Chromosomal fragile site

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Silencing of the FMR1 gene in Fragile X syndrome. FMR1 co-localizes with a rare fragile site, visible here as a gap on the long arms of the X chromosome. FragileX.png
Silencing of the FMR1 gene in Fragile X syndrome. FMR1 co-localizes with a rare fragile site, visible here as a gap on the long arms of the X chromosome.

A chromosomal fragile site is a specific heritable point on a chromosome that tends to form a gap or constriction and may tend to break [1] when the cell is exposed to partial replication stress. [2] Based on their frequency, fragile sites are classified as "common" or "rare". [3] To date, more than 120 fragile sites have been identified in the human genome. [3] [4]

Contents

Common fragile sites are considered part of normal chromosome structure and are present in all (or nearly all) individuals in a population. Under normal conditions, most common fragile sites are not prone to spontaneous breaks. Common fragile sites are of interest in cancer studies because they are frequently affected in cancer and they can be found in healthy individuals. Sites FRA3B (harboring the FHIT gene) and FRA16D (harboring the WWOX gene) are two well known examples and have been a major focus of research.

Rare fragile sites are found in less than 5% of the population, and are often composed of two- or three-nucleotide repeats. They are often susceptible to spontaneous breakage during replication, frequently affecting neighboring genes. Clinically, the most important rare fragile site is FRAXA in the FMR1 gene, which is associated with the fragile X syndrome, the most common cause of hereditary intellectual disability.

For a database of fragile sites in human chromosomes, see [5]

Rare fragile sites

Classification

Rare fragile sites (RFSs) are classified into two sub-groups based on the compounds that elicit breakage: folate-sensitive groups (for examples, see [6] ), and nonfolate-sensitive groups, which are induced by bromodeoxyuridine (BrdU) or distamycin A, [7] an antibiotic that preferentially binds to AT-pairs of DNA. [8] The folate-sensitive group is characterized by an expansion of CGG repeats, [9] while the nonfolate-sensitive group contains many AT-rich minisatellite repeats. [10]

Mechanisms of instability

The CGG and AT-rich repeats characteristic of RFSs can form hairpins [11] and other non-B DNA structures that block replication forks and can result in breakage. [12] [13] [14] DNA polymerase has been shown to pause at CTG and CGG triplet repeat sequences, which can result in continual expansion via slippage. [15]

Common fragile sites

Classification

Unlike RFSs, common fragile sites (CFSs) are not the result of nucleotide repeat expansion mutations. They are a part of the normal human genome and are typically stable when not under replicative stress. [16] The majority of breakages at CFSs are induced by low doses of the antibiotic aphidicolin (APH). [17] Co-treatment with low concentrations of the topoisomerase I inhibitor, camptothecin (CPT), reduces APH-induced breakage. [18] CFS regions are highly conserved in mouse [19] [20] and other species, including primates, cat, dog, pig, horse, cow, Indian mole rat, and yeast (for review, see [4] ). While CFSs could be a result of higher-order chromosome structure, the conservation throughout species could also indicate that they may have some conserved biological purpose. [21]

Mechanisms of instability

The instability of CFSs is proposed to stem from late replication: CFSs are likely to initiate proper replication but slow to complete it, introducing breaks from unreplicated regions of DNA. [4] Late-replication may be a result of formation of non-B DNA structures like hairpins and toroids that stall the replication fork in AT rich regions, analogous to the proposed mechanism of rare fragile site instability. [22] Ataxia-telengiectasia and Rad3 Related (ATR) checkpoint kinase is required for maintaining stability of CFS under both stressed and normal replicating conditions. [23] Breakage is reduced after treatment with CPT (camptothecin) (without APH), signifying that CPT also has a necessary role in stabilizing CFSs. [18]

Clinical relevance

Fragile sites are associated with numerous disorders and diseases, both heritable and not. The FRAXA site is perhaps most famous for its role in Fragile X syndrome, but fragile sites are clinically implicated in many other important diseases, such as cancer.

