Draft:Unstable DNA sequence

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Unstable DNA sequence are segments of genetic material that exhibit high rates of mutation or variation over time, resulting in significant genetic diversity within populations or even individual organisms.

Such sequences are found in various regions of the genome, including both coding and non-coding regions. They are characterized by their propensity to change through mechanisms such as trinucleotide repeat expansion, slipped strand mispairing, or unequal crossing over during meiosis. Instability in such sequences is found to have a causative association with a wide variety of genetic disorders, making it an important area of investigation in genetics and molecular biology.

The instability of DNA is also harnessed in scientific research and forensic science, particularly in the form of variable number tandem repeats (VNTRs) and short tandem repeats (STRs) analysis, which are used for DNA profiling and studying genetic relatedness.

History[edit]

The discovery of unstable DNA sequences involved several key milestones in genetic research.

Image showing a child with fragile X syndrome

It took almost two centuries to establish the connection between unstable DNA sequences and the development of diseases. As early as the mid-1800s, there were records of anticipation in genetic disorders. However, many geneticists disregarded this phenomenon, considering it to be a result of biased observations[1]. Nonetheless, the identification of CGG expansion in fragile X syndrome and CAG expansion in spinal and bulbar muscular atrophy (SBMA) offered compelling proof that the expansion of triplet sequences was the fundamental genetic mutation responsible for these diseases.

Fragile X Syndrome[edit]

In 1991, researchers studying fragile X syndrome found that the FMR1 gene has an unstable CGG trinucleotide repeat sequence in its promoter region[2]. Individuals with this syndrome have an abnormal expansion of these CGG repeats, leading to the silencing of the FMR1 gene and inhibiting FMRP protein production. This results in global developmental delays, communication disorders, intellectual disabilities and learning problems.

Image showing the impacts of spinal and bulbar muscular atrophy (SBMA)

Spinal and Bulbar Muscular Atrophy[edit]

Again, in 1991, scientists identified that individuals affected by SBMA have abnormal expansions of CAG repeats within the androgen receptor gene[3]. These repeats become unstable and tend to increase in length over successive generations. The expanded CAG repeats affect the production and function of the androgen receptor, ultimately leading to the progressive degeneration and weakening of muscle tissue in the spinal and bulbar regions.

Unstable DNA Repeats and Other Disorders[edit]

Following the discoveries in fragile X syndrome and SBMA, researchers began exploring other genetic disorders to determine if unstable DNA sequences played a role. This led to the identification of additional disorders caused by the repeats, including CTG expansion in myotonic dystrophy type 1 (1992), CCTG repeat expansion in myotonic dystrophy type 2 [4], and CAG expansion in Huntington’s disease (HD) (1993)[5].

Repeat Expansion Mechanisms and Disease Pathogenesis[edit]

Scientists have since focused on understanding the mechanisms underlying repeat expansions and their impact on disease pathogenesis. Several theories regarding the cause of instability have emerged, including DNA replication slippage, DNA repair challenges, and DNA secondary structure formation[6]. The precise mechanisms by which repeat expansions occur and lead to disease are still an active area of research.

Types of unstable DNA sequences[edit]

Unstable DNA sequences can be classified into five subcategories: microsatellites, trinucleotide repeat sequences (TRSs), minisatellites, inverted repeats, and DNA duplication regions. The instability of these sequences contributes significantly to genomic diversity, disease mechanisms, and evolution.

Microsatellites[edit]

Microsatellites, also known as simple sequence repeats (SSRs), consist of short, repeated sequences of DNA. These sequences are prone to expansions or contractions in the number of repeats, leading to genomic instability. Studies in Saccharomyces cerevisiae (baker's yeast) have revealed that poly(GT) and poly(G) tracts, which are common forms of SSRs, show dramatic alterations in length due to the instability of these sequences. Such changes often involve one or two repeat unit additions or deletions and can interact with telomeres, affecting chromosomal stability[7].

