Editing Repeated sequence (DNA)

{{Short description|Patterns of nucleic acids that occur in multiple copies throughout the genome}}

'''Repeated sequences''' (also known as '''repetitive elements''', '''repeating units''' or '''repeats''') are short or long patterns that occur in multiple copies throughout the [[genome]]. In many organisms, a significant fraction of the [[genomic DNA]] is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans.<ref>{{cite journal | vauthors = de Koning AP, Gu W, Castoe TA, Batzer MA, Pollock DD | title = Repetitive elements may comprise over two-thirds of the human genome | journal = PLOS Genetics | volume = 7 | issue = 12 | pages = e1002384 | date = December 2011 | pmid = 22144907 | pmc = 3228813 | doi = 10.1371/journal.pgen.1002384 | doi-access = free }}</ref> Some of these repeated sequences are necessary for maintaining important genome structures such as [[telomere]]s or [[centromere]]s.<ref name=Lower19>{{cite journal | vauthors = Lower SE, Dion-Côté AM, Clark AG, Barbash DA | title = Special Issue: Repetitive DNA Sequences | journal = Genes | volume = 10 | issue = 11 | pages = 896 | date = November 2019 | pmid = 31698818 | pmc = 6895920 | doi = 10.3390/genes10110896 | doi-access = free }}</ref>

Repeated sequences are categorized into different classes depending on features such as structure, length, location, origin, and mode of multiplication. The disposition of repetitive elements throughout the genome can consist either in directly adjacent arrays called [[tandem repeat]]s or in repeats dispersed throughout the genome called [[interspersed repeat]]s.<ref>{{Cite web |title=Repeated Sequence (DNA) — an overview |work=ScienceDirect Topics |url=https://www.sciencedirect.com/topics/neuroscience/repeated-sequence-dna |access-date=2022-10-04 |publisher=ScienceDirect}}</ref> Tandem repeats and interspersed repeats are further categorized into subclasses based on the length of the repeated sequence and/or the mode of multiplication.

While some repeated DNA sequences are important for cellular functioning and genome maintenance, other repetitive sequences can be harmful. Many repetitive DNA sequences have been linked to human diseases such as Huntington's disease and Friedreich's ataxia. Some repetitive elements are neutral and occur when there is an absence of selection for specific sequences depending on how transposition or [[Chromosomal crossover|crossing over]] occurs.<ref name=Lower19 /> However, an abundance of neutral repeats can still influence genome evolution as they accumulate over time. Overall, repeated sequences are an important area of focus because they can provide insight into human diseases and genome evolution.<ref name=Lower19 />

== History ==
In the 1950s, [[Barbara McClintock]] first observed DNA transposition and illustrated the functions of the [[centromere]] and [[telomere]] at the Cold Spring Harbor Symposium.<ref>{{cite journal | vauthors = McClintock B | title = Chromosome organization and genic expression | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 16 | pages = 13–47 | date = 1951-01-01 | pmid = 14942727 | doi = 10.1101/sqb.1951.016.01.004 }}</ref> McClintock's work set the stage for the discovery of repeated sequences because transposition, centromere structure, and telomere structure are all possible through repetitive elements, yet this was not fully understood at the time. The term "repeated sequence" was first used by [[Roy John Britten]] and D. E. Kohne in 1968; they found out that more than half of the eukaryotic genomes were repetitive DNA through their experiments on reassociation of DNA.<ref>{{cite journal | vauthors = Britten RJ, Kohne DE | title = Repeated sequences in DNA. Hundreds of thousands of copies of DNA sequences have been incorporated into the genomes of higher organisms | journal = Science | volume = 161 | issue = 3841 | pages = 529–540 | date = August 1968 | pmid = 4874239 | doi = 10.1126/science.161.3841.529 }}</ref> Although the repetitive DNA sequences were conserved and ubiquitous, their biological role was yet unknown. In the 1990s, more research was conducted to elucidate the evolutionary dynamics of [[minisatellite]] and [[microsatellite]] repeats because of their importance in DNA-based forensics and [[molecular ecology]]. DNA-dispersed repeats were increasingly recognized as a potential source of genetic [[Genetic variation|variation]] and [[Genetic regulation|regulation]]. Discoveries of deleterious repetitive DNA-related diseases stimulated further interest in this area of study.<ref>{{cite journal | vauthors = Shapiro JA, von Sternberg R | title = Why repetitive DNA is essential to genome function | journal = Biological Reviews of the Cambridge Philosophical Society | volume = 80 | issue = 2 | pages = 227–250 | date = May 2005 | pmid = 15921050 | doi = 10.1017/s1464793104006657 | s2cid = 18866824 }}</ref> In the 2000s, the data from full eukaryotic genome sequencing enabled the identification of different promoters, enhancers, and regulatory RNAs which are all coded by repetitive regions. Today, the structural and regulatory roles of repetitive DNA sequences remain an active area of research.

