Repeated sequences (also known as repetitive elements, repeating units or repeats) are patterns of nucleic acids (DNA or RNA) that occur in multiple copies throughout the genome. Repetitive DNA was first detected because of its rapid re-association kinetics. In many organisms, a significant fraction of the genomic DNA is highly repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans.
Repetitive elements found in genomes fall into different classes, depending on their structure and/or the mode of multiplication. The disposition of repetitive elements consists either in arrays of tandemly repeated sequences, or in repeats dispersed throughout the genome (see below).
Debates regarding the potential functions of these elements have been long standing. Controversial references to ‘junk’ or ‘selfish’ DNA were put forward early on, implying that repetitive DNA segments are remainders from past evolution or autonomous self-replicating sequences hacking the cell machinery to proliferate. Originally discovered by Barbara McClintock, dispersed repeats have been increasingly recognized as a potential source of genetic variation and regulation. Together with these regulatory roles, a structural role of repeated DNA in shaping the 3D folding of genomes has also been proposed. This hypothesis is only supported by a limited set of experimental evidence. For instance in human, mouse and fly, several classes of repetitive elements present a high tendency for co-localization within the nuclear space, suggesting that DNA repeats positions can be used by the cell as a genome folding map.
Tandem repeats in human diseaseEdit
Tandem repeat sequences, particularly trinucleotide repeats, underlie several human disease conditions. Trinucleotide repeats may expand in the germline over successive generations leading to increasingly severe manifestations of the disease. The disease conditions in which expansion occurs include Huntington’s disease, fragile X syndrome, several spinocerebellar ataxias, myotonic dystrophy and Friedrich ataxia. Trinucleotide repeat expansions may occur through strand slippage during DNA replication or during DNA repair synthesis.
Hexanucleotide GGGGCC repeat sequences in the C9orf72 gene are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. CAG trinucleotide repeat sequences underlie several spinocerebellar ataxias (SCAs-SCA1; SCA2; SCA3; SCA6; SCA7; SCA12; SCA17). Huntington’s disease results from an unstable expansion of repeated CAG sequences in exon 1 of the huntingtin gene (HTT). HTT encodes a scaffold protein that directly participates in repair of oxidative DNA damage. It has been noted that genes containing pathogenic CAG repeats often encode proteins that themselves have a role in the DNA damage response and that repeat expansions may impair specific DNA repair pathways. Faulty repair of DNA damages in repeat sequences may cause further expansion of these sequences, thus setting up a vicious cycle of pathology.
Major categories of repeated sequence or repeats:
- Tandem repeats: are copies which lie adjacent to each other, either directly or inverted. Satellite DNA - typically found in centromeres and heterochromatin. Minisatellite - repeat units from about 10 to 60 base pairs, found in many places in the genome, including the centromeres. Microsatellite - repeat units of less than 10 base pairs; this includes telomeres, which typically have 6 to 8 base pair repeat units.
- Interspersed repeats (aka. interspersed nuclear elements): Transposable elements. DNA transposons.retrotransposons.LTR-retrotransposons (HERVs).non LTR-retrotransposons.SINEs (Short Interspersed Nuclear Elements).LINEs (Long Interspersed Nuclear Elements).SVAs
In primates, the majority of LINEs are LINE-1 and the majority of SINEs are Alu's. SVAs are hominoid specific.
In prokaryotes, CRISPR are arrays of alternating repeats and spacers.
Repeated sequences evolutionary derived from viral infection events.
Note: The following are covered in detail in "Computing for Comparative Microbial Genomics".
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.
Many researchers have historically left out repetitive parts when analyzing and publishing whole genome data.
- 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.
- Ohno S (1972). "So much "junk" DNA in our genome". Brookhaven Symposia in Biology. 23: 366–70. PMID 5065367.
- Orgel LE, Crick FH, Sapienza C (December 1980). "Selfish DNA". Nature. 288 (5792): 645–6. doi:10.1038/288645a0. PMID 7453798.
- Mcclintock B (1 January 1956). "Controlling elements and the gene". Cold Spring Harbor Symposia on Quantitative Biology. 21: 197–216. doi:10.1101/SQB.1956.021.01.017. PMID 13433592.
- Shapiro JA, von Sternberg R (May 2005). "Why repetitive DNA is essential to genome function". Biological Reviews of the Cambridge Philosophical Society. 80 (2): 227–50. doi:10.1017/S1464793104006657. PMID 15921050.
- Cournac A, Koszul R, Mozziconacci J (January 2016). "The 3D folding of metazoan genomes correlates with the association of similar repetitive elements". Nucleic Acids Research. 44 (1): 245–55. doi:10.1093/nar/gkv1292. PMC 4705657. PMID 26609133.
- Usdin K, House NC, Freudenreich CH (22 January 2015). "Repeat instability during DNA repair: Insights from model systems". Critical Reviews in Biochemistry and Molecular Biology. 50 (2): 142–67. doi:10.3109/10409238.2014.999192. PMC 4454471. PMID 25608779.
- Abugable AA, Morris JL, Palminha NM, Zaksauskaite R, Ray S, El-Khamisy SF (September 2019). "DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms". DNA Repair. 81: 102669. doi:10.1016/j.dnarep.2019.102669. PMID 31331820.
- Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WM, Truant R (January 2017). "Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex". Human Molecular Genetics. 26 (2): 395–406. doi:10.1093/hmg/ddw395. PMID 28017939.
- Massey TH, Jones L (January 2018). "The central role of DNA damage and repair in CAG repeat diseases". Disease Models & Mechanisms. 11 (1): dmm031930. doi:10.1242/dmm.031930. PMC 5818082. PMID 29419417.
- Villarreal LP (2005). Viruses and the Evolution of Life. ASM Press. ISBN 978-1-55581-309-3.[page needed]
- Ussery DW, Wassenaar TM, Borini S (2009). "Word Frequencies and Repeats". Computing for Comparative Microbial Genomics. Computational Biology. Vol. 8. pp. 137–150. doi:10.1007/978-1-84800-255-5_8. ISBN 978-1-84800-254-8.
- De Bustos A, Cuadrado A, Jouve N (November 2016). "Sequencing of long stretches of repetitive DNA". Scientific Reports. 6 (1): 36665. doi:10.1038/srep36665. PMID 27819354.
- 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. PMID 29743957.