Trinucleotide Repeat Sequences[edit]

TRSs are a subset of microsatellites. Expansion of trinucleotide repeats beyond a certain threshold can lead to a range of genetic disorders, such as fragile X syndrome and Huntington's disease[8]. This form of instability is the basis for the phenomenon of genetic anticipation, where the severity of a disorder increases, or its onset occurs earlier in successive generations. Trinucleotide repeat expansions serve as an example of how unstable DNA sequences can impact human health.

Minisatellites[edit]

Minisatellites, also known as variable number tandem repeats (VNTRs), are specific regions of DNA characterized by the presence of short repeating units, typically ranging in length from 6 to 100 base pairs[9]. These repeating units are lined up consecutively, one after another, along the DNA strand.

Minisatellites are often found in non-coding regions of the genome, meaning they do not typically contain instructions for protein synthesis. They are scattered throughout the genome and can be present in both coding and non-coding DNA regions. Due to their high variability between individuals, they have been utilized in DNA fingerprinting[10].

Inverted Repeats[edit]

A schematic showing an example of an inverted repeat sequence involving the repeat of 5 nucleotides (5'-TTACG-3')

Inverted repeats are specific DNA sequences in which the nucleotide sequence on one strand is reversed and complementary to the sequence on the other strand[11]. This means that the sequence reads the same when read in the opposite direction on the complementary strand. Inverted repeats are typically separated by a non-repetitive sequence in between.

Long inverted repeats within the genomes of various organisms exhibit substantial instability. This instability can manifest in both mitotic and germline cells, leading to mutations that range from small rearrangements to complete deletions of sequences. Such instability highlights the complex nature of genomic repeats and their susceptibility to mutations[12].

DNA Duplication Regions[edit]

Genomic regions prone to duplication can exhibit high levels of instability, as demonstrated by the mouse pink-eyed unstable mutation. This mutation, which affects coat colour, shows a high frequency of reversion due to a tandem duplication of genomic DNA at the p locus. The instability associated with DNA duplications underscores the dynamic nature of the genome and its impact on phenotypic variation[13].

Causes of unstable DNA sequences[edit]

Repetitive sequences can contribute to the instability of DNA sequences due to their unique structural characteristics and their susceptibility to replication errors. However, it is important to note that not all repetitive sequences are inherently unstable. Some repetitive sequences are naturally stable, while others are prone to instability due to their specific sequence characteristics and genomic context. Instability is often context-dependent.

DNA Replication Slippage[edit]

Image showing the formation of a DNA stem-loop (hairpin loop)

DNA replication slippage occurs when the replication machinery encounters a repetitive sequence, such as a trinucleotide repeat region[14]. The repetitive nature of these sequences can present challenges during replication, as the template and newly synthesized strands can misalign. One type of replication slippage is known as "looping out" formation. When the replication machinery encounters a repeat sequence, it can cause the newly synthesized strand to slip and form a loop due to the misalignment of the complementary nucleotides[15]. This results in the addition of extra repeat units to the nascent strand.

DNA Repair Challenges[edit]

Repetitive sequences can pose challenges for DNA repair mechanisms. When DNA is damaged, repair processes are initiated to restore the integrity of the DNA molecule. However, repetitive sequences may hinder accurate repair. The repetitive nature of the sequence makes it difficult for the repair machinery to identify the correct template for repair, leading to errors[16]. This can result in repeat length alterations or other structural changes, promoting instability.

DNA Secondary Structure Formation[edit]

Repetitive sequences have the potential to form secondary structures within the DNA molecule, such as hairpin loops or slipped structures[17]. These secondary structures can arise due to the complementarity between different segments of the repetitive sequence. The formation of these structures can interfere with normal DNA replication and repair processes, leading to replication errors, DNA breaks, or abnormal recombination events, all of which can contribute to instability.

Unstable DNA sequences in diseases[edit]

Unstable DNA sequences are associated with different diseases. The more well-studied ones are cancers and various neurological disorders.

Cancer[edit]

DNA instability can result in the activation of oncogenes, genes that have the potential to cause a cell to become cancerous, or the inactivation of tumor suppressor genes, which normally prevent cell division from occurring too rapidly or uncontrollably. For instance, microsatellite instability, which affects the lengths of short tandem repeats within the genome, is a hallmark of certain types of colorectal cancer[18]. This form of instability can lead to mutations in genes critical for DNA repair, cell cycle regulation, or apoptosis, thereby promoting cancer development.