== Types and functions ==

Many repeat sequences are likely to be non-functional, decaying remnants of [[Transposable element]]s, these have been labelled "[[Junk DNA|junk]]" or "[[Selfish genetic element|selfish]]" DNA.<ref>{{cite journal | vauthors = Ohno S | title = So much "junk" DNA in our genome | journal = Brookhaven Symposia in Biology | volume = 23 | pages = 366–370 | date = 1972 | pmid = 5065367 }}</ref><ref>{{cite journal | vauthors = Orgel LE, Crick FH, Sapienza C | title = Selfish DNA | journal = Nature | volume = 288 | issue = 5792 | pages = 645–6 | date = December 1980 | pmid = 7453798 | doi = 10.1038/288645a0 | s2cid = 4370178 | bibcode = 1980Natur.288..645O }}</ref><ref>{{cite journal | vauthors = Palazzo AF, Gregory TR | title = The case for junk DNA | journal = PLOS Genetics | volume = 10 | issue = 5 | pages = e1004351 | date = May 2014 | pmid = 24809441 | doi = 10.1371/journal.pgen.1004351 | pmc = 4014423 | doi-access = free }}</ref> Nevertheless, occasionally some repeats may be [[Exaptation|exapted]] for other functions.<ref>{{cite journal | vauthors = Joly-Lopez Z, Bureau TE | title = Exaptation of transposable element coding sequences | journal = Current Opinion in Genetics & Development | volume = 49 | pages = 34–42 | date = April 2018 | pmid = 29525543 | doi = 10.1016/j.gde.2018.02.011 }}</ref>

=== Tandem repeats ===
[[Tandem repeat]]s are repeated sequences which are directly adjacent to each other in the genome.<ref>{{Cite web |title=Tandem Repeat |url=https://www.genome.gov/genetics-glossary/Tandem-Repeat |access-date=2022-09-30 |website=Genome.gov |language=en}}</ref> Tandem repeats may vary in the number of nucleotides comprising the repeated sequence, as well as the number of times the sequence repeats. When the repeating sequence is only 2–10 nucleotides long, the repeat is referred to as a short tandem repeat (STR) or [[microsatellite]].<ref>{{cite journal | vauthors = Sznajder ŁJ, Swanson MS | title = Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy | journal = International Journal of Molecular Sciences | volume = 20 | issue = 13 | pages = 3365 | date = July 2019 | pmid = 31323950 | pmc = 6651174 | doi = 10.3390/ijms20133365 | doi-access = free }}</ref> When the repeating sequence is 10–60 nucleotides long, the repeat is referred to as a [[minisatellite]].<ref>{{Cite web |title=Minisatellite Repeats (MeSH Descriptor Data 2024) |id=D018598 |url=https://meshb.nlm.nih.gov/record/ui?name=Minisatellite |work=Medical Subject Headings |publisher=National Library of Medicine }}</ref> For minisatellites and microsatellites, the number of times the sequence repeats at a single locus can range from twice to hundreds of times.

