Many traits with single-gene inheritance demonstrate complications that can obscure the expected patterns in pedigrees. Chief among these are traits with incomplete penetrance, which means that individuals with a genotype corresponding to a trait do not actually show the phenotype, either because of environmental effects or because of interactions with other genes. Penetrance is the proportion of individuals with a particular genotype that show the expected trait. If the penetrance is less than 100%, then the trait shows reduced, or incomplete, penetrance. Familial cancers often show incomplete penetrance. For example, retinoblastoma caused by certain mutations in the Rb gene and breast cancer caused by certain mutations in the BRCA1 and BRCA2 genes are incompletely penetrant. That is, some people who inherit a mutation in these genes that predisposes to cancer do not in fact develop cancer. Similarly, some mutations in the apoliprotein E (APOE) gene increase the risk of developing Alzheimer’s disease. However, not everyone who inherits these forms of the gene develops Alzheimer’s disease, so these alleles are also incompletely penetrant.

Another common complication in human pedigrees is variable expressivity, which means that a particular phenotype is expressed with a different degree of severity in different individuals. Don’t confuse variable expressivity with incomplete penetrance. With variable expressivity, the trait is always expressed, though the severity varies; with incomplete penetrance, the trait is sometimes expressed and sometimes not. Variation among individuals in the expression of a trait can result from the action of other genes, from effects of the environment, or both. An example is provided by deficiency of the enzyme alpha-1 antitrypsin (α1AT) discussed in Chapter 15, which is associated with loss of lung elasticity and emphysema. Among individuals with emphysema due to α1AT deficiency, the severity of the symptoms varies dramatically from one patient to the next. In this case, tobacco smoking is an environmental factor that increases the severity of the disease.

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Incomplete penetrance and variable expressivity both provide examples where a given genotype does not always produce the same phenotype, since the expression of genes is often influenced by other genes, the environment, or a combination of the two.