Microsatellite

A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 2–5 base pairs) are repeated, typically 5–50 times.[1] Microsatellites occur at thousands of locations within an organism's genome; additionally, they have a higher mutation rate than other areas of DNA[2] leading to high genetic diversity.

Microsatellites and their longer cousins, the minisatellites, together are classified as VNTR (variable number of tandem repeats) DNA. The name "satellite" refers to the early observation that centrifugation of genomic DNA in a test tube separates a prominent layer of bulk DNA from accompanying "satellite" layers of repetitive DNA. A type of microsatellites called short tandem repeats (STRs) are often used by forensic geneticists because although the repeating sequence of base pairs of a specific microsatellite does not change from person to person, the number of times the sequence repeats does change. This allows the number of repeats of a sequence to identify a person through his/her DNA if the number of sequence repeats matches the initial DNA basis used for comparison. STRs can also eliminate a person from suspicion or reduce the suspicion of a person if he/she does not have the same number of sequence repeats as the comparate DNA . This also applies to all other organisms that have STRs. Microsatellites are often called simple sequence repeats (SSRs) by plant geneticists.

They are widely used for DNA profiling in kinship analysis (especially paternity testing) and in forensic identification. They are also used in genetic linkage analysis/marker assisted selection to locate a gene or a mutation responsible for a given trait or disease. Microsatellites are also used in population genetics to measure levels of relatedness between subspecies, groups and individuals.

Structures, locations, and functions

A microsatellite is a tract of tandemly repeated (i.e. adjacent) DNA motifs that range in length from two to five nucleotides, and are typically repeated 5-50 times. For example, the sequence TATATATATA is a dinucleotide microsatellite, and GTCGTCGTCGTCGTC is a trinucleotide microsatellite (with A being Adenine, G Guanine, C Cytosine, and T Thymine). Repeat units of four and five nucleotides are referred to as tetra- and pentanucleotide motifs, respectively. Microsatellites are distributed throughout the genome.[3][4][5] Many are located in non-coding parts of the human genome and therefore do not produce proteins, but they can also be located in regulatory regions and within the coding region.

Microsatellites in non-coding regions do not have any specific function, and therefore cannot be selected against; this allows them to accumulate mutations unhindered over the generations and gives rise to variability that can be used for DNA fingerprinting and identification purposes. Other microsatellites are located in regulatory flanking or intronic regions of genes, or directly in codons of genes - microsatellite mutations in such cases can lead to phenotypic changes and diseases, notably in triplet expansion diseases such as fragile X syndrome and Huntington's disease.

The telomeres at the ends of the chromosomes, thought to be involved in ageing/senescence, consist of repetitive DNA, with the hexanucleotide repeat motif TTAGGG in vertebrates. They are thus classified as minisatellites. Similarly, insects have shorter repeat motifs in their telomeres that could arguably be considered microsatellites.

Mutation mechanisms and mutation rates

DNA strand slippage during replication of an STR locus. Boxes symbolize repetitive DNA units. Arrows indicate the direction in which a new DNA strand (white boxes) is being replicated from the template strand (black boxes). Three situations during DNA replication are depicted. (a) Replication of the STR locus has proceeded without a mutation. (b) Replication of the STR locus has led to a gain of one unit owing to a loop in the new strand; the aberrant loop is stabilized by flanking units complementary to the opposite strand. (c) Replication of the STR locus has led to a loss of one unit owing to a loop in the template strand. (Forster et al. 2015)

Unlike point mutations, which affect only a single nucleotide, microsatellite mutations lead to the gain or loss of an entire repeat unit, and sometimes two or more repeats simultaneously. Thus, the mutation rate at microsatellite loci is expected to differ from other mutation rates, such as base substitution rates. The actual cause of mutations in microsatellites is debated.