Tandem repeats have a wide variety of biological functions in the genome. For example, minisatellites are often hotspots of meiotic [[homologous recombination]] in eukaryotic organisms.<ref name=Wahls98>{{cite journal | vauthors = Wahls WP | title = Meiotic recombination hotspots: shaping the genome and insights into hypervariable minisatellite DNA change | journal = Current Topics in Developmental Biology | volume = 37 | pages = 37–75 | date = 1998 | pmid = 9352183 | pmc = 3151733 | doi = 10.1016/s0070-2153(08)60171-4 | isbn = 9780121531379 }}</ref> Recombination is when two homologous chromosomes align, break, and rejoin to swap pieces. Recombination is important as a source of genetic diversity, as a mechanism for repairing damaged DNA, and a necessary step in the appropriate segregation of chromosomes in meiosis.<ref name=Wahls98 /> The presence of repeated sequence DNA makes it easier for areas of homology to align, thereby controlling when and where recombination occurs.

In addition to playing an important role in recombination, tandem repeats also play important structural roles in the genome. For example, [[telomere]]s are composed mainly of tandem TTAGGG repeats.<ref>{{cite journal | vauthors = Janssen A, Colmenares SU, Karpen GH | title = Heterochromatin: Guardian of the Genome | journal = Annual Review of Cell and Developmental Biology | volume = 34 | issue = 1 | pages = 265–288 | date = October 2018 | pmid = 30044650 | doi = 10.1146/annurev-cellbio-100617-062653 | s2cid = 51718804 | url = http://www.escholarship.org/uc/item/7294g81k | doi-access = free }}</ref> These repeats fold into highly organized [[G-quadruplex|G quadruplex]] structures which protect the ends of chromosomal DNA from degradation.<ref name=Qi05>{{cite journal | vauthors = Qi J, Shafer RH | title = Covalent ligation studies on the human telomere quadruplex | journal = Nucleic Acids Research | volume = 33 | issue = 10 | pages = 3185–92 | date = 2005-06-02 | pmid = 15933211 | pmc = 1142406 | doi = 10.1093/nar/gki632 }}</ref> Repetitive elements are enriched in the middle of chromosomes as well. [[Centromere]]s are the highly compact regions of chromosomes which join sister chromatids together and also allow the mitotic spindle to attach and separate sister chromatids during cell division.<ref>{{Cite web |title=Centromere |url=https://www.genome.gov/genetics-glossary/Centromere |access-date=2022-09-30 |website=Genome.gov |language=en}}</ref> Centromeres are composed of a 177 base pair tandem repeat named the α-satellite repeat.<ref name=Qi05 /> Pericentromeric heterochromatin, the DNA which surrounds the centromere and is important for structural maintenance, is composed of a mixture of different satellite subfamilies including the α-, β- and γ-satellites as well as HSATII, HSATIII, and sn5 repeats.<ref>{{cite journal | vauthors = Miga KH | title = Completing the human genome: the progress and challenge of satellite DNA assembly | journal = Chromosome Research | volume = 23 | issue = 3 | pages = 421–6 | date = September 2015 | pmid = 26363799 | doi = 10.1007/s10577-015-9488-2 | s2cid = 15229421 }}</ref>
[[File:Tandem_and_interspersed_repeat_schematic.png|thumb|350x350px|Tandem and interspersed repeat]]
Some repetitive sequences, such as those with structural roles discussed above, play roles necessary for proper biological functioning. Other tandem repeats have deleterious roles which drive diseases. Many other tandem repeats, however, have unknown or poorly understood functions.<ref>{{cite journal | vauthors = Padeken J, Zeller P, Gasser SM | title = Repeat DNA in genome organization and stability | journal = Current Opinion in Genetics & Development | volume = 31 | pages = 12–19 | date = April 2015 | pmid = 25917896 | doi = 10.1016/j.gde.2015.03.009 | series = Genome architecture and expression }}</ref>

