic diversity and changed allele frequencies among populations.

Natural selection

Differential survival and reproduction associated with heritable variation, causing fitness-enhancing variants to increase in frequency.

Fitness

An individual's genetic contribution to future generations through survival and reproduction.

Why is not every human genetic difference an adaptation?

Mutation, drift, founder effects, gene flow, and demographic history can change allele frequencies without natural selection.

Local adaptation

Evolution of traits or alleles that increase fitness in a particular local environment.

Adaptive introgression

Introgressed genetic variation that subsequently increases in frequency because natural selection favors it.

Huerta-Sánchez et al. Tibetan EPAS1 paper: central question

Did Tibetans acquire the high-altitude-associated EPAS1 haplotype through archaic introgression, followed by natural selection?

Huerta-Sánchez et al. Tibetan EPAS1 paper: main finding

The Tibetan EPAS1 haplotype is highly similar to Denisovan-like DNA and likely entered modern humans through archaic introgression before rising through selection.

Huerta-Sánchez et al. Tibetan EPAS1 paper: EPAS1 phenotype

Derived EPAS1 variants are associated with lower hemoglobin levels at high altitude, limiting excessive increases in blood viscosity.

Huerta-Sánchez et al. Tibetan EPAS1 paper: why aren't Tibetan-Han allele-frequency differences alone proof of selection?

Drift, founder effects, and demographic history can also generate allele-frequency differences, so additional evidence of selection is required.

Huerta-Sánchez et al. Tibetan EPAS1 paper: evidence for introgression

The unusual selected haplotype is shared with Denisovans, is common in Tibetans, rare in Han, and its pattern is unlikely to result from incomplete ancestral lineage sorting.

Huerta-Sánchez et al. Tibetan EPAS1 paper: evolutionary medicine significance

Different evolutionary histories can produce genetic differences that alter physiological responses and health consequences in the same environment.

Constraint

Anything that limits the range of phenotypes evolution can produce.

Physical, chemical, or biological constraint

Limits imposed by properties of the physical or biological world that natural selection cannot simply overcome.

Phylogenetic constraint

Evolutionary change is limited because inherited features of a lineage restrict which phenotypes can readily evolve.

Why can't natural selection create a perfectly optimized organism?

Selection can act only on available variation and is limited by constraints, trade-offs, conflicts, and historical contingency.

Trade-off

Improving fitness through one trait or function imposes a cost on another trait or function.

Physical trade-off

Improving one physical property necessarily compromises another because of structural or mechanical limitations.

Energetic trade-off

Limited energy invested in one biological function cannot simultaneously be invested in another.

Genetic correlation

Two traits are genetically linked because some of the same genetic variation influences both, potentially constraining independent evolution.

Pleiotropy

A single gene or genetic variant affects multiple phenotypic traits.

Antagonistic pleiotropy

A genetic variant has multiple fitness effects that oppose one another, such as increasing fitness early in life while causing costs later.

Why can antagonistic pleiotropy maintain disease-associated alleles?

Early reproductive benefits can be strongly favored even when the same allele causes health costs later in life.

Evolutionary conflict

Two parties influence the same trait but have different fitness-maximizing outcomes.

Torres-Tamayo et al. cephalopelvic-fit paper: traditional obstetrical dilemma

Human childbirth was thought uniquely difficult because selection for bipedalism constrained pelvic dimensions while large brains increased neonatal head size.

Torres-Tamayo et al. cephalopelvic-fit paper: methodological problem with earlier comparisons

Human-centered measurements underestimated obstetric constraints in other primates, so the study used species-specific 3D measurements.

Torres-Tamayo et al. cephalopelvic-fit paper: main finding

Humans have the tightest cephalopelvic fit among living apes but are not unique across primates; some other primates have even more extreme proportions.

Torres-Tamayo et al. cephalopelvic-fit paper: broader lesson

Apparent human uniqueness can disappear when comparative analyses use measurements appropriate to each species rather than assuming humans are the standard.

Phylogeny

Representation of the evolutionary history and relationships among groups of organisms.

Most recent common ancestor (MRCA)

The most recent ancestor from which all members of a specified group directly descend.

How should a phylogenetic tree be read?

Relatedness is determined by shared branching ancestry, not by how close species names appear on the page.

Do rotations of branches change a phylogeny?

No; branches can be rotated around nodes without changing the evolutionary relationships represented.

Derived trait

A trait that evolved from the ancestral state within a lineage.

Phylogenetic comparative methods

Statistical methods that use phylogenies to test hypotheses while accounting for shared evolutionary history.

Why aren't species independent data points?

Closely related species inherit traits from common ancestors, so similarities may reflect shared ancestry rather than independent adaptation.

Why control for phylogeny in comparative studies?

To distinguish patterns caused by shared ancestry from those associated with independent evolutionary changes or adaptation.

Peto's paradox

Across species, cancer risk does not increase as dramatically with body size and lifespan as expected from the greater number of cells and cell divisions.

Abegglen et al. elephant cancer paper: central question

What mechanisms may explain elephants' unexpectedly low cancer risk, and how do elephant cells respond to DNA damage compared with human cells?

Abegglen et al. elephant cancer paper: TP53 finding

African elephants had at least 20 TP53 copies, whereas humans have one copy with two alleles.

Abegglen et al. elephant cancer paper: cellular finding

Elephant lymphocytes underwent substantially more p53-mediated apoptosis after DNA damage than healthy human cells.

Abegglen et al. elephant cancer paper: proposed mechanism

Expanded TP53 copy number may increase removal of DNA-damaged cells through apoptosis and contribute to elephant cancer resistance.