One proposed cause of such length changes is replication slippage, caused by mismatches between DNA strands while being replicated during meiosis.[6] DNA polymerase, the enzyme responsible for reading DNA during replication, can slip while moving along the template strand and continue at the wrong nucleotide. DNA polymerase slippage is more likely to occur when a repetitive sequence (such as CGCGCG) is replicated. Because microsatellites consist of such repetitive sequences, DNA polymerase may make errors at a higher rate in these sequence regions. Several studies have found evidence that slippage is the cause of microsatellite mutations.[7][8] Typically, slippage in each microsatellite occurs about once per 1,000 generations.[9] Thus, slippage changes in repetitive DNA are three orders of magnitude more common than point mutations in other parts of the genome.[10] Most slippage results in a change of just one repeat unit, and slippage rates vary for different allele lengths and repeat unit sizes,[11] and within different species.[12] If there is a large size difference between individual alleles, then there may be increased instability during recombination at meiosis.[10]

Another possible cause of microsatellite mutations are point mutations, where only one nucleotide is incorrectly copied during replication. A study comparing human and primate genomes found that most changes in repeat number in short microsatellites appear due to point mutations rather than slippage.[13]

Microsatellite mutation rates

Microsatellite mutation rates vary with base position relative to the microsatellite, repeat type, and base identity.[13] Mutation rate rises specifically with repeat number, peaking around six to eight repeats and then decreasing again.[13] Increased heterozygosity in a population will also increase microsatellite mutation rates,[14] especially when there is a large length difference between alleles. This is likely due to homologous chromosomes with arms of unequal lengths causing instability during meiosis.[15]

Direct estimates of microsatellite mutation rates have been made in numerous organisms, from insects to humans. In the desert locust Schistocerca gregaria, the microsatellite mutation rate was estimated at 2.1 x 10−4 per generation per locus.[16] The microsatellite mutation rate in human male germ lines is five to six times higher than in female germ lines and ranges from 0 to 7 x 10−3 per locus per gamete per generation.[11] In the nematode Pristionchus pacificus, the estimated microsatellite mutation rate ranges from 8.9 × 10−5 to 7.5 × 10−4 per locus per generation.[17]

Biological effects of microsatellite mutations

Many microsatellites are located in non-coding DNA and are biologically silent. Others are located in regulatory or even coding DNA - microsatellite mutations in such cases can lead to phenotypic changes and diseases. Recent studies provided evidence that microsatellites may act as enhancers regulating disease-relevant genes.[18][19]

Effects on proteins

In mammals, 20% to 40% of proteins contain repeating sequences of amino acids encoded by short sequence repeats.[20] Most of the short sequence repeats within protein-coding portions of the genome have a repeating unit of three nucleotides, since that length will not cause frame-shifts when mutating.[21] Each trinucleotide repeating sequence is transcribed into a repeating series of the same amino acid. In yeasts, the most common repeated amino acids are glutamine, glutamic acid, asparagine, aspartic acid and serine.

Mutations in these repeating segments can affect the physical and chemical properties of proteins, with the potential for producing gradual and predictable changes in protein action.[22] For example, length changes in tandemly repeating regions in the Runx2 gene lead to differences in facial length in domesticated dogs (Canis familiaris), with an association between longer sequence lengths and longer faces.[23] This association also applies to a wider range of Carnivora species.[24] Length changes in polyalanine tracts within the HoxA13 gene are linked to Hand-Foot-Genital Syndrome, a developmental disorder in humans.[25] Length changes in other triplet repeats are linked to more than 40 neurological diseases in humans.[26] Evolutionary changes from replication slippage also occur in simpler organisms. For example, microsatellite length changes are common within surface membrane proteins in yeast, providing rapid evolution in cell properties.[27] Specifically, length changes in the FLO1 gene control the level of adhesion to substrates.[28] Short sequence repeats also provide rapid evolutionary change to surface proteins in pathenogenic bacteria; this may allow them to keep up with immunological changes in their hosts.[29] Length changes in short sequence repeats in a fungus (Neurospora crassa) control the duration of its circadian clock cycles.[30]

Effects on gene regulation

Length changes of microsatellites within promoters and other cis-regulatory regions can also change gene expression quickly, between generations. The human genome contains many (>16,000) short sequence repeats in regulatory regions, which provide ‘tuning knobs’ on the expression of many genes.[18][31]

Length changes in bacterial SSRs can affect fimbriae formation in Haemophilus influenzae, by altering promoter spacing.[29] Minisatellites are also linked to abundant variations in cis-regulatory control regions in the human genome.[31] Microsatellites in control regions of the Vasopressin 1a receptor gene in voles influence their social behavior, and level of monogamy.[32]

