Homozygote

A homozygote is an individual with two identical alleles at a given locus 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). Homozygosity is determined on a locus-by-locus basis and is not used to characterize a whole genome. In terms of human disease, all diseases of genetic origin (as well as many diseases in which genetic predisposition is a key factor) require or are promoted by a loss of wildtype homozygosity. Further, some diseases and states require the gain of a mutant homozygosity. These two pathways to disease broadly correspond to the concepts of dominant and recessive inheritance of disease, although there are some caveats.

Certain physiological functions require two functional alleles of a given gene. In such cases, the loss of homozygosity caused by mutation to either of the alleles leads to a decreased level of wildtype protein synthesis and/or expression of protein coded for by the mutant allele. 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, loss of homozygous wildtype is the key: Individuals homozygous for the mutant allele are no worse off than individuals who have one mutant allele and one wildtype allele.

There are many physiological functions that do not require wildtype gene products to be expressed from both alleles for normal functioning. Disease states that alter these functions must, therefore, feature the total loss of wildtype allele expression. Furthermore, certain disease states require not only the loss of wildtype expression, but the expression of two mutant alleles coding for the same protein. In practice, such conditions are exceedingly rare and not currently of clinical significance. These so-called recessive gain of function mutations primarily have been found to affect channels and membrane proteins responsible for signaling pathways.