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1
Krasilnikova, Maria M., and Sergei M. Mirkin. "Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2286–95. http://dx.doi.org/10.1128/mcb.24.6.2286-2295.2004.
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ABSTRACT Friedreich's ataxia (GAA) n repeats of various lengths were cloned into a Saccharymyces cerevisiae plasmid, and their effects on DNA replication were analyzed using two-dimensional electrophoresis of replication intermediates. We found that premutation- and disease-size repeats stalled the replication fork progression in vivo, while normal-size repeats did not affect replication. Remarkably, the observed threshold repeat length for replication stalling in yeast (∼40 repeats) closely matched the threshold length for repeat expansion in humans. Further, replication stalling was strikingly orientation dependent, being pronounced only when the repeat's homopurine strand served as the lagging strand template. Finally, it appeared that length polymorphism of the (GAA) n · (TTC) n repeat in both expansions and contractions drastically increases in the repeat's orientation that is responsible for the replication stalling. These data represent the first direct proof of the effects of (GAA) n repeats on DNA replication in vivo. We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.
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RIVALS, ERIC. "A SURVEY ON ALGORITHMIC ASPECTS OF TANDEM REPEATS EVOLUTION." International Journal of Foundations of Computer Science 15, no. 02 (April 2004): 225–57. http://dx.doi.org/10.1142/s012905410400239x.
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Local repetitions in genomes are called tandem repeats. A tandem repeat contains multiple, but slightly different copies of a repeated unit. It changes over time as the copies are altered by mutations, when additional copies are created by amplification of an existing copy, or when a copy is removed by contraction. Theses changes let tandem repeats evolve dynamically. From this statement follow two problems. TANDEM REPEAT HISTORY aims at recovering the history of amplifications and mutations that produced the tandem repeat sequence given as input. Given the tandem repeat sequences at the same genomic location in two individuals and a cost function for amplifications, contractions, and mutations, the purpose of TANDEM REPEAT ALLELE ALIGNMENT is to find an alignment of the sequences having minimal cost. We present a survey of these two problems that allow to investigate evolutionary mechanisms at work in tandem repeats.
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Sui, Xin, Fu Juan Feng, Dan Zhao, Min Min Chen, and Shi Jie Han. "Development of Pinus koraiensis SSR Primers Based on EST-SSR Information Technology." Advanced Materials Research 183-185 (January 2011): 259–66. http://dx.doi.org/10.4028/www.scientific.net/amr.183-185.259.
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A total 408 SSRs were distributed in 18,181 ESTs sequences in Pinaceae in NCBI (National Center for Biotechnology Information) searched by SSRIT software, accounting for 2.24% of the whole EST sequences. We designed 132 pairs of EST-SSR primers by primer3. Of the designed 132 pairs, 29 pairs were able to produce an amplification product in the 10 Pinus koraiensis DNA samples, but only five primers in the 29 pairs exhibited polymorphism. Dinucleotide repeats were the most common repeat class. The repeated primitives of dinucleotide were 10, accounting for 52.73% of the whole repeated primitives; the repeat numbers were 87. The second most common repeat class was trinucleotide. The repeated primitives of trinucleotide were 27, accounting for 42.27% of the whole repeated primitives, and repeat numbers were 78.
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Balakrishnan, Ridin, and Stefanie Forest. "To Repeat or Not to Repeat: An Evaluation of Critical Values in Chemistry Laboratory Testing." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S14—S15. http://dx.doi.org/10.1093/ajcp/aqz112.027.