Effects within introns

Microsatellites within introns also influence phenotype, through means that are not currently understood. For example, a GAA triplet expansion in the first intron of the X25 gene appears to interfere with transcription, and causes Friedreich Ataxia.[33] Tandem repeats in the first intron of the Asparagine synthetase gene are linked to acute lymphoblastic leukaemia.[34] A repeat polymorphism in the fourth intron of the NOS3 gene is linked to hypertension in a Tunisian population.[35] Reduced repeat lengths in the EGFR gene are linked with osteosarcomas.[36]

An archaic form of splicing preserved in Zebrafish is known to use microsatellite sequences within intronic mRNA for the removal of introns in the absence of U2AF2 and other splicing machinery. It is theorized that these sequences form highly stable cloverleaf configurations that bring the 3' and 5' intron splice sites into close proximity, effectively replacing the spliceosome. This method of RNA splicing is believed to have diverged from human evolution at the formation of tetrapods and to represent an artifact of an RNA world.[37]

Effects within transposons

Almost 50% of the human genome is contained in various types of transposable elements (also called transposons, or ‘jumping genes’), and many of them contain repetitive DNA.[38] It is probable that short sequence repeats in those locations are also involved in the regulation of gene expression.[39]

Analysis

Microsatellites are widely used for DNA profiling in kinship analysis (most commonly in paternity testing), in forensic identification (typically matching a crime stain to a victim or perpetrator), and in population genetics. Also, microsatellites are used for mapping locations within the genome, specifically in genetic linkage analysis/marker assisted selection to locate a gene or a mutation responsible for a given trait or disease. As a special case of mapping, they can be used for studies of gene duplication or deletion. These applications are realized by various technical methods.

Amplification

Microsatellites can be amplified for identification by the polymerase chain reaction (PCR) process, using the unique sequences of flanking regions as primers. DNA is repeatedly denatured at a high temperature to separate the double strand, then cooled to allow annealing of primers and the extension of nucleotide sequences through the microsatellite. This process results in production of enough DNA to be visible on agarose or polyacrylamide gels; only small amounts of DNA are needed for amplification because in this way thermocycling creates an exponential increase in the replicated segment.[40] With the abundance of PCR technology, primers that flank microsatellite loci are simple and quick to use, but the development of correctly functioning primers is often a tedious and costly process.

A number of DNA samples from specimens of Littorina plena amplified using polymerase chain reaction with primers targeting a variable simple sequence repeat (SSR, a.k.a. microsatellite) locus. Samples were run on a 5% polyacrylamide gel and visualized using silver staining.

Design of microsatellite primers

If searching for microsatellite markers in specific regions of a genome, for example within a particular intron, primers can be designed manually. This involves searching the genomic DNA sequence for microsatellite repeats, which can be done by eye or by using automated tools such as repeat masker. Once the potentially useful microsatellites are determined, the flanking sequences can be used to design oligonucleotide primers which will amplify the specific microsatellite repeat in a PCR reaction.

Random microsatellite primers can be developed by cloning random segments of DNA from the focal species. These random segments are inserted into a plasmid or bacteriophage vector, which is in turn implanted into Escherichia coli bacteria. Colonies are then developed, and screened with fluorescently–labelled oligonucleotide sequences that will hybridize to a microsatellite repeat, if present on the DNA segment. If positive clones can be obtained from this procedure, the DNA is sequenced and PCR primers are chosen from sequences flanking such regions to determine a specific locus. This process involves significant trial and error on the part of researchers, as microsatellite repeat sequences must be predicted and primers that are randomly isolated may not display significant polymorphism.[10][41] Microsatellite loci are widely distributed throughout the genome and can be isolated from semi-degraded DNA of older specimens, as all that is needed is a suitable substrate for amplification through PCR.