=== Interspersed repeats ===
[[Interspersed repeat]]s are identical or similar DNA sequences which are found in different locations throughout the genome.<ref>{{Cite web |title=Interspersed repetitive sequences - Latest research and news {{!}} Nature |url=https://www.nature.com/subjects/interspersed-repetitive-sequences |access-date=2022-09-30 |website=www.nature.com}}</ref> Interspersed repeats are distinguished from tandem repeats in that the repeated sequences are not directly adjacent to each other but instead may be scattered among different chromosomes or far apart on the same chromosome. Most interspersed repeats are [[transposable element]]s (TEs), mobile sequences which can be "cut and pasted" or "copied and pasted" into different places in the genome.<ref name=Wicker07>{{cite journal | vauthors = Wicker T, Sabot F, Hua-Van A, Bennetzen JL, Capy P, Chalhoub B, Flavell A, Leroy P, Morgante M, Panaud O, Paux E, SanMiguel P, Schulman AH | display-authors = 6 | title = A unified classification system for eukaryotic transposable elements | journal = Nature Reviews. Genetics | volume = 8 | issue = 12 | pages = 973–982 | date = December 2007 | pmid = 17984973 | doi = 10.1038/nrg2165 | s2cid = 32132898 }}</ref> TEs were originally called "jumping genes" for their ability to move, yet this term is somewhat misleading as not all TEs are discrete genes.<ref name=Nicolau21>{{cite journal | vauthors = Nicolau M, Picault N, Moissiard G | title = The Evolutionary Volte-Face of Transposable Elements: From Harmful Jumping Genes to Major Drivers of Genetic Innovation | journal = Cells | volume = 10 | issue = 11 | pages = 2952 | date = October 2021 | pmid = 34831175 | pmc = 8616336 | doi = 10.3390/cells10112952 | doi-access = free }}</ref>

Transposable elements that are transcribed into RNA, reverse-transcribed into DNA, then reintegrated into the genome are called [[retrotransposon]]s.<ref name=Wicker07 /> Just as tandem repeats are further subcategorized based on the length of the repeating sequence, there are many different types of retrotransposons. Long interspersed nuclear elements ([[Long interspersed nuclear element|LINEs]]) are typically 3–7 kilobases in length.<ref name=Kramerov11>{{cite journal | vauthors = Kramerov DA, Vassetzky NS | title = SINEs | journal = Wiley Interdisciplinary Reviews. RNA | volume = 2 | issue = 6 | pages = 772–786 | date = 2011 | pmid = 21976282 | doi = 10.1002/wrna.91 | s2cid = 222199613 }}</ref> Short interspersed nuclear elements ([[Short interspersed nuclear element|SINEs]]) are typically 100-300 base pairs and no longer than 600 base pairs.<ref name=Kramerov11 /> Long-terminal repeat retrotransposons (LTRs) are a third major class of retrotransposons and are characterized by highly repetitive sequences as the ends of the repeat.<ref name=Wicker07 /> When a transposable element does not proceed through RNA as an intermediate, it is called a [[DNA transposon]].<ref name=Wicker07 /> Other classification systems refer to retrotransposons as "Class I" and DNA transposons as "Class II" transposable elements.<ref name=Nicolau21 />

Transposable elements are estimated to constitute 45% of the human genome.<ref>{{cite journal | vauthors = Lee HE, Ayarpadikannan S, Kim HS | title = Role of transposable elements in genomic rearrangement, evolution, gene regulation and epigenetics in primates | journal = Genes & Genetic Systems | volume = 90 | issue = 5 | pages = 245–257 | date = 2015 | pmid = 26781081 | doi = 10.1266/ggs.15-00016 | doi-access = free }}</ref> Since uncontrolled propagation of TEs could wreak havoc on the genome, many regulatory mechanisms have evolved to silence their spread, including DNA methylation, histone modifications, non-coding RNAs (ncRNAs) including small interfering RNA (siRNA), chromatin remodelers, histone variants, and other epigenetic factors.<ref name=Nicolau21 /> However, TEs play a wide variety of important biological functions. When TEs are introduced into a new host, such as from a virus, they increase genetic diversity.<ref name=Nicolau21 /> In some cases, host organisms find new functions for the proteins which arise from expressing TEs in an evolutionary process called TE exaptation.<ref name=Nicolau21 /> Recent research also suggests that TEs serve to maintain higher-order chromatin structure and 3D genome organization.<ref>{{cite journal | vauthors = Mangiavacchi A, Liu P, Della Valle F, Orlando V | title = New insights into the functional role of retrotransposon dynamics in mammalian somatic cells | journal = Cellular and Molecular Life Sciences | volume = 78 | issue = 13 | pages = 5245–56 | date = July 2021 | pmid = 33990851 | pmc = 8257530 | doi = 10.1007/s00018-021-03851-5 }}</ref> Furthermore, TEs contribute to regulating the expression of other genes by serving as distal [[Enhancer (genetics)|enhancers]] and transcription factor binding sites.<ref>{{cite journal | vauthors = Ichiyanagi K | title = Epigenetic regulation of transcription and possible functions of mammalian short interspersed elements, SINEs | journal = Genes & Genetic Systems | volume = 88 | issue = 1 | pages = 19–29 | date = 2013 | pmid = 23676707 | doi = 10.1266/ggs.88.19 | doi-access = free }}</ref>

The prevalence of interspersed elements in the genome has garnered attention for more research on their origins and functions. Some specific interspersed elements have been characterized, such as the Alu repeat and LINE1.

