Types of Repetitive DNA (Genetics & Inherited Conditions)
The eukaryotic nuclear genome is characterized by repetitive DNA elements including nucleotide sequences of varying length and base composition either localized to a particular region of the genome or dispersed throughout the genome (for example, on different chromosomes). Some repetitive DNA elements are found in the genome a few times, whereas others may be repeated millions or billions of times; thus, the percentage of the total genome represented by repetitive DNA varies widely among taxa. Tandem repeats are repetitive DNA sequences lying adjacent to each other in a block or array, whereas interspersed repeats are repetitive DNA sequences found throughout the genome surrounded by unique (nonrepetitive) DNA sequences.
The two major classes of tandem repetitive DNAs (TR-DNAs) are those that are localized to a particular region (or regions) of the genome and those that are dispersed throughout the genome. TR-DNAs include repeating units that are oriented in “head-to-tail” arrays. The repetitive units of an array may include genes, promoters, and intergenic spacers or repeats of simple nucleotide sequences. For example, in the kangaroo rat the simple sequence AAG is repeated 2.4 billion times.
Localized TR-DNA is often composed of members of multigene families. For example, in humans there are 350 copies of the ribosomal RNA (rRNA) genes on five different chromosomes that occur as tandemly repeated arrays....
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Origin and Evolution of Dispersed Repetitive DNA Elements (Genetics & Inherited Conditions)
Dispersed repetitive DNA is believed to be an evolutionary device that catalyzes the formation of new genes. Within a species, DNA sequences are thought to maintain similarity by gene conversion (a type of DNA repair mechanism during meiosis believed to maintain the DNA coding sequence of the organism being replicated) while repetitive sequences disrupt this process and allow new genes to evolve. SINEs are believed to disrupt gene conversions between chromosomes, while the longer LINE elements disrupt the gene conversions within the chromosome. SINEs are transposable elements capable of “jumping” from one locus to another via an RNA intermediate.
SINEs are called nonviral retropseudogenes because they are believed to have been derived from genes encoding small, untranslated RNAs (for example, tRNAs). SINES were created when the RNA transcript was reverse transcribed into DNA and then was inserted into the genome. In their current state, and although they resemble the genes from which they derived, they no longer function properly.
The best-characterized SINEs in humans are highly repetitive Alu sequences, so named because they are cleaved multiple times by the endonuclease AluI, derived from the bacterium Arthrobacter luteus. Between 500,000 and 1 million Alu copies are scattered across the human genome; each Alu sequence is approximately...
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Are Interspersed Repeated Elements “Junk” DNA? (Genetics & Inherited Conditions)
Repeated DNA elements were once believed to be “selfish” or “junk” DNA, concerned only with their own proliferation within the host cell’s genome. Recent studies, however, reveal that repetitive elements interact with the genome with profound evolutionary consequences. For example, satellite DNA found near the centromere may play a role in assembling and fusing chromosomal microtubules during cell division. In addition, transposable genetic elements such as SINEs, LINEs, and Alu sequences may have played a significant role in the evolution of particular proteins. For example, Alu elements flanking the primordial human growth hormone gene are believed to be responsible for the evolution of a relatively new member of the gene family, the chorionic somatomammotropin gene. Transposable repeated elements may have contributed substantially to the origin of new gene functions by initiating a copy of an existing gene (which, over time, may acquire a different function) or by creating a “composite” gene composed of domains from two or more previously unrelated genes.
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Classification of Simple Tandem Repeats (Genetics & Inherited Conditions)
Tandemly repeated simple DNA sequences are classified into four major groups based on three characteristics: the number of nucleotides in the repetitive unit, the number of times the unit is repeated, and whether the element is localized or scattered across the genome. The four groups include satellites, minisatellites, microsatellites, and dispersed Alu sequences. Satellite DNA is composed of tandemly repeated basic DNA sequences, ranging from two to hundreds of nucleotides in length and repeated more than one thousand times, locally, in the DNA. Satellite DNA represents an example of a localized simple repeat typically found in the centromeric region of a chromosome. Tandemly repeated basic DNA sequences, ranging from nine to one hundred nucleotides in length, repeated ten to one hundred times, and scattered throughout the genome are known as minisatellites. Microsatellites are also dispersed repetitive sequence elements; however, microsatellites are composed of short DNA sequence repeats of a basic unit one to six nucleotides in length that are tandemly repeated ten to one hundred times at each locus. The most common microsatellite loci in humans are dinucleotide arrays of (CA)N. However, on average, at least one tri- or tetranucleotide microsatellite locus is found in each 10 kb of human genomic DNA. In a separate group, the basic unit of dispersed Alu sequences is one to five...