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Abstract It is common laboratory practice to repeat critical values before reporting the result. However, the benefits of repeat testing are unclear. There are slight differences in values whenever tests are repeated, owing to the inherent imprecision of instruments. Repeating critical values delays reporting of results and, ultimately, clinical intervention. Modern instruments have ultrasensitive level sensors, clot detectors, and better precision, making this practice costly and clinically inefficient. This study aimed to evaluate critical values pairs (original and repeats) to determine if repeats were necessary. Our instruments are programmed to automatically repeat critical values for several analytes. In total, 3,891 critical value pairs (potassium, n = 1111; sodium, n = 677; glucose, n = 987; calcium, n = 214; phosphorus, n = 86; magnesium, n = 399; and bicarbonate/CO2, n = 417) that were performed from April to July 2018 at our core laboratory were analyzed. Data were extracted using software developed to evaluate clinical laboratory data for quality assurance. Analysis of the distribution of critical values within and outside the analytical measurement range (AMR) for each of the analytes was performed. The repeat pairs were analyzed for significant differences (>CAP allowable error), mean absolute and percentage difference between the two determinations, and the number of results that were no longer critical on repeat testing. A cost-time analysis was also performed. For all critical values, a total of 49 (1.26%) showed significant differences between the initial and the repeated results. There were significant differences in 35 (0.92%) of the 3,800 repeats within and in 14 (15.38%) of the 91 repeats outside the AMR. For the 3,800 critical values within the AMR, the mean absolute difference and percent difference between the two testing determinations were: potassium, 0.02 mmol/L (0.42%); sodium, 0.19 mmol/L (0.13%); glucose, 0.44 mg/dL (0.16%); calcium, 0.01 mg/dL (0.14%); phosphorus, 0.01 mg/dL (0.16%); magnesium, 0.01 mg/dL (0.31%); and bicarbonate (CO2), 0.57 mEq/L (1.73%), respectively. A total of 254 (6.53%) initial critical values turned out to be noncritical when repeated, although most were just above or below the cutoff. During the study period, the analytical time for critical value repeats was around 355 hours and the cost was just over $1,300. Data from our study suggest that repeated testing is very similar to the original result and therefore redundant. A higher percentage of results had a significant difference when outside the AMR and repeating just these results can be considered. This study did not capture results that were just below or above the critical value cutoffs, and several of these would have likely been critical on repeat testing. Our analysis suggests that these chemistry critical values should not be routinely repeated, allowing for potential cost savings and improved patient care by reporting critical values sooner, resulting in faster clinical intervention.
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Gilmour, D. S., and J. T. Lis. "Protein-DNA cross-linking reveals dramatic variation in RNA polymerase II density on different histone repeats of Drosophila melanogaster." Molecular and Cellular Biology 7, no. 9 (September 1987): 3341–44. http://dx.doi.org/10.1128/mcb.7.9.3341.
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In Drosophila melanogaster the five histone genes are within a 5-kilobase region which is repeated 100 times at a single chromosomal site. These 5-kilobase repeats are of two distinct classes, short and long, that differ by approximately 200 base pairs of DNA in the spacer region between the H1 and H3 genes. Since the mRNA-homologous regions of the repeats are highly conserved, one cannot examine differential expression of the repeats by classical hybridization methods. In this study, we assessed their transcriptional activity by measuring in vivo the relative amounts of RNA polymerase II that were cross-linked by UV irradiation to the two different histone repeats. The RNA polymerase II density on the long repeat in Schneider line 2 cells was strikingly lower (10-fold) than the density on the short repeat. The magnitude of this difference cannot be accounted for by reduced transcription of only one or two genes of the repeat. The density of topoisomerase I, an indicator of transcriptional activity, was also much higher on the short repeat than on the long repeat of line 2 cells. In contrast, the RNA polymerase II density was slightly higher on the long repeat than on the short repeat in a second cell line, KcH. The major difference between active (KcH) and inactive (S2) long repeats resides in the H1-H3 nontranscribed spacer. This portion of the spacer may contain a component necessary for expression that can act over a moderate distance and affect multiple genes of the repeat.
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Gilmour, D. S., and J. T. Lis. "Protein-DNA cross-linking reveals dramatic variation in RNA polymerase II density on different histone repeats of Drosophila melanogaster." Molecular and Cellular Biology 7, no. 9 (September 1987): 3341–44. http://dx.doi.org/10.1128/mcb.7.9.3341-3344.1987.
