Molecular Evolution and Genetic Disease
The role of codon repeats in evolution and genetic disease
Introduction
Codon expansions are responsible for many genetic diseases in humans. The codon repeat diseases are caused by expansions of specific tandem DNA codon repeats and occur in the coding region of the gene. The protein structure resulting from the codon expansion is the cause of the pathology that expresses itself in the degeneration of the nervous system. Huntington's Disease (HD) is an example of this sort of pathology resulting from a codon (CAG) expansion.
Nucleotides are the molecules that comprise DNA and include adenine (A), guanine (G), cytosine (C), and thymine (T). A tri-nucleotide repeat is a recurring pattern of three nucleotides. In HD, an individual with CAG repeats in the intermediate range of 27-35 repeats is not likely to manifest signs of HD. However, repeats in this range have been found to be unstable during meiosis, and the CAG repeat size may expand to a deleterious allele when passed on to offspring This type of mutation is caused by replication slippage (also called slipped-strand mispairing) which occurs in genes. Replication slippage can occur in two ways: forward replication slippage (causes a deletion mutation) and backward replication slippage (causes a insertion mutation). Codon expansions affect the production of a protein and thus the gene expression may be altered.
Researchers study the structure and nature of these mutations in animal models such as the Drosophila melanogaster (fruit-fly). Fruit flies exhibit codon repeats in the glass gene of the eye and may help explain why these diseases worsen with each generation. Intergenerational expansion, also called genetic anticipation, may increase the severity of the disease as the number of these codon repeats increases. With each consecutive generation, the strand continues to slip and the disease becomes more severe.
As the diagram below shows, children of an affected individual have a 50% chance of being affected themselves.
References
Genetic Testing and Mental Health
http://www.nursingworld.org/OJIN/TOPIC13/tpc13_4.htm
Genetics of Huntington's Disease
www.kumc.edu/hospital/huntingtons/genetics.html
Replication Slippage
http://www.cyber-dyne.com/~tom/prion_repeat_deletions.html#aaa