Heterozygote

An individual is heterozygous at a given locus if he has different alleles on both homologous chromosomes within the 22 autosomal chromosomes or the paired sex chromosomes of a female (males, with two different sex chromosomes, are classified as hemizygous at the sex chromosome). Heterozygosity is determined on a locus-by-locus basis and is not used to characterize a whole genome or individual. In terms of human disease, when the wildtype phenotype is determined by a dominant allele, heterozygotes show the wildtype phenotype and disease states are characterized by the loss of heterozygosity. When the wildtype allele is recessive, heterozygotes with one disease causing allele show the diseased phenotype.

There are many physiological functions that do not require wildtype gene products to be expressed from both alleles for normal functioning. In such cases, heterozygosity at the given locus is correlated to wildtype phenotype. Disease states that alter these functions must therefore feature the loss of heterozygosity. Such inheritance is typically termed recessive inheritance. A classic example of autosomal recessive inheritance is cystic fibrosis. The wildtype allele codes for the CFTR protein that regulates ion transport and helps maintain body fluids. Although most people without cystic fibrosis have two wild-type alleles, only one is needed to prevent cystic fibrosis. Cystic fibrosis develops when both alleles are mutated. If each allele was subject to a different mutation, the subject is termed a compound heterozygote at the locus, otherwise the subject is deemed homozygous for a disease-causing allele. In practice, compound heterozygotes are often (erroneously) referred to as homozygous recessive so long as each of their mutations is associated with the same disease state.

Certain physiological functions require two functional alleles of a given gene. In such cases, heterozygotes produce a decreased level of wildtype protein synthesis in addition to potentially producing some disease associated proteins. Such inheritance is typically termed dominant inheritance. A classic example of such a disease state is Huntington's disease. Briefly, a mutation of the Huntington gene produces an extended form of the mutant Huntington protein which causes cell death in selective areas of the brain. In this disease state, acquisition of heterozygous genotype is the key: individuals homozygous for the mutant allele are no worse off than individuals heterozygous at the locus.