===Intrachromosomal recombination===

[[Homologous recombination]] between chromosomal repeated sequences in somatic cells of ''[[Nicotiana tabacum]]'' was found to be increased by exposure to [[mitomycin C]], a bifunctional alkylating agent that [[crosslinking of DNA|crosslinks DNA]] strands.<ref name = Lebel1993>{{cite journal |vauthors=Lebel EG, Masson J, Bogucki A, Paszkowski J |title=Stress-induced intrachromosomal recombination in plant somatic cells |journal=Proc Natl Acad Sci U S A |volume=90 |issue=2 |pages=422–6 |date=January 1993 |pmid=11607349 |pmc=45674 |doi=10.1073/pnas.90.2.422 |doi-access=free |bibcode=1993PNAS...90..422L }}</ref>  This increase in recombination was attributed to increased intrachromosomal recombinational repair.<ref name = Lebel1993/>  By this process, mitomycin C damaged DNA in one sequence is repaired using intact information from the other repeated sequence.

=== Direct and inverted repeats ===
While tandem and interspersed repeats are distinguished based on their location in the genome, direct and inverted repeats are distinguished based on the ordering of the nucleotide bases. [[Direct repeat]]s occur when a nucleotide sequence is repeated with the same directionality. [[Inverted repeat]]s occur when a nucleotide sequence is repeated in the inverse direction. For example, a direct repeat of "CATCAT" would be another repetition of "CATCAT". In contrast, the inverted repeated would be "ATGATG". When there are no nucleotides separating the inverted repeat, such as "CATCATATGATG", the sequence is called a palindromic repeat. Inverted repeats can play structural roles in DNA and RNA by forming stem loops and cruciforms.<ref>{{cite journal | vauthors = Pearson CE, Zorbas H, Price GB, Zannis-Hadjopoulos M | title = Inverted repeats, stem-loops, and cruciforms: significance for initiation of DNA replication | journal = Journal of Cellular Biochemistry | volume = 63 | issue = 1 | pages = 1–22 | date = October 1996 | pmid = 8891900 | doi = 10.1002/(SICI)1097-4644(199610)63:1<1::AID-JCB1>3.0.CO;2-3 | s2cid = 22204780 | eissn = 1097-4644 }}</ref>

==Evolutionary emergence of meiosis==

The evolutionary origin of [[meiosis|meiotic]] [[sexual reproduction]] is regarded as a long-standing evolutionary enigma.<ref name = Colnaghi2022>{{cite journal |vauthors=Colnaghi M, Lane N, Pomiankowski A |title=Repeat sequences limit the effectiveness of lateral gene transfer and favored the evolution of meiotic sex in early eukaryotes |journal=Proc Natl Acad Sci U S A |volume=119 |issue=35 |pages=e2205041119 |date=August 2022 |pmid=35994648 |pmc=9436333 |doi=10.1073/pnas.2205041119 |url=}}</ref>  In [[prokaryote]]s, [[horizontal gene transfer|lateral gene transfer]] emerged as an early evolved form of sexual interaction.  However, repeat sequences in prokaryotic DNA limit the effectiveness of lateral gene transfer at purging deleterious [[mutation]]s,<ref name = Colnaghi2022/> as well as limiting the accurate repair of [[DNA damage (naturally occurring)|DNA damages]] by [[homologous recombination]]. Colnoghi et al.<ref name = Colnaghi2022/> proposed that such constraints on the beneficial effects of sexual interaction in prokaryotes favored the evolution of meiotic sex and thus the emergence of [[eukaryote]]s.  It was concluded that the transition to homologous pairing along linear chromosomes that occurs during meiosis was the crucial innovation in meiotic sexual reproduction, and this innovation was instrumental in the evolutionary expansion of eukaryotic genomes that facilitated increased functional and morphological complexity.<ref name = Colnaghi2022/>