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In Drosophila melanogaster the five histone genes are within a 5-kilobase region which is repeated 100 times at a single chromosomal site. These 5-kilobase repeats are of two distinct classes, short and long, that differ by approximately 200 base pairs of DNA in the spacer region between the H1 and H3 genes. Since the mRNA-homologous regions of the repeats are highly conserved, one cannot examine differential expression of the repeats by classical hybridization methods. In this study, we assessed their transcriptional activity by measuring in vivo the relative amounts of RNA polymerase II that were cross-linked by UV irradiation to the two different histone repeats. The RNA polymerase II density on the long repeat in Schneider line 2 cells was strikingly lower (10-fold) than the density on the short repeat. The magnitude of this difference cannot be accounted for by reduced transcription of only one or two genes of the repeat. The density of topoisomerase I, an indicator of transcriptional activity, was also much higher on the short repeat than on the long repeat of line 2 cells. In contrast, the RNA polymerase II density was slightly higher on the long repeat than on the short repeat in a second cell line, KcH. The major difference between active (KcH) and inactive (S2) long repeats resides in the H1-H3 nontranscribed spacer. This portion of the spacer may contain a component necessary for expression that can act over a moderate distance and affect multiple genes of the repeat.
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Darling, April L., Leonid Breydo, Emma G. Rivas, Niad T. Gebru, Dali Zheng, Jeremy D. Baker, Laura J. Blair, Chad A. Dickey, John Koren, and Vladimir N. Uversky. "Repeated repeat problems: Combinatorial effect of C9orf72-derived dipeptide repeat proteins." International Journal of Biological Macromolecules 127 (April 2019): 136–45. http://dx.doi.org/10.1016/j.ijbiomac.2019.01.035.
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Lieben, Liesbet. "Repeat, repeat, repeat — gene expression variability explained." Nature Reviews Genetics 17, no. 2 (December 30, 2015): 69. http://dx.doi.org/10.1038/nrg.2015.27.
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Wilkinson, Gerald S., Frieder Mayer, Gerald Kerth, and Barbara Petri. "Evolution of Repeated Sequence Arrays in the D-Loop Region of Bat Mitochondrial DNA." Genetics 146, no. 3 (July 1, 1997): 1035–48. http://dx.doi.org/10.1093/genetics/146.3.1035.
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Analysis of mitochondrial DNA control region sequences from 41 species of bats representing 11 families revealed that repeated sequence arrays near the tRNA-Pro gene are present in all vespertilionine bats. Across 18 species tandem repeats varied in size from 78 to 85 bp and contained two to nine repeats. Heteroplasmy ranged from 15% to 63%. Fewer repeats among heteroplasmic than homoplasmic individuals in a species with up to nine repeats indicates selection may act against long arrays. A lower limit of two repeats and more repeats among heteroplasmic than homoplasmic individuals in two species with few repeats suggests length mutations are biased. Significant regressions of heteroplasmy, θ and π, on repeat number further suggest that repeat duplication rate increases with repeat number. Comparison of vespertilionine bat consensus repeats to mammal control region sequences revealed that tandem repeats of similar size, sequence and number also occur in shrews, cats and bighorn sheep. The presence of two conserved protein-binding sequences in all repeat units indicates that convergent evolution has occurred by duplication of functional units. We speculate that D-loop region tandem repeats may provide signal redundancy and a primitive repair mechanism in the event of somatic mutations to these binding sites.
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La Spada, Albert R. "Repeat meeting’s repeat performance." Trends in Genetics 15, no. 9 (September 1999): 350–51. http://dx.doi.org/10.1016/s0168-9525(99)01806-5.
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Ayad, Lorraine A. K., Panagiotis Charalampopoulos, and Solon P. Pissis. "SMART: SuperMaximal approximate repeats tool." Bioinformatics 36, no. 8 (December 24, 2019): 2589–91. http://dx.doi.org/10.1093/bioinformatics/btz953.
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Abstract Summary State-of-the-art repeat analysis tools rely on extending maximal repeated pairs to enumerate maximal k-mismatch repeats. These pairs can be quadratic in n, the length of the input sequence, and thus greedy heuristics are applied to speed up the extension. Here, we introduce supermaximal k-mismatch repeats, which are linear in n and capture all maximal k-mismatch repeats: every maximal k-mismatch repeat is a substring of some supermaximal k-mismatch repeat. We present SMART, a tool based on recent algorithmic advances implemented in C++ to compute supermaximal k-mismatch repeats directly, and show that these elements are statistically much more significant than the output of the state-of-the-art. Availability and implementation http://github.com/lorrainea/smart (GNU GPL v3.0). Supplementary information Supplementary data are available at Bioinformatics online.
