A Brief Review of Short Tandem Repeat Mutation
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Review A Brief Review of Short Tandem Repeat Mutation Hao Fan1;2 and Jia-You Chu1* 1 Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming 650118, China; 2 Biochemistry Department, Kunming Medical College, Kunming 650031, China. Short tandem repeats (STRs) are short tandemly repeated DNA sequences that involve a repetitive unit of 1{6 bp. Because of their polymorphisms and high muta- tion rates, STRs are widely used in biological research. Strand-slippage replication is the predominant mutation mechanism of STRs, and the stepwise mutation model is regarded as the main mutation model. STR mutation rates can be influenced by many factors. Moreover, some trinucleotide repeats are associated with human neurodegenerative diseases. In order to deepen our knowledge of these diseases and broaden STR application, it is essential to understand the STR mutation pro- cess in detail. In this review, we focus on the current known information about STR mutation. Key words: short tandem repeats, mutation Introduction Short tandem repeats (STRs), also known as mi- type decreases as the size of the repeat unit increases. crosatellites or simple sequence repeats, are short The most common STRs in the human genome are tandemly repeated DNA sequences that involve a dinucleotide repeats (5 ). On the other hand, ac- repetitive unit of 1{6 bp (1 ), forming series with cording to the repeat structure, STRs are classified lengths of up to 100 nucleotides (nt). STRs are widely into perfect repeats (simple repeats), containing only found in prokaryotes and eukaryotes, including hu- one repetitive unit, and imperfect repeats (compound mans. They appear scattered more or less evenly repeats), consisting of different composition repeats throughout the human genome, accounting for about (7 ). 3% of the entire genome. However, their distribution Since the last decade of the 20th century, scien- within chromosomes is not quite uniform|they ap- tists have been interested in the direct functions of pear less frequently in subtelomeric regions (2 ). Most STRs in some of their host organisms. Although STRs are found in the noncoding regions, while only STRs widely exist in organisms, most of them are about 8% locate in the coding regions (3 ). Moreover, thought to have no biological uses at all and are re- their densities vary slightly among chromosomes. In garded as \junk DNA". However, several interesting humans, chromosome 19 has the highest density of hypotheses suggest that STRs actually play an impor- STRs (4 ). On average, one STR occurs per 2,000 bp tant role in many organisms. In many disease-causing in the human genome (5 ). The most common STRs bacteria, some \contingency genes" reside in STR se- in humans are A-rich units: A, AC, AAAN, AAN, and quences. The STRs in such genes could cause frame- AG (5 ; 6 ). The STR locus is named as, for example, shift mutations, which will change the expression of D3S1266, where D represents DNA, 3 means chromo- some proteins. These proteins are not necessary for some 3 on which the STR locus locates, S stands for the viability of the bacteria, but they can help bacte- STR, and 1266 is the unique identifier. ria to evade the human immune system. Some STRs On the basis of different repeat units, STRs can be may take part in regulating the transcription. From classified into different types. On the one hand, ac- yeasts to humans, many proteins involved in tran- cording to the length of the major repeat unit, STRs scriptional regulation contain glutamine-rich domains are classified into mono-, di-, tri-, tetra-, penta-, and and trinucleotide repeats encoding series of polyglu- hexanucleotide repeats. The total number of each tamine (8 ). Moreover, researches have shown that some STRs can regulate the transcription of the epi- *Corresponding author. dermal growth factor gene (9 ), the tyrosine hydrox- E-mail: [email protected] ylase gene (10 ), and the PIG3 gene (11 ). In addi- This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Geno. Prot. Bioinfo. Vol. 5 No. 1 2007 7 Short Tandem Repeat Mutation tion, some STRs may influence the regulation of gene Mechanisms of STR Mutation expression. For example, in mammalian genomes, (CA)n and (CT)n near particular genes can affect STRs were identified in eukaryotic DNA at the be- the expression of these genes (12 ; 13 ). STRs may ginning of the 1970s. However, for the past decades, also affect recombination (14 ), generation of nucle- the mechanisms of STR mutation remain poorly un- osome positioning signals (15 ), and maintenance of derstood. Up to date, three possible mechanisms chromatin spatial organization (16 ). have been proposed: (1) unequal crossing over in meiosis; (2) retrotransposition mechanism; (3) strand- Although currently more and more