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Polymorphism at Loci Composed of Simple Tandem Repeats (Genetics & Inherited Conditions)
For purposes of convenience, the four groups of simple tandem repeats discussed above (satellite DNA, minisatellites, microsatellites, and Alu sequences) are sometimes collectively referred to as variable number tandem repeats (VNTRs).
Separate VNTR loci are thought of as alleles; therefore, in humans each VNTR locus will be represented by two alleles, one paternal and the other maternally inherited. All VNTR loci exhibit high rates of mutation. For these reasons, VNTR loci are highly polymorphic, that is, a large number of alleles exist at any given locus. This polymorphism can be assayed using laboratory techniques such as polymerase chain reaction (PCR) or Southern blotting to examine the differences in the lengths of the alleles (repetitive elements) at a particular DNA locus. Length differences at VNTR loci arise as a result of mispairing of repeats during replication, mitosis, or meiosis, theoretically resulting in the loss or gain of one to many of the repeat units. Empirical studies and computer-based modeling experiments have demonstrated each mutation usually increases or decreases the number of repeated units of an allele in a “one-step” manner. In other words, most mutations result in the loss or gain of only one repeated unit.
The multiallelic variation arising through this variation in repeat copy number provides useful genetic markers for many different...
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Transposable Elements and Human Disease (Genetics & Inherited Conditions)
Retrotranspositions of LINEs and SINEs into coding or noncoding genomic DNAs represent major insertional mutations. The effects of such insertions vary but are usually deleterious, leading to debilitating human diseases. Among a growing list of diseases known in some cases to be caused by the insertion of LINEs or SINEs are Duchenne muscular dystrophy, Glanzmann thrombasthenia, hemophilia, hypercholesterolemia, neurofibromatosis, Sandhoff disease, and Tay-Sachs disease. Translocation of repeated sequences has also been demonstrated to “turn on” tumorogenic oncogenes (for example, one type of colon cancer is associated with the insertion of repetitive DNA).
Other studies suggest “unstable” VNTRs (including minisatellite, microsatellite, and Alu loci) can also cause disease. These studies suggest a threshold number of repeats of the basic nucleotide unit may exist that can be accommodated at a given locus. When this threshold number of repeats is exceeded by overamplification of the basic repeated unit, serious diseases may arise. Among the diseases attributed to overamplification of tandem repeats of simple DNA sequences are fragile X syndrome and Huntington’s disease.
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Further Reading (Genetics & Inherited Conditions)
Lander, E. S., L. M. Linton, B. Birren, et al. “Initial Sequencing and Analysis of the Human Genome.” Nature 409, no. 6822 (2001): 860-921. The initial release of the human genome sequence.
Li, Wen-Hsiung. Molecular Evolution. Sunderland, Mass.: Sinauer Associates, 1997. Provides a basic introduction to the different types of variable tandem repeats, their uses in the biological sciences, and how they affect genome organization.
Maichele, A. J., N. J. Farwell, and J. S. Chamberlain. “A B2 Repeat Insertion Generates Alternate Structures of the Mouse Muscle Gamma-phosphorylase Kinase Gene.” Genomics 16, no. 1 (1993): 139-149. An excellent example of how retrotransposition of repetitive DNA elements may alter the function of, or give rise to, new structural proteins.
Maraia, Richard J., ed. The Impact of Short Interspersed Elements (SINEs) on the Host Genome. Austin, Tex.: R. G. Landes, 1995. A comprehensive treatise on the origin, evolution, and functional roles that SINEs play in the biology of organisms and in biomedicine.
Shapiro, James A. “A 21st Century View of Evolution: Genome System Architecture, Repetitive DNA, and Natural Genetic Engineering.” Gene 345 (2005): 91-100. A broad overview of genome organization focused on information storage and evolution. The author relates moveable and repetitive DNA sequences to system engineering...
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Web Sites of Interest (Genetics & Inherited Conditions)
DNA Repeat Sequences and Disease. http://neuromuscular.wustl.edu/mother/dnarep.htm
Function of Repetitive DNA. http://www.repetitive-dna.org
Junk DNA-–Repetitive Sequences. http://biol.lf1.cuni.cz/ucebnice/en/repetitive_dna.htm
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