FRA3B and FRA16D lie within the large tumor-suppressor genes, FHIT [24] and WWOX , [25] respectively. High frequency of deletions at breakpoints within these fragile sites has been associated with many cancers, including breast, lung, and gastric cancers (for review, see [4] )

MicroRNA genes, which are preferentially involved in chromosomal alterations, are frequently located at fragile sites. [26] Chromosomal alterations may lead to deregulation of microRNA, which could be of diagnostic and prognostic significance for cancers. [27]

Additionally, the Hepatitis B virus (HBV) [28] and HPV-16 virus, the strain of human papilloma virus most likely to produce cancer, appear to integrate preferentially in or around fragile sites, and it has been proposed that this is crucial to the development of tumors. [29] [30] Fragile sites have also been implicated in a variety of syndromes (for a review, see [31] ). For example, breakage at or near the FRA11b locus has been implicated in Jacobsen syndrome, which is characterized by loss of part of the long arm of chromosome 11 accompanied by mild mental retardation. [32] The FRAXE site is associated in the development of a form of mental retardation without any distinctive phenotypic features. [31] Seckel syndrome, a genetic disease characterized by low levels of ATR, results in increased instability of chromosomes at fragile sites. [33]

Fragile sites and affected genes

Related Research Articles

A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

<span class="mw-page-title-main">Constitutive heterochromatin</span>

Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and throughout the chromosomes. In humans there is significantly more constitutive heterochromatin found on chromosomes 1, 9, 16, 19 and Y. Constitutive heterochromatin is composed mainly of high copy number tandem repeats known as satellite repeats, minisatellite and microsatellite repeats, and transposon repeats. In humans these regions account for about 200Mb or 6.5% of the total human genome, but their repeat composition makes them difficult to sequence, so only small regions have been sequenced.

<span class="mw-page-title-main">Bloom syndrome</span> Medical condition

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family. Mutations in other members of this family, namely WRN and RECQL4, are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both and by cancer predisposition.

Trinucleotide repeat disorders, a subset of microsatellite expansion diseases, are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

<span class="mw-page-title-main">FMR1</span> Human protein and coding gene

FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.

Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. This appellation can refer to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

<span class="mw-page-title-main">Microsatellite instability</span> Condition of genetic hypermutability

Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.

<span class="mw-page-title-main">FHIT</span> Protein-coding gene in the species Homo sapiens

Bis(5'-adenosyl)-triphosphatase also known as fragile histidine triad protein (FHIT) is an enzyme that in humans is encoded by the FHIT gene.

<span class="mw-page-title-main">WWOX</span> Protein-coding gene in the species Homo sapiens

WW domain-containing oxidoreductase is an enzyme that in humans is encoded by the WWOX gene.

<span class="mw-page-title-main">AFF2</span> Protein-coding gene in humans

AF4/FMR2 family member 2 is a protein that in humans is encoded by the AFF2 gene. Mutations in AFF2 are implicated in cases of breast cancer.

<span class="mw-page-title-main">Sergei Mirkin</span> Russian-American molecular biologist

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Non-allelic homologous recombination (NAHR) is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Breakage-fusion-bridge cycle</span>

Breakage-fusion-bridge (BFB) cycle is a mechanism of chromosomal instability, discovered by Barbara McClintock in the late 1930s.

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46, XX. The expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. About 1:150-1:200 women in the US population carry a premutation. Women who carry an FMR1 premutation have a roughly 20% risk of being diagnosed with FXPOI, compared to 1% for the general population, and an 8-15% risk of developing the neurogenerative tremor/ataxia disorder (FXTAS). FMR1 premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats. Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the FMR1 gene and are affected with Fragile X syndrome.

Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.

David L. Nelson is an American human geneticist, currently an associate director at the Intellectual and Developmental Disabilities Research Center (1995), and professor at the Department of Molecular and Human Genetics at Baylor College of Medicine BCM since 1999. Since 2018, he is the director at the Cancer and Cell Biology Ph.D program, and the director of Integrative Molecular and Biomedical Sciences Ph.D since 2015 at BCM.

References

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  2. ↑ Schwartz, M.; Zlotorynski, E.; Kerem, B. (2005), "The molecular basis of common and rare fragile sites", Cancer Letters, 232 (1): 13–26, doi:10.1016/j.canlet.2005.07.039, PMID   16236432
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  30. ↑ Wilke, CM; Hall, BK; Hoge, A; Paradee, W; Smith, DI; Glover, TW (Feb 1996). "FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites". Human Molecular Genetics. 5 (2): 187–95. doi: 10.1093/hmg/5.2.187 . PMID   8824874.
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  33. ↑ Casper, AM; Durkin, SG; Arlt, MF; Glover, TW (Oct 2004). "Chromosomal instability at common fragile sites in Seckel syndrome". American Journal of Human Genetics. 75 (4): 654–60. doi:10.1086/422701. PMC   1182052 . PMID   15309689.
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