Neurological Disorders[edit]

Unstable DNA repeat expansions have been identified as the cause of over 50 neurodevelopmental, neurodegenerative, and neuromuscular disorders. These include, but not limited to, fragile X syndrome (FXS), spinocerebellar ataxias (SCAs), Huntington’s disease (HD), myotonic dystrophy type 1 and 2 (DM1&DM2), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS)[19].

Moreover, recent years have discovered that diseases such as neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy 1 (OPML1), and familial adult myoclonic epilepsies (FAME 1–4, 6&7), are all associated with trinucleotide repeat expansions[20].

Unstable DNA sequences in forensic science[edit]

Short Tandem Repeats (STRs) and Variable Number Tandem Repeats (VNTRs) are utilized as markers in forensic science. These molecular markers exploit the highly unstable and polymorphic regions among individual genomes, facilitating the analysis of biological samples in criminal investigations and essential for individual identification[21].

The utilization of STR and VNTR markers represents a leap forward in forensic science, allowing the sensitive and accurate analysis of biological evidence[22]. These techniques have become foundational in the field, enabling the identification of individuals from even highly degraded or minimal biological samples[23][24].

References[edit]

  1. ^ Budworth, H., McMurray, C. T. (1 January 2013). "A brief history of triplet repeat diseases". Trinucleotide Repeat Protocols. Methods in Molecular Biology. Vol. 1010. pp. 3–17. doi:10.1007/978-1-62703-411-1_1. ISBN 978-1-62703-410-4. PMC 3913379. PMID 23754215.
  2. ^ Willemsen, R., Levenga, J., Oostra, B. A. (30 June 2011). "CGG repeat in the FMR1 gene: size matters". Clinical Genetics. 80 (3): 214–225. doi:10.1111/j.1399-0004.2011.01723.x. PMC 3151325. PMID 21651511.
  3. ^ Grunseich, C., Kats, I., Bott, L. C., Striano, P., Kokkinis, A., Fox, D., Chen, K.-L., Schindler, A. B., Mankodi, A., Shrader, J. A., Schwartz, D. P., Lehky, T., Liu, C.-Y., Fischbeck, K. H. (1 November 2014). "Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat". Neuromuscular Disorders. 24 (11): 978–981. doi:10.1016/j.nmd.2014.06.441. PMC 4252652. PMID 25047668.
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  7. ^ Henderson, S. T., Petes, T. D. (1 June 1992). "Instability of Simple Sequence DNA in Saccharomyces cerevisiae". Molecular and Cellular Biology. 12 (6): 2749–2757. doi:10.1128/mcb.12.6.2749-2757.1992. PMID 1588966.
  8. ^ Depienne, C., Mandel, J. (1 May 2021). "30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?". American Journal of Human Genetics. 108 (5): 764–785. doi:10.1016/j.ajhg.2021.03.011. PMC 8205997. PMID 33811808.
  9. ^ Vergnaud, G. (1 July 2000). "Minisatellites: Mutability and genome architecture". Genome Research. 10 (7): 899–907. doi:10.1101/gr.10.7.899. PMID 10899139.
  10. ^ Bakhtiari, M., Park, J., Ding, Y.-C., Shleizer-Burko, S., Neuhausen, S. L., Halldórsson, B. V., Stefánsson, K., Gymrek, M., Bafna, V. (6 April 2021). "Variable number tandem repeats mediate the expression of proximal genes". Nature Communications. 12 (1): 2075. doi:10.1038/s41467-021-22206-z. PMC 8024321. PMID 33824302.
  11. ^ Ussery, D. W., Wassenaar, T. M., Borini, S. (1 January 2009). Ussery DW, Wassenaar TM, Borini S (eds.). Computing for Comparative Microbial Genomics. Computational Biology. Vol. 8. doi:10.1007/978-1-84800-255-5. ISBN 978-1-84800-254-8.