== Repeated sequences in human disease ==
For humans, some repeated DNA sequences are associated with diseases. Specifically, tandem repeat sequences, underlie several [[Trinucleotide repeat disorder|human disease conditions]], particularly trinucleotide repeat diseases such as [[Huntington's disease]], [[fragile X syndrome]], several [[spinocerebellar ataxia]]s, [[myotonic dystrophy]] and [[Friedreich ataxia|Friedreich's ataxia]].<ref name="pmid25608779">{{cite journal | vauthors = Usdin K, House NC, Freudenreich CH | title = Repeat instability during DNA repair: Insights from model systems | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 50 | issue = 2 | pages = 142–167 | date = 22 January 2015 | pmid = 25608779 | pmc = 4454471 | doi = 10.3109/10409238.2014.999192 }}</ref> [[Trinucleotide repeat expansion]]s in the [[germline]] over successive generations can lead to increasingly severe manifestations of the disease. [[Trinucleotide repeat expansion|These trinucleotide repeat expansions]] may occur through [[Slipped strand mispairing|strand slippage]] during [[DNA replication]] or during [[DNA repair]] synthesis.<ref name="pmid25608779" /> It has been noted that [[gene]]s containing pathogenic CAG repeats often encode proteins that themselves have a role in the [[DNA damage (naturally occurring)|DNA damage]] response and that repeat expansions may impair specific DNA repair pathways.<ref name="Massey2018">{{cite journal | vauthors = Massey TH, Jones L | title = The central role of DNA damage and repair in CAG repeat diseases | journal = Disease Models & Mechanisms | volume = 11 | issue = 1 | pages = dmm031930 | date = January 2018 | pmid = 29419417 | pmc = 5818082 | doi = 10.1242/dmm.031930 }}</ref> Faulty repair of DNA damages in repeat sequences may cause further expansion of these sequences, thus setting up a vicious cycle of pathology.<ref name="Massey2018" />

=== Huntington's disease ===
[[File:Huntington's_disease_(5880985560).jpg|thumb|280x280px|Image of the repeated DNA sequence in Huntington's disease.]]
[[Huntington's disease]] is a neurodegenerative disorder which is due to the expansion of repeated trinucleotide sequence CAG in [[exon]] 1 of the ''[[huntingtin]]'' gene (''HTT''). This gene is responsible for encoding the protein huntingtin which plays a role in preventing apoptosis,<ref>{{cite journal | vauthors = Cattaneo E, Zuccato C, Tartari M | title = Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 919–930 | date = December 2005 | pmid = 16288298 | doi = 10.1038/nrn1806 | s2cid = 10119487 }}</ref> otherwise known as cell death, and [[DNA repair|repair of oxidative DNA damage]].<ref>{{cite journal | vauthors = Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WM, Truant R | title = Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex | journal = Human Molecular Genetics | volume = 26 | issue = 2 | pages = 395–406 | date = January 2017 | pmid = 28017939 | doi = 10.1093/hmg/ddw395 | doi-access = free }}</ref>  In Huntington's disease the expansion of the trinucleotide sequence CAG encodes for a mutant huntingtin protein with an expanded polyglutamine domain.<ref>{{cite journal | vauthors = Schulte J, Littleton JT | title = The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology | journal = Current Trends in Neurology | volume = 5 | pages = 65–78 | date = January 2011 | pmid = 22180703 | pmc = 3237673 }}</ref> This domain causes the protein to form aggregates in nerve cells preventing normal cellular function and resulting in neurodegeneration.
[[File:Fragile_X_Chromosomal_Differences.png|thumb|280x280px|Fragile X repeated CCG DNA sequence in comparison to a normal X chromosome.]]

