The simple model of polygenic inheritance, where multiple genes contribute to a trait, can be refined by considering how these genes interact. For many quantitative traits, the effects of different alleles are additive, meaning each allele contributes a small, cumulative amount to the final phenotype. For example, consider kernel color in wheat, which is controlled by several genes. Alleles that produce red pigment contribute to the color’s intensity, so a plant with more “red” alleles will have darker kernels, while one with fewer will have lighter kernels. An individual kernel’s final color is the sum of these small effects, which helps explain the continuous range of colors observed in a population.

However, the path from genotype to phenotype for polygenic traits can be complicated by non-additive interactions between genes.

Pleiotropy

Some genes affect more than one phenotypic trait. This is called pleiotropy. There are numerous examples of pleiotropy in humans. They generally involve important proteins that are needed for the normal development or functioning of more than one organ system. An example of pleiotropy in humans occurs with the gene that codes for the main protein in collagen, a substance that helps form bones. This protein is also important in the ears and eyes. Mutations in the gene result in problems not only in bones but also in these sensory organs, which is how the gene’s pleiotropic effects were discovered.

Another example of pleiotropy occurs with sickle cell anemia. This recessive genetic disorder occurs when there is a mutation in the gene that normally encodes the red blood cell protein called hemoglobin. People with the disorder have two alleles for sickle-cell hemoglobin, so named for the sickle shape (Figure 2) that their red blood cells take on under certain conditions such as physical exertion. The sickle-shaped red blood cells clog small blood vessels, causing multiple phenotypic effects, including stunting of physical growth, certain bone deformities, kidney failure, and strokes.

Dive Deeper

There are lots of examples of pleiotropy in the natural world, including in humans. Learn more about pleiotropy in the following article.

Pleiotropy: One Gene Can Affect Multiple Traits ( Lobo, I. 2008. Nature Education)

Epistasis

In other instances, genes can interact in a way where one gene masks or modifies the phenotypic effect of another. This type of interaction is called epistasis. “Epistasis” is a word composed of Greek roots meaning “standing upon.” The alleles that are being masked or silenced are said to be hypostatic to the epistatic alleles that are doing the masking. Often the biochemical basis of epistasis is a gene pathway in which the expression of one gene is dependent on the function of a gene that precedes or follows it in the pathway.

A classic example of epistasis is coat color in house mice. One gene determines the kind of pigment pattern expressed in the fur (agouti banding or a solid black coat), while a second gene controls whether any pigment is produced at all. If a mouse carries the combination that prevents pigment production, its coat will be white (albino) regardless of whether the first gene specifies agouti or solid black. In this case, the pigment-production gene is epistatic to the pigment-pattern gene, effectively overriding its instructions and altering the expected phenotypes (Figure 3).

Connections to Human Health

Epistatic interactions can contribute to complex diseases in humans. Read the following article to learn about how epistasis was discovered to play critical role in the genetics of the neurodegenerative disease Alzheimer’s.

Epistasis: Gene Interaction and the Phenotypic Expression of Complex Diseases Like Alzheimer’s ( Lobo, I. 2008. Nature Education)

 

Environmental effects on phenotypic variation

While the combined action of many genes explains how continuous variation can arise from discrete genetic units, it is only part of the story. The relationship between genotype and phenotype is further complicated by the fact that genes do not operate in a vacuum. The environment in which an organism develops and lives implicitly plays a role in shaping the final outcome of its traits. Most phenotypes in nature are not determined solely by genotype. Instead, they result from complex interactions between an individual’s genetic makeup and the environment.  In other words, it’s not nature vs. nurture, its nature and nurture. Traits influenced by multiple factors—including various genes and environmental variables—are known as multifactorial traits.

This means that even individuals with the same genotype can exhibit different phenotypes under varying environmental conditions.

Multifactorial traits can be conceptualized using the following relationship:

Genotype × Environment ⇒ Phenotype (G × E ⇒ P)

This equation emphasizes that the phenotype is not just a product of the genotype alone but arises from the dynamic interplay between genetic potential and environmental influences.

Many common diseases are multifactorial, influenced by both genetic predispositions and environmental exposures. For instance, certain alleles may increase an individual’s susceptibility to developing type 2 diabetes, but lifestyle factors such as diet, physical activity, and body weight heavily influence whether the disease actually manifests. This means that individuals with a genetic predisposition can potentially prevent or delay the onset of the disease by adopting healthier lifestyle choices.

Similarly, cancer development is often a multifactorial process. While some cancers are driven by inherited genetic mutations (e.g., BRCA1 and BRCA2 genes associated with breast cancer), many others result from interactions between genetic susceptibilities and environmental exposures to carcinogens. For example, a person with a genetic predisposition to lung cancer may only develop the disease if they are exposed to carcinogens like tobacco smoke or air pollutants. Therefore, not all individuals with the susceptibility genotype will develop the cancer phenotype; environmental factors play a key role in determining the outcome.

In agriculture, understanding genotype-environment interactions is essential for improving crop yields and livestock productivity. Farmers and breeders select for genotypes that perform well under specific environmental conditions. For example, developing drought-resistant crop varieties involves selecting plants with genotypes that allow them to thrive in arid conditions. However, even the best genotypes may fail to produce optimal phenotypes if environmental conditions are unfavorable, such as poor soil quality or extreme temperatures.

This genotype-environment interaction is particularly significant for polygenic traits, which are controlled by multiple genes, each contributing a small effect to the phenotype. For example, skin color in humans is a polygenic trait with a wide range of variation among individuals and populations worldwide. Genetic differences in melanin production and distribution account for much of this diversity. However, environmental exposure to ultraviolet (UV) radiation from sunlight can also affect skin color by stimulating the production of melanin, the pigment responsible for skin coloration. This process, known as tanning, is a protective response against DNA damage caused by UV light. As illustrated in Figure 2, increased exposure to UV light leads to the darkening of the skin, demonstrating how the environment can influence phenotype by modulating gene expression.

Environmental factors can influence phenotypes not only by interacting with genetic predispositions but also by affecting gene expression through mechanisms such as epigenetics. Epigenetic modifications involve changes in gene activity without altering the underlying DNA sequence. These modifications can be triggered by environmental factors like diet, stress, and exposure to toxins, leading to changes in how genes are expressed.

An illustrative case is the Dutch Hunger Winter of 1944–1945, where severe famine conditions led to long-term health effects in individuals who were in utero during the famine. Studies have shown that these individuals had epigenetic changes in genes related to growth and metabolism, resulting in increased rates of obesity, cardiovascular disease, and other health issues in adulthood. This example underscores the significant impact that environmental factors can have on gene expression and phenotype, even across generations.

Another important concept in understanding genotype-environment interactions is the norm of reaction, which describes the range of phenotypes that can be produced by a single genotype under different environmental conditions. This concept highlights the idea of phenotypic plasticity, the ability of an organism to alter its phenotype in response to environmental changes (Figure 3).

For example, the water flea Daphnia can develop protective spines when exposed to chemical cues from predators during development. Genetically identical Daphnia raised without these cues do not develop spines. This demonstrates how the same genotype can lead to different phenotypes depending on environmental conditions.

In plants, genetically identical individuals can exhibit significant variations in traits like height, leaf size, and flowering time based on environmental factors such as light availability, water, and nutrient supply. Understanding phenotypic plasticity is critical for predicting how organisms may respond to environmental changes, such as those resulting from climate change.