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 inf luenced
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: chujy@[Link] ylase gene (10 ), and the PIG3 gene (11 ). In addi-
This is an open access article under the CC BY license ([Link]
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 Inf inite alleles model (IAM)
slippage (25 ). Kruglyak et al (27 ) showed that the Kimura and Crow proposed this model in 1964 (32 )
rate of slippage was the highest in dinucleotide STRs based on an assumption that each new mutation pro-
and the lowest in tetranucleotide STRs. This is con- duces a new allele and all mutations are equiproba-
sistent with the observation that the longer the repeat ble. Therefore, it can involve any number of tandem
unit, the less the total amount of STRs. Probably the repeats and always results in a new allele state not
longer repeat units would require the strand to slip previously existing in the population. However, many
further before the bases could pair correctly again, studies on STR mutation showed that this model was
and then they become less common in the genomes. incompatible with real mutation processes.
Besides the repeat unit, other factors such as the
number, location, and sequence of repeats are also
Stepwise mutation model (SMM)
likely to affect the rate and direction of slippage
(28 ). For instance, in humans, the rate of slippage This model was developed by Ota and Kimura in 1973
events exponentially increases with the increasing re- (33 ). It was originally used to describe the changes of
peat number (29 ). charged proteins inferred from electrophoretic mobil-

Geno. Prot. Bioinfo. Vol. 5 No. 1 2007 9

 Short Tandem Repeat Mutation

ity, which was later shown to be ineffective. However, approach (39 ), have strongly suggested that STR mu-
it proved to be suitable for describing STR mutations. tation rate increases with repeat number. Some stud-
SMM is based on the following assumptions: (1) small ies displayed a positive association between mutation
changes in repeat number; (2) equal probabilities of rate and repeat number in many vertebrate species
increasing and decreasing repeat number; (3) unlim- (40 ) including humans (17 ). The direction of mu-
ited allele size; (4) independence of the rate and size of tation may be different for alleles of different sizes
mutations from the repeat number. SMM is in agree- within a locus (41 ). An expansion occurs more fre-
ment with the strand-slippage replication mechanism, quently in short STRs, while a reduction of repeat
which is currently accepted as the main mechanism for number exists in longer ones (29 ).
STR mutation.
In this model, alleles can mutate up or down by Repeat unit
one or a small number of repeat units (25 ). The
model that only changes one repeat unit each time The mutation rate of dinucleotide repeats is higher
is called strict (single-step) SMM. When the change than that of trinucleotide repeats (19 , 42 ). These re-
is more than one unit each time, it is called two-phase sults agree with the slippage studies mentioned above.
mutation model (TPM), which is also termed as gen-
eralized or multistep mutation model (MMM). In gen- Repeat structure
eral, SMM refers to the strict SMM. Some reports sug-
In autosomes, Y chromosome, and tumor cells, it was
gested that SMM was consistent with the distribution
found that the mutation frequency was appreciably
of alleles at STR loci (34 ). But many other studies
higher in heterozygotes with large allele span (43 ),
demonstrated that strict SMM might not be sufficient
indicating that the repeat structure could have some
to account for allele frequency distributions at STR
contributions to the STR mutation process.
alleles. These studies imply that the more complex
the repeat structure is, the lower the likelihood that
strict stepwise mutational events will happen (35 ). Base composition of repeat unit
TPM was developed by Di Rienzo et al in 1994 Sequences of the unit with a high AT content mutate
(35 ), which predicts the expected variance in repeat faster than those with a high GC content (19 ), sug-
number under different mutational processes and de- gesting that the template stability could influence the
mographic histories. It incorporates the mutational mutation rate. Perhaps the sequences with high GC
process of SMM, but allows for mutations of a larger content could reduce the frequency of strand-slippage
magnitude to occur. As the variance in repeat num- events.
ber increases, the frequency of multistep mutations in-
creases. If the distribution of STR alleles corresponds
to MMM, such STR mutations could be caused by un- Flanking sequence
equal crossing over. TPM is found in various organ- Glenn et al observed a significant negative correlation
isms including Primates (36 ). Huang et al reported between allelic diversity and GC content of flanking
that the proportion of multistep mutations in human sequences (44 ). However, others did not agree with
dinucleotide repeats is 62.9% (17 ). Other researchers it (45 ). Further studies are required to find out the
reported a much lower value of the average frequency true role of GC content of STR flanking sequences in
of multistep human STR mutations, with an average the STR mutation process.
of 23.8% (18 , 37 ).
Recombination
Factors Inf luencing STR Muta- The published research results were controversial on
whether recombination is associated with STR muta-
tion
tion. Some detected a correlation, while others found
no correlation. In humans, genome-wide analyses pro-
Repeat number
vided no evidence for a strong positive correlation be-
One of the key effective factors influencing STR mu- tween recombination rate and STR mutation (17 , 46 ).
tation is repeat number. Studies using different meth- The STR loci from a non-recombining region of the
ods, such as familial approach (38 ) and population human Y chromosome display the same mutation rate

