- Anticipation (genetics)
In
genetics , anticipation is a phenomenon whereby the symptoms of agenetic disorder become apparent at an earlier age as it is passed on to the nextgeneration . In most cases, an increase of severity of symptoms is also noted. Anticipation is common intrinucleotide repeat disorders such asHuntington's disease ,myotonic dystrophy andfragile X syndrome , where adynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.Trinucleotide Repeats and Expansion
Trinucleotide repeats are apparent in a number of loci in the
human genome . They have been found inintrons ,exons and 5' or3' UTR 's. They consist of a pattern of threenucleotides (e.g. CGG) which is repeated a number of times. Duringmeiosis , unstable repeats can undergo triplet expansion (see later section); in this case, thegerm cells produced have a greater number of repeats than are found in the somatic tissues.The mechanism behind the expansion of the triplet repeats is not well understood. One theory is that the increasing number of repeats influence the overall shape of the
DNA , which can have an effect on its interaction withDNA polymerase and thus the expression of the gene.Fact|date=March 2008Disease mechanisms
For many of the loci, trinucleotide expansion is harmless [citation] , but in some areas expansion has detrimental effects that cause symptoms. When the trinucleotide repeat is present within the protein-coding region, the repeat expansion leads to production of a mutant protein with
gain of function . This is the case forHuntington's disease , where the trinucleotide repeat encodes a long stretch of glutamine residues. When the repeat is present in an untranslated region, it could affect theexpression of thegene in which the repeat is found (ex.fragile X ) or many genes through adominant negative effect (ex.Myotonic dystrophy ).In order have a deleterious effect, the number of repeats must cross a certain
threshold . For example, normal individuals have between 5 and 30 CTG repeats within the 3' UTR of "DMPK", the gene that is altered inmyotonic dystrophy . If the number of repeats becomes greater than 50, the person is only mildly affected - perhaps having only cataracts. However, meiotic instablity could result in adynamic mutation that increases the number of repeats in offspring inheriting the mutant allele. Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe - including electricalmyotonia . As the number progresses upwards past 400, the symptoms show themselves during childhood or infancy.Diseases with Anticipation and their Repeats
Click on section title for internal link to a thorough list
*Autosomal Dominant
**Several spinal cerebellar atrophies
**Huntington's Disease - CAG
**Myotonic Dystrophy - CTG*Autosomal Recessive
**Friedreich Ataxia - GAA*X-Linked
**Fragile X syndrome - CGGExternal links
* [http://www.anticipation.info/texte/def_genetic/GENETIC_ANTICIPATION.html Anticipation.info]
*
Wikimedia Foundation. 2010.