More recent techniques involve using oligonucleotide sequences consisting of repeats complementary to repeats in the microsatellite to "enrich" the DNA extracted (Microsatellite enrichment). The oligonucleotide probe hybridizes with the repeat in the microsatellite, and the probe/microsatellite complex is then pulled out of solution. The enriched DNA is then cloned as normal, but the proportion of successes will now be much higher, drastically reducing the time required to develop the regions for use. However, which probes to use can be a trial and error process in itself.[42]

ISSR-PCR

ISSR (for inter-simple sequence repeat) is a general term for a genome region between microsatellite loci. The complementary sequences to two neighboring microsatellites are used as PCR primers; the variable region between them gets amplified. The limited length of amplification cycles during PCR prevents excessive replication of overly long contiguous DNA sequences, so the result will be a mix of a variety of amplified DNA strands which are generally short but vary much in length.

Sequences amplified by ISSR-PCR can be used for DNA fingerprinting. Since an ISSR may be a conserved or nonconserved region, this technique is not useful for distinguishing individuals, but rather for phylogeography analyses or maybe delimiting species; sequence diversity is lower than in SSR-PCR, but still higher than in actual gene sequences. In addition, microsatellite sequencing and ISSR sequencing are mutually assisting, as one produces primers for the other.

Limitations

Repetitive DNA is not easily analysed by Next Generation DNA Sequencing methods, which struggle with homopolymeric tracts. Therefore, microsatellites are normally analysed by conventional PCR amplication and amplicon size determination, sometimes followed by Sanger DNA sequencing. The use of PCR means that microsatellite length analysis is prone to PCR limitations like any other PCR-amplified DNA locus. A particular concern is the occurrence of ‘null alleles’:

Applications

A partial human STR profile obtained using the Applied Biosystems Identifiler kit

Forensic analysis

Microsatellite analysis became popular in the field of forensics in the 1990s. It is used for the genetic fingerprinting of individuals. The microsatellites in use today for forensic analysis are all tetra- or penta-nucleotide repeats, as these give a high degree of error-free data while being robust enough to survive degradation in non-ideal conditions. Shorter repeat sequences tend to suffer from artifacts such as PCR stutter and preferential amplification, as well as the fact that several genetic diseases are associated with tri-nucleotide repeats such as Huntington's disease. Longer repeat sequences will suffer more highly from environmental degradation and do not amplify by PCR as well as shorter sequences.[44]

The analysis is performed by extracting nuclear DNA from the cells of a forensic sample of interest, then amplifying specific polymorphic regions of the extracted DNA by means of the polymerase chain reaction. Once these sequences have been amplified, they are resolved either through gel electrophoresis or capillary electrophoresis, which will allow the analyst to determine how many repeats of the microsatellites sequence in question there are. If the DNA was resolved by gel electrophoresis, the DNA can be visualized either by silver staining (low sensitivity, safe, inexpensive), or an intercalating dye such as ethidium bromide (fairly sensitive, moderate health risks, inexpensive), or as most modern forensics labs use, fluorescent dyes (highly sensitive, safe, expensive).[45] Instruments built to resolve microsatellite fragments by capillary electrophoresis also use fluorescent dyes.[45] It is also used to follow up bone marrow transplant patients.[46] In the United States, 13 core microsatellite loci have been decided upon to be the basis by which an individual genetic profile can be generated.[47]

These profiles are stored on a local, state and national level in DNA databanks such as CODIS. The British data base for microsatellite loci identification is the UK National DNA Database (NDNAD). The British SGM+ system[48][49] uses 10 loci and a sex marker, rather than the American[50] 13 loci.

Y-STRs (microsatellites on the Y chromosome) are often used in genealogical DNA testing.

Population genetics

Consensus neighbor-joining tree of 249 human populations and six chimpanzee populations. Created based on 246 microsatellite markers.[51]

Microsatellites were popularized in population genetics during the 1990s because as PCR became ubiquitous in laboratories researchers were able to design primers and amplify sets of microsatellites at low cost. Their uses are wide-ranging.[52] A microsatellite with a neutral evolutionary history makes it applicable for measuring or inferring bottlenecks,[53] local adaptation,[54] the allelic fixation index (FST),[55] population size,[56] and gene flow.[57] As next generation sequencing becomes more affordable the use of microsatellites has decreased, however they remain a crucial tool in the field.[58]

See also

References

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