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Repeated sequence (DNA)

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Repeated sequences (also known as repetitive elements, repeating units or repeats) are short or long patterns of nucleic acids (DNA or RNA) 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.[1] Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.[2]

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 repeats or in repeats dispersed throughout the genome called interspersed repeats.[3] 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 crossing over occurs.[2] 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.[2]

History of Discovery

In the 1950s, Barbara McClintock first observed DNA transposition and illustrated the functions of the centromere and telomere at the Cold Spring Harbor Symposium.[4] 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.[5] 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 variation and regulation. Discoveries of deleterious repetitive DNA-related diseases stimulated further interest in this area of study.[6] 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

Tandem Repeats

Tandem repeats are repeated sequences which are directly adjacent to each other in the genome[7]. 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[8]. When the repeating sequence is 10-60 nucleotides long, the repeat is referred to as a minisatellite[9]. 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[10]. 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[10]. 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, telomeres are comprised mainly of tandem TTAGGG repeats[11]. These repeats fold into highly organized G quadruplex structures which protect the ends of chromosomal DNA from degradation[12]. Repetitive elements are enriched in the middle of chromosomes as well. Centromeres 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[13]. Centromeres are composed of a 177 base pair tandem repeat named the α-satellite repeat[12]. Pericentromeric heterochromatin, the DNA which surrounds the centromere and is important for structural maintenance, is comprised of a mixture of different satellite subfamilies including the α-, β- and γ-satellites as well as HSATII, HSATIII, and sn5 repeats[14][15].

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[16]. Tandem repeats remain an active area of scientific research.

Interspersed Repeats

Interspersed repeats are identical or similar DNA sequences which are found in different locations throughout the genome[17]. 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 elements (TEs), mobile sequences which can be “cut and pasted” or “copied and pasted” into different places in the genome[18]. TEs were originally called “jumping genes” for their ability to move, yet this term is somewhat misleading as not all TEs are discrete genes[19].

Transposable elements that are transcribed into RNA, reverse-transcribed into DNA, then reintegrated into the genome are called retrotransposons[18]. 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 (LINEs) are typically 3-7 kilobases in length[20]. Short interspersed nuclear elements (SINEs) are typically 100-300 base pairs and no longer than 600 base pairs[20]. 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[18]. When a transposable element does not proceed through RNA as an intermediate, it is called a DNA transposon[18]. Other classification systems refer to retrotransposons as “Class I” and DNA transposons as “Class II” transposable elements[19].

Transposable elements are estimated to comprise 45% of the human genome[21]. 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[19]. 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[19]. In some cases, host organisms find new functions for the proteins which arise from expressing TEs in an evolutionary process called TE exaptation[19]. Recent research also suggests that TEs serve to maintain higher-order chromatin structure and 3D genome organization[22]. Furthermore, TEs contribute to regulating the expression of other genes by serving as distal enhancers and transcription factor binding sites[23].

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. Interspersed elements remain an active area of research relevant to evolutionary origins, biology, and medicine.

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 repeats occur when a nucleotide sequence is repeated with the same directionality. Inverted repeats 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 "TACTAC." When there are no nucleotides separating the inverted repeat, such as "CATCATTACTAC," the sequence is called a palindromic repeat. Inverted repeats can play structural roles in DNA and RNA by forming stem loops and cruciforms[24].

Biotechnology

Main article: Microsatellite § Analysis

Repetitive DNA is hard to sequence using next-generation sequencing techniques: 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.[25]

Many researchers have historically left out repetitive parts when analyzing and publishing whole genome data.[26]