  12. ^ Collick, A., Drew, J. E., Penberth, J., Bois, P. R. J., Luckett, J., Scaërou, F., Jeffreys, A. J., Reik, W. (1 March 1996). "Instability of long inverted repeats within mouse transgenes". The EMBO Journal. 15 (5): 1163–1171. doi:10.1002/j.1460-2075.1996.tb00455.x. PMID 8605887.
  13. ^ Gondo, Y., Gardner, J. A., Nakatsu, Y., Durham‐Pierre, D., Deveau, S. A., Kuper, C., Brilliant, M. H. (1 January 1993). "High-frequency genetic reversion mediated by a DNA duplication: the mouse pink-eyed unstable mutation". Proceedings of the National Academy of Sciences of the United States of America. 90 (1): 297–301. doi:10.1073/pnas.90.1.297.
  14. ^ Viguera, E. (15 May 2001). "Replication slippage involves DNA polymerase pausing and dissociation". The EMBO Journal. 20 (10): 2587–2595. doi:10.1093/emboj/20.10.2587. PMID 11350948.
  15. ^ Bzymek, M., Saveson, C. J., Feschenko, V. V., Lovett, S. (15 January 1999). "Slipped misalignment mechanisms of deletion formation: in vivo susceptibility to nucleases". Journal of Bacteriology. 181 (2): 477–482. doi:10.1128/jb.181.2.477-482.1999. PMC 93401. PMID 9882661.
  16. ^ Carusillo, A., Mussolino, C. (10 July 2020). "DNA damage: From threat to treatment". Cells. 9 (7): 1665. doi:10.3390/cells9071665. PMC 7408370. PMID 32664329.
  17. ^ Bzymek, M., Lovett, S. T. (17 July 2001). "Instability of repetitive DNA sequences: The role of replication in multiple mechanisms". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8319–8325. doi:10.1073/pnas.111008398. PMID 11459970.
  18. ^ Kuismanen, S. A., Holmberg, M. T., Salovaara, R., De La Chapelle, A., Peltomäki, P. (1 May 2000). "Genetic and epigenetic modification of MLH1 accounts for a major share of Microsatellite-Unstable colorectal cancers". The American Journal of Pathology. 156 (5): 1773–1779. doi:10.1016/s0002-9440(10)65048-1. PMC 1876911. PMID 10793088.
  19. ^ Malik, I., Kelley, C. P., Wang, E. T., Todd, P. K. (17 June 2021). "Molecular mechanisms underlying nucleotide repeat expansion disorders". Nature Reviews. Molecular Cell Biology (Print). 22 (9): 589–607. doi:10.1038/s41580-021-00382-6. PMC 9612635. PMID 34140671.
  20. ^ Figueiredo, A. S., Loureiro, J., Macedo-Ribeiro, S., Silveira, I. (7 March 2023). "Advances in nucleotide repeat expansion diseases: transcription gets in phase". Cells. 12 (6): 826. doi:10.3390/cells12060826. PMC 10047669. PMID 36980167.
  21. ^ Phillips, M. L. (1 June 2008). "Crime Scene Genetics: Transforming Forensic Science through Molecular Technologies". BioScience. 58 (6): 484–489. doi:10.1641/b580604.
  22. ^ Roewer, L. (1 January 2013). "DNA fingerprinting in forensics: past, present, future". Investigative Genetics. 4 (1): 22. doi:10.1186/2041-2223-4-22. PMID 24245688.
  23. ^ Thomson, J. A., Phillips, C., Beckett, D. J., Summerfield, O., Lincoln, P. J. (1 January 1996). "Analysis of STR Loci in old blood stains using automated and manual genotyping systems". 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995. Advances in Forensic Haemogenetics. Vol. 6. pp. 328–330. doi:10.1007/978-3-642-80029-0_95. ISBN 978-3-540-60492-1.
  24. ^ Udogadi, N. S., Khadija, A. M., Bukola, A. T., Precious, I. O., Davidson, E. A. (1 January 2020). "Forensic DNA profiling: Autosomal short tandem repeat as a prominent marker in crime investigation". The Malaysian Journal of Medical Science. 27 (4): 22–35. doi:10.21315/mjms2020.27.4.3. PMC 7444828. PMID 32863743.
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