Slipped strand mispairing (SSM, also known asreplication slippage) is a mutation process which occurs duringDNA replication. It involvesdenaturation and displacement of theDNA strands, resulting in mispairing of the complementary bases.[1] Slipped strand mispairing is one explanation for the origin and evolution ofrepetitive DNA sequences.[2]
It is a form ofmutation that leads to either a trinucleotide or dinucleotide expansion, or sometimes contraction, duringDNA replication.[3] A slippage event normally occurs when a sequence of repetitive nucleotides (tandem repeats) are found at the site of replication. Tandem repeats are unstable regions of the genome where frequent insertions and deletions of nucleotides can take place, resulting in genome rearrangements.[4]DNA polymerase, the main enzyme to catalyze the polymerization of freedeoxyribonucleotides into a newly forming DNA strand, plays a significant role in the occurrence of this mutation. When DNA polymerase encounters a direct repeat, it can undergo a replication slippage.[5]
Strand slippage may also occur during the DNA synthesis step ofDNA repair processes. Within DNA trinucleotide repeat sequences, the repair ofDNA damage by the processes ofhomologous recombination,non-homologous end joining,DNA mismatch repair orbase excision repair may involve strand slippage mispairing leading totrinucleotide repeat expansion when the repair is completed.[6]
Slipped strand mispairing has also been shown to function as aphase variation mechanism in certain bacteria.[7]
Slippage occurs through five main stages:
Tandem repeats (the main influence for slippage replication) can be found in coding and non-coding regions. If these repeats are found in coding regions then the variations to the polynucleotide sequence can result in the formation of abnormal proteins in eukaryotes. Many human diseases have been reported to be associated with trinucleotide repeat expansions includingHuntington's disease.[8] The HD gene[9] is found in all human genomes. In the event that a slippage event occurs there can be a large expansion in the tandem repeats of the HD gene.[9] An individual who is not affected by Huntington's disease will have 6-35 tandem repeats at the HD locus. However, an affected individual will have 36- 121 repeats present.[8] The expansion of the HD locus results in a dysfunctional protein leading to Huntington's disease.
Huntington disease is normally progressive and results in movement, cognitive and psychiatric disorders. These disorders can lead to a severe impact on an individual's daily activities, making it hard for proper communication and independent actions to take place.[10] Replication slippage can also lead to other neurodegenerative diseases in humans. These includespinal and bulbar muscular atrophy ( trinucleotide expansion in the AR gene),dentatorubral–pallidoluysian atrophy ( trinucleotide expansion in the DRPLA gene),spinocerebellar ataxia type 1 ( trinucleotide expansion in the SCA1gene),Machado-Joseph disease ( trinucleotide expansion in the SCA3 gene),myotonic dystrophy ( trinucleotide expansion in the DMPK gene), andFriedreich's ataxia ( a trinuncleotide expansion in the X25 gene).[8] Therefore, replication slippage leads to a form of trinucleotide expansion which results in serious changes to protein structure.
SSM events can result in either insertions or deletions. Insertions are thought to be self-accelerating: as repeats grow longer, the probability of subsequent mispairing events increases. Insertions can expand simple tandem repeats by one or more units. In long repeats, expansions may involve two or more units. For example, insertion of a single repeat unit in GAGAGA expands the sequence to GAGAGAGA, while insertion of two repeat units in [GA]6 would produce [GA]8. Genomic regions with a high proportion of repeated DNA sequences (tandem repeats,microsatellites) are prone to strand slippage duringDNA replication andDNA repair.
Trinucleotide repeat expansion is a cause of a number of human diseases includingfragile X syndrome,Huntington's disease, severalspinocerebellar ataxias,myotonic dystrophy andFriedrich ataxia.[6]
The combination of SSM events withpoint mutation is thought to account for the evolution of more complex repeat units. Mutations followed by expansion would result in the formation of new types of adjacentshort tandem repeat units. For example, atransversion could change the simple two- base repeat [GA]10 to [GA]4GATA[GA]2. This could then be expanded to[GA]4[GATA]3[GA]2 by two subsequent SSM events. Simplerepetitive DNA sequences containing a variety of adjacent short tandem repeats are commonly observed in non-protein coding regions ofeukaryoticgenomes.