Heterozygote advantage is a powerful exception to the idea that natural selection always removes harmful alleles. By favoring heterozygotes, selection can maintain genetic variation and stable allele frequencies within populations across generations.

Core concept: heterozygote advantage and fitness

What heterozygote advantage means

Heterozygote advantage occurs when individuals with two different alleles at a locus (e.g., $A a$) have higher fitness than either homozygote ($A A$ or $a a$).

Diagram illustrating overdominance in the sickle-cell system by mapping genotype to phenotype and relative fitness. The heterozygote ($Aa$) is shown with the highest fitness because it gains malaria resistance without the severe pathology of sickle-cell disease seen in the $aa$ homozygote. This is a concrete example of the fitness ranking $w_{Aa} > w_{AA}$ and $w_{Aa} > w_{aa}$. Source

This pattern is a type of balancing selection because it tends to preserve multiple alleles in the gene pool rather than eliminating one.

Fitness in an evolutionary (AP Bio) sense

Fitness is evaluated by reproductive success, not strength or size, and it depends on the environment.

Because relative fitness compares genotypes, it is often scaled so that the highest-fitness genotype has $w = 1$.

How heterozygote advantage maintains variation

Selection does not always reduce diversity

If both homozygotes are selected against (each for different reasons), neither allele is consistently eliminated. Instead, the heterozygote is favored, which can maintain a stable polymorphism (two or more alleles persisting in a population).

Schematic showing how overdominance (heterozygote advantage) can generate stable equilibrium allele frequencies (labeled as $\hat{p}$ and $\hat{q}$) under a given set of genotype fitnesses. It contrasts a case where populations share the same overdominant fitness regime with a case where fitness values differ between populations, shifting the equilibrium frequencies. This helps connect genotype fitness differences to population-level outcomes like maintained polymorphism and equilibrium allele frequencies. Source

Key outcomes:

• Both alleles remain in the population because each allele is “protected” when rare by appearing in heterozygotes.

• Allele frequencies can approach an equilibrium where the gain in heterozygotes offsets losses in homozygotes.

• Genotype frequencies may deviate from Hardy–Weinberg expectations if selection is acting strongly (especially if fitness differences are large).

Why environment matters

Heterozygote advantage is often context-dependent:

• In one environment, $A a$ may have the highest fitness; in another, the advantage may disappear or reverse.

• Spatial or temporal variation (different habitats or changing conditions) can help preserve the advantage over time.

Classic biology example (conceptual)

A well-known case involves a disease-resistance tradeoff:

• One homozygous genotype may be vulnerable to an infectious disease.

• The other homozygous genotype may suffer a genetic disorder or reduced survival.

• The heterozygote may avoid the worst effects of both, producing the highest reproductive output in that environment.

This illustrates why selection can maintain an allele that is harmful in one genotype (often a homozygote) if it provides an advantage in heterozygotes.

Evidence and reasoning patterns students should use

When evaluating a heterozygote advantage claim, look for:

• Fitness ranking: $w_{A a} > w_{A A}$ and $w_{A a} > w_{a a}$.

• Persistence of both alleles: neither allele trends to fixation under the same conditions.

• Tradeoffs: each homozygote has a distinct disadvantage (e.g., disease susceptibility vs. physiological cost).

• Population-level consequence: maintained genetic variation, which can increase the ability of a population to respond to future environmental changes.