biological func- slippage replication. Among these mechanisms, tions of STRs are being discovered, most of them re- strand-slippage replication appears to be widely re- main unknown. Therefore, further study of the muta- garded as the main pattern of STR mutation. tion and variability of STRs is required to understand their biological functions. Unequal crossing over in meiosis This is a well-known mechanism generating large High Mutation Rates of STRs blocks of satellite DNA. It is associated with the ex- change of repeat units between homologous chromo- Unique DNA sequences in a genome exhibit a very somes. However, this process involves different chro- low mutation rate (approximately 10¡9 nt per gener- mosomes, thus it plays a restricted role in STR muta- ation), whereas the mutation rates in STR sequences tion. Nevertheless, this mechanism may be responsi- are several orders of magnitude higher (3 ), ranging ble for STR multistep mutations (17 ), which will be from 10¡6 to 10¡2 nt per generation. STR muta- mentioned later. tion rates are specific for organisms in vivo. For in- stance, the STR mutation rate in yeast (16 ) and hu- Retrotransposition mechanism man (17 ; 18 ) is 10¡5 nt and 10¡3{10¡5 nt per cell This mechanism speculates that A-rich STRs are gen- division, respectively. erated by a 30 extension of retrotranscripts, similar to There is apparently great variation in mutation the polyadenylation of mRNA. Evidence has shown rates among loci. Chakraborty et al (19 ) showed that the association between the most common human in human nonpathogenic STR loci, dinucleotide re- STRs with A-rich content and transposable elements peats display the highest mutation rate, while those (6 ). However, a high density of transposable elements of tetranucleotide STRs are 50% lower. However, the does not always coincide with a high density of STRs. mutation rates of disease-associated trinucleotide re- Further studies are needed to elucidate whether it is peats exceed the normal value by four to seven times. really a mechanism for STR mutation. Several approaches have been developed for eluci- dating the mutation rates of STRs, such as the famil- Strand-slippage replication ial approach (17 ), biological model approach, pop- ulation approach (20 ), and germline cell approach. This model was first proposed by Kornberg et al in The familial approach is the most direct one, where 1964 (23 ), which has also been called DNA slippage, both the mutation rate and mutation type can be di- polymerase slippage, or slipped strand mispairing. At rectly examined during STR transmission from the present, it appears to be widely accepted as the main parents to the offspring (17 ). In the biological model explanation of the STR mutation process. The slip- approach, an STR is cloned into a vector and propa- page occurs during DNA replication, with a conse- gated in its host, then the spontaneous rates of STR quence of mispairing (by one or more repeat units) mutations can be evaluated and the effects of various between the nascent and template strands. Next, the factors on STR mutation can be estimated. Using the repeated DNA fragment is forced to \loop out" at population approach, the common evolutionary origin the mismatch site. If DNA synthesis continues on of STRs can be detected and the mutation events can this molecule, then the repeat number of the STR is be traced back many generations (21 ). STR mutation altered (Figure 1) (24 ). rates can also be directly analyzed in germline cells by However, the slippage rate is not the same as the the germline cell approach, especially in sperms (22 ). apparent mutation rate of STR. Experiments in vitro 8 Geno. Prot. Bioinfo. Vol. 5 No. 1 2007 Fan and Chu Fig. 1 Schematic illustration of the strand-slippage replication at STR (24 ). have demonstrated that DNA slippage occurs at very The genesis of STRs assumes that the generation high rates (25 ). But in vivo, most of the DNA loops of STRs requires short \proto-STR", which is subse- are recognized and eliminated by the mismatch re- quently extended by DNA slippage (30 ). Once proto- pair system. It has been shown that a functional mis- STR arises, the repeat sequence acquires the ability match repair system reduces the STR mutation rate of mutation. The minimum number of repeats needed between 100 and 1,000 folds (26 ). Thus, the observed for further expansion is four to five repeats for a din- STR mutation rate depends on the rate of slippage ucleotide STR and two repeats for a tetranucleotide and the efficiency of the repair system correcting the STR (31 ). mismatches. Several factors can affect the rate of slippage events, among which the repeat unit is the most im- Models of STR Mutation portant factor. A negative correlation was suggested between the length of the repeat unit and the rate of Infinite alleles model (IAM) slippage (25 ).