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Tandem Repeat

A tandem repeat is a very unstable portion of DNA in which units of two or more nucleotides are consecutively repeated. Repeats of 9 or fewer nucleotides are referred to either as microsatellites, or simple tandem repeats, or short tandem repeats. Ten or more nucleotides in a sequence constitute a minisatellite. A repeat unit of over 135 nucleotides is termed a megasatellite. Expansions or contractions of tandem repeats result in significant phenotypic variations in diverse organisms ranging from microbes to mammals. While some of these observable changes can be helpful, others may be detrimental to the organism, even causing the onset of illnesses like Huntington’s disease and spinobulbar muscular atrophy.

Figure 1. Adapted from Gemayel at al. 2010. Demonstrates features of tandem repeats.

Contents 1.	 Mechanisms of Mutations in Tandem Repeats 1.1	Recombination 1.2	Strand-Slippage Replication 2.	 Examples of Phenotypic Variations 2.1	 Mutations within the Dopamine Receptor D4 (DRD4) in Humans 2.1.1 Susceptibility to Alcohol-Related Cues 2.1.2 Increased Promiscuity and Infidelity 2.2 Neurodegenerative Diseases 2.2.1 Huntington’s Disease

Mechanisms of Mutations in Tandem Repeats

Mutations in tandem repeat sequences often produce variations in phenotype. Particularly, the increase or decrease in the number of consecutively repeated units can cause various changes in an organism. Currently, two models have been proposed to describe the mechanisms by which tandem repeats may expand or contract: recombination and strand-slippage replication.

Recombination

The recombination model indicates that expansion or contraction of repeats can occur during cross-over events that take place within a chromosome or between chromosomes. When this happens, nucleotides within a double-stranded DNA molecule recombine with other bound nucleotides at a different point along the molecule. Unequal cross-over events within a tandem repeat sequence may result in elongating or contracting the particular sequence (Figure 2a).

Strand-Slippage Replication

The strand-slippage replication model demonstrates that variations in tandem repeats can produced while the DNA is undergoing replication. Either the nascent or template DNA strand may denature from the other and mispair, creating a portion of DNA that loops out (Figure 2b). When the nascent strand of DNA loops out and pairs incorrectly with the template strand, this results in an expansion of the repeat sequence. Conversely, when the template strand loops out and pairs with the nascent strand, this leads to a contraction of the repeat sequence.

Figure 2. Adapted from Gemayel et al. 2010. Illustrates two models of mutations in tandem repeat sequences: the recombination model (a) and strand slippage replication (b).

Examples of Phenotypic Effects

Mutations within the Dopamine Receptor D4 (DRD4) in Humans

The DRD4 contains a tandem repeat unit of 48 base-pairs. Correlations have been shown between expansions of this repeat, particularly when it is repeated seven or more times, with remarkable behavioral changes in humans. The ligand for this receptor, dopamine, is an important neurotransmitter that mediates various signaling cascades in neurons, thereby regulating synaptic transmission. Ultimately, it plays a significant role in learning, memory, reward, and motor function. Genetic variations in this receptor may impact its structure and, therefore, how it interacts with its ligand.

Susceptibility to Alcohol-Related Cues

Much research has been devoted to examining the potential relationship between social context and alcohol-consuming behavior from a genetic perspective. One example of this is the strong correlation that has been demonstrated between personal drinking behavior and the drinking behavior of surrounding individuals (Larsen et al. 2009). When an individual with at least one copy of the DRD4-7R+ allele is in the presence of other peers who are drinking heavily, the individual is more likely to consume more alcohol as compared to individuals without this allele. However, no difference was noted during light alcohol consumption by peers.

Increased Promiscuity and Infidelity

Both men and women with at least one DRD4-7R+ allele have reported significantly higher incidences of promiscuous sexual experiences, such as a one-night stand, as well as infidelity as compared to individuals without this allele. Data shows that 45% of sampled individuals with the 7R+ allele reported promiscuous sexual experiences and 50% reported having a sexual experience with an individual who was not their romantic partner. This is nearly twice as much as individuals lacking this allele, 24% of which reported engaging in promiscuous experiences and nearly 22% of who admitted to acts of infidelity. Furthermore, 7R+ individuals who cheated on their significant other reported engaging in sexual activities with over 50% more individuals than those without this allele. (Garcia et al. 2010)

Neurodegenerative Diseases

Huntington’s Disease

In healthy individuals, the CAG unit in exon 1 of the ITI5 gene may repeat from 6 to 35 times with no known independent function. However, elongation of this sequence of greater than 40 repeat units triggers the onset of Huntington’s disease, which is characterized by cognitive decline and psychiatric disturbances. The gene, ITI5, encodes the protein huntingtin. This scaffolding protein interacts with many other cellular components and, therefore, is important in mediating a number of cellular functions. Although the precise molecular mechanisms of the disease have yet to be determined, the expansion of CAG leads to an increase in glutamine residues on huntingtin. Considering the importance of huntingtin in DNA transcription and molecular transport, it is likely that the phenotypic variation of this protein leads to many molecular dysfunctions.