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Dynamic Mutation
[edit]Dynamic mutations are mutations that result in an unstable DNA sequence by expansion of existing polymorphic DNA repeat sequences across generations[1][2]. The unstable DNA sequence produced as a result of these mutations is heritable and is increasing the levels of phenotypic variability in a population[3]. The consequences of these repeat sequences depend on the genes that are affected and the location of these expansions[1]. They could alter the gene transcription, structure, stability, protein structure and function and lead to diseases; including neurological and Trinucleotide repeat disorders [4]. The length of the expansion repeat is correlated with disease severity and age of onset[2]. There are 20 known human disorders related to dynamic mutations, the majority of these disorders are autosomal dominant and involve expansion of trinucleotide repeats[4]. However, recessive or X-linked disorders and tetranucleotide and pentanucleotide repeat expansion have also been seen [4][1]. Each disease have their own repeat number threshold, when the repeat number increase beyond that threshold the disease phenotype is observed[5] .
Mechanisms
[edit]There are numerous processes and factors that affect the process of dynamic mutations and their stability. These factors are divided into two groups, cis-elements and trans-factors.
Cis-elements
[edit]Cis-elements are those directly associated with the expanding repeat[5]. These could be internal, which includes the copy number and the composition of the repeat[2]. Instability is related to repeat length, higher copy numbers with tandem repeats are more unstable [2][5]. Also could be external, such as methylation, replication origins and flanking sequence elements[2].
Trans-factors
[edit]Trans factors are those interacting with instability of the repeats, for example DNA metabolism [1][5]. Trans-acting factors are related to which parent transmits the mutations [5]. The behavior of the mutation differs depending on the sex of the parent transmitting the gene [3][5]. For the fragile X mutation, mothers can pass on the full mutation, however fathers who are carriers of the full mutation or affected themselves cannot pass it on to their offspring[3]. This is an example of maternal expansion bias, and the mutations are mostly likely caused by high extended time for oogenic meiosis[2]. The other kind is called paternal expansion bias, and the mutations are caused by mitotic cycles of spermatogenesis [2]. In the juvenile onset form of Huntington disease and spinocerebellar ataxia type I the mutations are mostly inherited from the father [5][3].
Pathogenic Pathways
[edit]Most of these disorders involve gain of function mutation, however loss of function is also observed as well[5]. Location of the repeat expansions play a huge role in the mechanism of pathogenesis.
Loss of function
[edit]There are two situations that might cause loss of gene function. The first one is interfering with transcription. In fragile X syndrome repeat extensions cause the FMR1 promoter to be methylated, which prevents the transcription of the gene[5]. Other disease examples of this type of loss of function are myoclonus epilepsy and Friedreich's ataxia [5]. The other situation is haploinsufficiency, which is the case of myotonic dystrophy[5]. The promoter of the SIX5 gene is expanded; therefore when it does not function properly, causing a reduction of the required SIX5 gene dosage[5].
Gain of function
[edit]Gain of function also could be caused by two different situations. The first one involves expansion of repeats in translated regions that encode polyglutamine[1][5]. These repeat expansions eventually cause polyglutamine tract and these expanded polyglutamines are toxic and change conformation accordingly[5]. Also, expanded nucleotide repeats in the 5' UTR, 3'UTR and introns could also interact with the function of the gene[1]. These untranslated repeats become toxic through RNA gain of function mechanism[1].
References
[edit]- ^ a b c d e f g van Eyk, CL; Richards, RI (2012). "Dynamic mutations: where are they now?". Advances in experimental medicine and biology. 769: 55–77. PMID 23560305. Cite error: The named reference "where" was defined multiple times with different content (see the help page).
- ^ a b c d e f g Pearson, Christopher E.; Edamura, Kerrie Nichol; Cleary, John D. "Repeat instability: mechanisms of dynamic mutations". Nature Reviews Genetics. 6 (10): 729–742. doi:10.1038/nrg1689.
- ^ a b c d Sutherland, Grant R.; Richards, Robert I (1994). "Dynamic Mutations". American Scientist. 82: 157–163. Cite error: The named reference "Sutherland" was defined multiple times with different content (see the help page).
- ^ a b c Nithianantharajah, Jess; Hannan, Anthony J. (June 2007). "Dynamic mutations as digital genetic modulators of brain development, function and dysfunction". BioEssays. 29 (6): 525–535. doi:10.1002/bies.20589. Cite error: The named reference "digital" was defined multiple times with different content (see the help page).
- ^ a b c d e f g h i j k l m n Richards, RI (1 October 2001). "Dynamic mutations: a decade of unstable expanded repeats in human genetic disease". Human molecular genetics. 10 (20): 2187–94. PMID 11673400. Cite error: The named reference "dec" was defined multiple times with different content (see the help page).