=== Fragile X syndrome ===
[[Fragile X syndrome]] is caused by the expansion of the DNA sequence CCG in the ''FMR1'' gene on the X chromosome.<ref>{{cite journal | vauthors = Penagarikano O, Mulle JG, Warren ST | title = The pathophysiology of fragile x syndrome | journal = Annual Review of Genomics and Human Genetics | volume = 8 | issue = 1 | pages = 109–129 | date = 2007-09-01 | pmid = 17477822 | doi = 10.1146/annurev.genom.8.080706.092249 }}</ref> This gene produces the RNA-binding protein FMRP. In the case of Fragile X syndrome the repeated sequence makes the gene unstable and therefore silences the gene ''FMR1.''<ref>{{cite journal | vauthors = Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ | display-authors = 6 | title = Fragile X syndrome | journal = Nature Reviews. Disease Primers | volume = 3 | issue = 1 | pages = 17065 | date = September 2017 | pmid = 28960184 | doi = 10.1038/nrdp.2017.65 | s2cid = 583204 }}</ref> Because the gene resides on the X chromosome, females who have two X chromosomes are less effected than males who only have on X chromosome and one Y chromosome because the second X chromosome can compensate for the silencing of the gene on the other X chromosome.

=== Spinocerebellar ataxias ===
The disease [[spinocerebellar ataxia]]s has CAG [[Trinucleotide repeat disorder|trinucleotide repeat sequences that underlie several types of spinocerebellar ataxias]] (SCAs-[[Spinocerebellar ataxia type 1|SCA1]]; [[Spinocerebellar ataxia|SCA2; SCA3; SCA6; SCA7; SCA12; SCA17]]).<ref name="Abugable2019">{{cite journal | vauthors = Abugable AA, Morris JL, Palminha NM, Zaksauskaite R, Ray S, El-Khamisy SF | title = DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms | journal = DNA Repair | volume = 81 | pages = 102669 | date = September 2019 | pmid = 31331820 | doi = 10.1016/j.dnarep.2019.102669 | doi-access = free }}</ref> Similar to Huntington's disease, the polyglutamine tail created due to this trinucleotide expansion causes aggregation of proteins, preventing normal cellular function and causing neurodegeneration.<ref>{{cite journal | vauthors = Honti V, Vécsei L | title = Genetic and molecular aspects of spinocerebellar ataxias | journal = Neuropsychiatric Disease and Treatment | volume = 1 | issue = 2 | pages = 125–133 | date = June 2005 | pmid = 18568057 | pmc = 2413192 | doi = 10.2147/nedt.1.2.125.61044 | doi-access = free }}</ref>

=== Friedreich's Ataxia ===
[[Friedreich's ataxia]] is a type of ataxia that has an expanded repeat sequence GAA in the frataxin gene.<ref>{{cite journal | vauthors = Bürk K | title = Friedreich Ataxia: current status and future prospects | journal = Cerebellum & Ataxias | volume = 4 | issue = 1 | pages = 4 | date = 2017 | pmid = 28405347 | pmc = 5383992 | doi = 10.1186/s40673-017-0062-x | doi-access = free }}</ref> The frataxin gene is responsible for producing the frataxin protein, which is a mitochondrial protein involved in energy production and cellular respiration.<ref>{{cite journal | vauthors = Mazzara PG, Muggeo S, Luoni M, Massimino L, Zaghi M, Valverde PT, Brusco S, Marzi MJ, Palma C, Colasante G, Iannielli A, Paulis M, Cordiglieri C, Giannelli SG, Podini P, Gellera C, Taroni F, Nicassio F, Rasponi M, Broccoli V | display-authors = 6 | title = Frataxin gene editing rescues Friedreich's ataxia pathology in dorsal root ganglia organoid-derived sensory neurons | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4178 | date = August 2020 | pmid = 32826895 | pmc = 7442818 | doi = 10.1038/s41467-020-17954-3 | bibcode = 2020NatCo..11.4178M }}</ref> The expanded GAA sequence results in the silencing of the first intron resulting in loss of function in the frataxin protein. The loss of a functional ''FXN'' gene leads to issues with mitochondrial functioning as a whole and can present phenotypically in patients as difficulty walking.

