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Molecular Basis of Heredity: Part 3. Genetic Variation

Author(s): Raye L. Alford, PhD

Complex Mechanisms of Hereditary Disease (II)

There are two types of genetic heterogeneity: allelic and locus. Allelic heterogeneity occurs when different mutations in a single gene cause a particular disease. One disease that shows allelic heterogeneity is cystic fibrosis (CF). More than 1,000 different mutations have been identified in the gene associated with CF. Understanding allelic heterogeneity is important for interpreting DNA test results and predicting disease severity. Locus heterogeneity occurs when a particular disorder can be caused by mutations in more than one gene. Understanding locus heterogeneity is important for selecting  the proper DNA tests to order for a patient, interpreting DNA test results, predicting disease severity based on DNA test results, and predicting disease risk for family members.

X-inactivation, sometimes called Lyonization, occurs during embryogenesis and is the process by which most genes on one of the X chromosomes of a female are inactivated. This mechanism provides dosage compensation and equates the level of gene expression of most X-linked genes in females to that of males who have only one X chromosome. There are some X-linked genes in females that escape inactivation. X-inactivation usually occurs randomly within the cells of a female such that approximately half of the cells of a female express the genes from one of her X chromosomes and the other half of her cells express the genes from her other X chromosome. However, skewing can occur in X-inactivation. Skewed X-inactivation is observed when one of the X chromosomes of a female is preferentially inactivated in substantially more than half of her cells. In some cases, skewing of X-inactivation is extreme and may be caused by variations in the survival of cells in which a particular X chromosome is inactivated. Skewing of X inactivation can, in rare cases, cause X-linked diseases to be expressed in females.