Genetic Anticipation

Genetic anticipation is a rather unusual type of genetic inheritance in which there is a progressive increase in mutation severity, that in some cases the mutation can result in a disease as it is passed along generation to generation from parents to offspring.

This unusual pattern of inheritance has been observed in a number of genetic diseases which includes neurodegenerative and neuromuscular disorders such as Myotonic dystrophy, Spinocerebellar ataxia type 1, Huntington’s disease, Dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and Fragile X syndrome. Full mechanisms which are underlying genetic anticipation for the most part are largely unknown, but the phenomenon is associated with a type of mutation called trinucleotide repeat expansions, with other explanations suggested as being telomere shortening and nongenetic factors such as increased surveillance for symptoms and signs of a particular disorder.

Trinucleotide repeats are repetitive sequences of 3 nucleotides that follow patterns of CNG where in N can be any nucleotide, which can be found in the human genome within coding and noncoding DNA sequences. Unusual structural features of trinucleotide repeat sequences are thought to make them unstable and thus prone to errors during cell division. Trinucleotide repeat sequences are also thought to be able to form slipped-stranded DNA which is the misalignment of 2 complementary strands of DNA during replication, which allows the sequences to be looped-out and become trapped within hairpin structures. Hairpin structures are thought to stabilize slipped-stranded DNA strands which after further replication results in an increase in the number of repeat sequences if the hairpin formed in the lagging DNA strand, or a decrease in repeat sequences if the hairpin formed on the template DNA strand. Slipped-stranded DNA structures are transient and formation can occur during any genetic process which includes DNA separation into single strands which includes DNA recombination, replication, and repair.

Function and structure of protein that is translated from a region can be affected if repeat sequencing expansion occurs within coding sections of DNA, which can result in a loss or gain in function in the protein that can be harmful. How trinucleotide repeat sequence expansion in noncoding DNA is able to cause pathogenesis which can be observed in some disorders is not fully understood, possible explanations may be RNA degradation, chromatin silencing, and protein sequestration. Trinucleotide repeat sequence expansion is a progressive process that as the number increases the more likely it becomes that further replication errors while arise, and the number of repeats will expand further. This continuous expansion alters gene expression and will result in more severe phenotype as the mutation is passed along from each generation to the next. An example of this can be seen as expansion of trinucleotide sequence CAG in gene ITI5 will cause Huntington’s disease, with the age of onset correlating with the length of CAG repeat, and the greatest changes in the number of trinucleotide repeat sequences are seen with paternal transmission of the gene.