10 Geno. Prot. Bioinfo. Vol. 5 No. 1 2007

Fan and Chu

to that of autosomal loci, suggesting that recombi- outside of their “normal” polymorphic ranges. Such
nation is not the predominant mechanism generating trinucleotide repeats are usually inside genes, most
STR variability. of which encode clusters of glutamine residues; oth-
ers, which reside outside the genes, are currently close
Sex enough to disrupt the genes’ functions. In general,
disease severity often appears to correlate with the
The mutation rates at most loci in germ cells are extent of abnormal expansion. For instance, the CGG
higher in males than in females (47 ). It is widely repeat, which encodes runs of arginine, resides on the
accepted that sperms undergo more DNA replication 50 end in the fragile X mental retardation-I syndrome.
cycles than eggs. The more replication cycles a cell Usually the number of repeats ranges from 6 to 46,
experiences, the higher frequency of mutation is. with an average of 29. When the repeats overrun 52
times, the STR region will be unstable during meio-
Age sis, with a consequence of rapid expanding. The CGG
repeat number in the carrier without any symptoms
The mean age of the men who carry STR mutations ranges from 60 to 200. However, the patient with
is significantly greater than that of the men lacking obvious symptoms carries more than 230 repeats of
of these mutations (18 , 38 ). This is probably because CGG (48 ). Therefore, in order to better understand
sperms experience more mitoses and thus have higher these human neurodegenerative diseases, it is impor-
mutation possibilities. A sperm of men undergoes tant to understand the particular mutation process of
about 380 and 540 mitoses by the age of 28 and 35, STRs.
respectively. Therefore, in a way, the mutation rate
of STRs depends on the age of men.
Application of STRs in Popula-
Interruptions in STR tion Genetics
A special mutation in STR is slippage, which in-
STRs have such properties as abundant, codominant,
duces insertion or deletion of one or several repeats.
highly polymorphic, and nearly selectively neutral.
Besides, STRs also display “nonspecific” mutations,
Besides, STRs contain DNA fragments that are small
such as transitions/transversions, single-nucleotide in-
enough to be amplified by polymerase chain reaction
sertions/deletions, and other events. Their frequency
and separated in high-resolution media like polyacry-
is low as compared to that of specific mutations,
lamide. With the availability of high-throughout cap-
but they disrupt the STR nucleotide sequences and
illary sequencers or mass spectrography, the sizing
change their mutability. STRs can be stabilized by
of alleles is no longer a bottleneck in STR analysis.
insertions of a different nucleotide composition.
Thus STRs are widely used in scientific and applied
research.
STR Mutation and Diseases STRs are extremely useful in applications such as
the construction of genetic maps (49 ), gene location,
The interest in STR mutation comes from the discov- genetic linkage analysis, identification of individuals,
ery that some trinucleotide repeats are involved in hu- paternity testing, as well as disease diagnosis (50 , 51 ).
man neurodegenerative diseases. Trinucleotide repeat STR analysis has also been employed in population
associated diseases are known to include many rare, genetics. Nevertheless, the application of STRs to
dominant, and mainly neurological disorders, such as population genetics requires a more detailed under-
fragile X syndrome, Huntington’s disease, myotonic standing of the STR mutation process.
dystrophy, and certain types of spinocerebellar ataxia. We can apply STRs to reconstruct the history of
To date, trinucleotide repeat associated diseases have migration and evolution of the species, as well as to
only been identified in humans. This has led to the assess biological diversity at various levels of biological
hypothesis that the presence of trinucleotide repeats organization (52 ). A method of absolute genetic dat-
within certain brain related genes may contribute to ing uses mutation rates as molecular clocks. Such a
the evolution of brain function. molecular clock based on STR, whose mutation rate is
Trinucleotide repeat associated diseases are char- very high, can be applied to human evolution. There-
acterized by the trinucleotide repeats that expand far fore, STRs are likely to reflect relatively recent diver-

Geno. Prot. Bioinfo. Vol. 5 No. 1 2007 11

 Short Tandem Repeat Mutation

gence (53 ). derstanding of STR mutation and its high informative

The difference in size between two different STR characteristics will increase the application of STR
alleles might be informative: the larger the difference, analysis in many more fields of science.
the more the number of mutation events. Thus there
is a “memory” of past mutation events (54 ). That is,
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