See also

References

  1. ^ de Koning AP, Gu W, Castoe TA, Batzer MA, Pollock DD (December 2011). "Repetitive elements may comprise over two-thirds of the human genome". PLOS Genetics. 7 (12): e1002384. doi:10.1371/journal.pgen.1002384. PMC 3228813. PMID 22144907.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ a b c Lower, Sarah E.; Dion-Côté, Anne-Marie; Clark, Andrew G.; Barbash, Daniel A. (2019-11-06). "Special Issue: Repetitive DNA Sequences". Genes. 10 (11): 896. doi:10.3390/genes10110896. ISSN 2073-4425. PMC 6895920. PMID 31698818.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ "Repeated Sequence (DNA) - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-10-04.
  4. ^ McClintock, B. (1951-01-01). "CHROMOSOME ORGANIZATION AND GENIC EXPRESSION". Cold Spring Harbor Symposia on Quantitative Biology. 16 (0): 13–47. doi:10.1101/sqb.1951.016.01.004. ISSN 0091-7451.
  5. ^ Britten, R. J.; Kohne, D. E. (1968-08-09). "Repeated Sequences in DNA: Hundreds of thousands of copies of DNA sequences have been incorporated into the genomes of higher organisms". Science. 161 (3841): 529–540. doi:10.1126/science.161.3841.529. ISSN 0036-8075.
  6. ^ Shapiro, James A.; von Sternberg, Richard (2005-05). "Why repetitive DNA is essential to genome function". Biological Reviews. 80 (2): 227–250. doi:10.1017/s1464793104006657. ISSN 1464-7931. {{cite journal}}: Check date values in: |date= (help)
  7. ^ "Tandem Repeat". Genome.gov. Retrieved 2022-09-30.
  8. ^ Sznajder, Łukasz J.; Swanson, Maurice S. (2019-07-09). "Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy". International Journal of Molecular Sciences. 20 (13): 3365. doi:10.3390/ijms20133365. ISSN 1422-0067. PMC 6651174. PMID 31323950.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  9. ^ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 2022-09-30.
  10. ^ a b Wahls, Wayne P. (1998). "Meiotic Recombination Hotspots: Shaping the Genome and Insights into Hypervariable Minisatellite DNA Change". Current topics in developmental biology. 37: 37–75. ISSN 0070-2153. PMC 3151733. PMID 9352183.
  11. ^ Janssen, Aniek; Colmenares, Serafin U.; Karpen, Gary H. (2018-10-06). "Heterochromatin: Guardian of the Genome". Annual Review of Cell and Developmental Biology. 34 (1): 265–288. doi:10.1146/annurev-cellbio-100617-062653. ISSN 1081-0706.
  12. ^ a b Qi, J. (2005-06-02). "Covalent ligation studies on the human telomere quadruplex". Nucleic Acids Research. 33 (10): 3185–3192. doi:10.1093/nar/gki632. ISSN 0305-1048. PMC 1142406. PMID 15933211.{{cite journal}}: CS1 maint: PMC format (link)
  13. ^ "Centromere". Genome.gov. Retrieved 2022-09-30.
  14. ^ Miga, Karen H. (2015-09-01). "Completing the human genome: the progress and challenge of satellite DNA assembly". Chromosome Research. 23 (3): 421–426. doi:10.1007/s10577-015-9488-2. ISSN 1573-6849.
  15. ^ Lee, C.; Wevrick, R.; Fisher, R. B.; Ferguson-Smith, M. A.; Lin, C. C. (1997-08-04). "Human centromeric DNAs". Human Genetics. 100 (3–4): 291–304. doi:10.1007/s004390050508. ISSN 0340-6717.
  16. ^ Padeken, Jan; Zeller, Peter; Gasser, Susan M (2015-04-01). "Repeat DNA in genome organization and stability". Current Opinion in Genetics & Development. Genome architecture and expression. 31: 12–19. doi:10.1016/j.gde.2015.03.009. ISSN 0959-437X.
  17. ^ "Interspersed repetitive sequences - Latest research and news | Nature". www.nature.com. Retrieved 2022-09-30.
  18. ^ a b c d Wicker, Thomas; Sabot, François; Hua-Van, Aurélie; Bennetzen, Jeffrey L.; Capy, Pierre; Chalhoub, Boulos; Flavell, Andrew; Leroy, Philippe; Morgante, Michele; Panaud, Olivier; Paux, Etienne; SanMiguel, Phillip; Schulman, Alan H. (2007). "A unified classification system for eukaryotic transposable elements". Nature Reviews Genetics. 8 (12): 973–982. doi:10.1038/nrg2165. ISSN 1471-0064.
  19. ^ a b c d e Nicolau, Melody; Picault, Nathalie; Moissiard, Guillaume (2021-10-29). "The Evolutionary Volte-Face of Transposable Elements: From Harmful Jumping Genes to Major Drivers of Genetic Innovation". Cells. 10 (11): 2952. doi:10.3390/cells10112952. ISSN 2073-4409. PMC 8616336. PMID 34831175.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ^ a b Kramerov, Dmitri A.; Vassetzky, Nikita S. (2011). "SINEs: SINEs". Wiley Interdisciplinary Reviews: RNA. 2 (6): 772–786. doi:10.1002/wrna.91.
  21. ^ Lee, Hee-Eun; Ayarpadikannan, Selvam; Kim, Heui-Soo (2015). "Role of transposable elements in genomic rearrangement, evolution, gene regulation and epigenetics in primates". Genes & Genetic Systems. 90 (5): 245–257. doi:10.1266/ggs.15-00016.
  22. ^ Mangiavacchi, Arianna; Liu, Peng; Della Valle, Francesco; Orlando, Valerio (2021). "New insights into the functional role of retrotransposon dynamics in mammalian somatic cells". Cellular and Molecular Life Sciences. 78 (13): 5245–5256. doi:10.1007/s00018-021-03851-5. ISSN 1420-682X. PMC 8257530. PMID 33990851.
  23. ^ Ichiyanagi, Kenji (2013). "Epigenetic regulation of transcription and possible functions of mammalian short interspersed elements, SINEs". Genes & Genetic Systems. 88 (1): 19–29. doi:10.1266/ggs.88.19. ISSN 1880-5779. PMID 23676707.
  24. ^ Pearson, Christopher E.; Zorbas, Haralabos; Price, Gerald B.; Zannis-Hadjopoulos, Maria (1996). <1::AID-JCB1>3.0.CO;2-3 "Inverted repeats, stem-loops, and cruciforms: Significance for initiation of DNA replication". Journal of Cellular Biochemistry. 63 (1). eISSN 1097-4644. ISSN 0730-2312.
  25. ^ De Bustos A, Cuadrado A, Jouve N (November 2016). "Sequencing of long stretches of repetitive DNA". Scientific Reports. 6 (1): 36665. Bibcode:2016NatSR...636665D. doi:10.1038/srep36665. PMC 5098217. PMID 27819354.
  26. ^ Slotkin RK (1 May 2018). "The case for not masking away repetitive DNA". Mobile DNA. 9 (1): 15. doi:10.1186/s13100-018-0120-9. PMC 5930866. PMID 29743957.
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