=== Myotonic dystrophy ===
[[Myotonic dystrophy]] is a disorder that presents as muscle weakness and consists of two main types: DM1 and DM2.<ref>{{cite journal | vauthors = Hahn C, Salajegheh MK | title = Myotonic disorders: A review article | journal = Iranian Journal of Neurology | volume = 15 | issue = 1 | pages = 46–53 | date = January 2016 | pmid = 27141276 | pmc = 4852070 }}</ref> Both types of myotonic dystrophy are due to expanded DNA sequences. In DM1 the DNA sequence that is expanded is CTG while in DM2 it is CCTG. These two sequences are found on different genes with the expanded sequence in DM2 being found on the ''ZNF9'' gene and the expanded sequence in DM1 found on the ''DMPK'' gene. The two genes don't encode for proteins unlike other disorders like Huntington's disease or Fragile X syndrome. It has been shown, however, that there is a link between RNA toxicity and the repeat sequences in DM1 and DM2.

=== Amyotrophic lateral sclerosis and Frontotemporal dementia ===
Not all diseases caused by repeated DNA sequences are trinucleotide repeat diseases. The diseases [[amyotrophic lateral sclerosis]] and [[frontotemporal dementia]] are caused by hexanucleotide GGGGCC repeat sequences in the ''[[C9orf72]]'' gene, causing RNA toxicity that leads to neurodegeneration.<ref>{{cite journal | vauthors = van Blitterswijk M, DeJesus-Hernandez M, Rademakers R | title = How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? | journal = Current Opinion in Neurology | volume = 25 | issue = 6 | pages = 689–700 | date = December 2012 | pmid = 23160421 | pmc = 3923493 | doi = 10.1097/WCO.0b013e32835a3efb }}</ref><ref name="Abugable2019" />

== Biotechnology ==
Repetitive DNA is hard to [[DNA sequencing|sequence]] using [[next-generation sequencing]] techniques because [[sequence assembly]] from short reads simply cannot determine the length of a repetitive part. This issue is particularly serious for microsatellites, which are made of tiny 1-6bp repeat units.<ref name=":5">{{cite journal | vauthors = De Bustos A, Cuadrado A, Jouve N | title = Sequencing of long stretches of repetitive DNA | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 36665 | date = November 2016 | pmid = 27819354 | pmc = 5098217 | doi = 10.1038/srep36665 | bibcode = 2016NatSR...636665D | doi-access = free }}</ref> Although they are difficult to sequence, these short repeats have great value in DNA fingerprinting and evolutionary studies. Many researchers have historically left out repetitive sequences when analyzing and publishing whole genome data due to technical limitations.<ref>{{cite journal | vauthors = Slotkin RK | title = The case for not masking away repetitive DNA | journal = Mobile DNA | volume = 9 | issue = 1 | pages = 15 | date = 1 May 2018 | pmid = 29743957 | pmc = 5930866 | doi = 10.1186/s13100-018-0120-9 | doi-access = free }}</ref>

Bustos. et al. proposed one method of sequencing long stretches of repetitive DNA.<ref name=":5" /> The method combines the use of a linear vector for stabilization and exonuclease III for deletion of continuing simple sequence repeats (SSRs) rich regions. First, SSR-rich fragments are cloned into a linear vector that can stably incorporate tandem repeats up to 30kb. Expression of repeats is prohibited by the transcriptional terminators in the vector. The second step involves the use of exonuclease III. The enzyme can delete nucleotide at the 3' end which results in the production of a unidirectional deletion of SSR fragments. Finally, this product which has deleted fragments is multiplied and analyzed with colony PCR. The sequence is then built by an ordered sequencing of a set of clones containing different deletions.

== See also ==
{{cmn|
* [[FREP]]
* [[Genome]]
* [[Eukaryotic chromosome fine structure]]
* [[Genetic marker]]
* [[Intergenic region]] 
* [[Noncoding DNA]]
* [[Polymorphic simple sequence repeats database]]
* [[Regulator gene]]
* [[Satellite DNA]]
}}

== References ==
{{reflist}}

== External links ==
* [http://darwin2.freeshell.org Function of Repetitive DNA]
* {{MeshName|DNA+Repetitious+Region}}

{{Repeated sequence}}
{{Self-replicating organic structures}}

{{DEFAULTSORT:Repeated Sequence (Dna)}}
[[Category:Repetitive DNA sequences| ]]