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Chainey, Spencer P., Sophie J. Curtis-Ham, R. Mark Evans, and Gordon J. Burns. "Examining the extent to which repeat and near repeat patterns can prevent crime." Policing: An International Journal 41, no. 5 (October 1, 2018): 608–22. http://dx.doi.org/10.1108/pijpsm-12-2016-0172.
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Purpose The purpose of this paper is to examine the extent and variation in the estimates to which crime can be prevented using patterns of repeats and near repeats, and whether hotspot analysis complements these patterns. Design/methodology/approach Crime data for four study areas in New Zealand are used to examine differences in the extent of burglary repeat and near repeat victimisation. Hotspots of burglary are also created to determine the extent to which burglary repeats and near repeats spatially intersect hotspots. Findings The extent of repeats and near repeats varies, meaning there is variation in the estimated prevention benefits that repeat and near repeat patterns offer. In addition, at least half of the burglaries repeats and near repeats were not located within hotspots. Research limitations/implications The use of other techniques for examining crime concentration could be used to improve the research observations. Practical implications By showing that levels of repeats and near repeats vary, the extent to which these observations coincide in hotspots offers practitioners a better means of determining whether repeat and near repeat patterns are reliable for informing crime prediction and crime prevention activities. Originality/value The paper is the first known research study that explicitly measures the variation in the extent of repeats and near repeats and the spatial intersection of these patterns within crime hotspots. The results suggest that rather than considering the use of repeat and near repeat patterns as a superior method for predicting and preventing crime, value remains in using hotspot analysis for determining where crime is likely to occur, particularly when hotspot analysis emphasises other locations for resource targeting.
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Kapila, Ritu, Sandip Das, Malathi Lakshmikumaran, and P. S. Srivastava. "A novel species-specific tandem repeat DNA family from Sinapis arvensis: detection of telomere-like sequences." Genome 39, no. 4 (August 1, 1996): 758–66. http://dx.doi.org/10.1139/g96-095.
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DNA sequences representing a tandemly repeated DNA family of the Sinapis arvensis genome were cloned and characterized. The 700-bp tandem repeat family is represented by two clones, pSA35 and pSA52, which are 697 and 709 bp in length, respectively. Dot matrix analysis of the sequences indicates the presence of repeated elements within each monomeric unit. Sequence analysis of the repetitive region of clones pSA35 and pSA52 shows that there are several copies of a 7-bp repeat element organized in tandem. The consensus sequence of this repeat element is 5′-TTTAGGG-3′. These elements are highly mutated and the difference in length between the two clones is due to different copy numbers of these elements. The repetitive region of clone pSA35 has 26 copies of the element TTTAGGG, whereas clone pSA52 has 28 copies. The repetitive region in both clones is flanked on either side by inverted repeats that may be footprints of a transposition event. Sequence comparison indicates that the element TTTAGGG is identical to telomeric repeats present in Arabidopsis, maize, tomato, and other plants. However, Bal31digestion kinetics indicates non-telomeric localization of the 700-bp tandem repeats. The clones represent a novel repeat family as (i) they contain telomere-like motifs as subrepeats within each unit; and (ii) they do not hybridize to related crucifers and are species-specific in nature. Key words : Brassica species, Sinapis arvensis, tandem repeats, telomeres.
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CLARK, EVE V., and JOSIE BERNICOT. "Repetition as ratification: How parents and children place information in common ground*." Journal of Child Language 35, no. 2 (April 16, 2008): 349–71. http://dx.doi.org/10.1017/s0305000907008537.
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ABSTRACTRepetition is used for a range of functions in conversation. In this study, we examined all the repetitions used in spontaneous conversations by 41 French adult–child dyads, with children aged 2 ; 3 and 3 ; 6, to test the hypotheses that adults repeat to establish that they have understood, and that children repeat to ratify what adults have said. Analysis of 978 exchanges containing repetitions showed that adults use them to check on intentions and to correct errors, while children use them to ratify what the adult said. With younger children, adults combine their repeats with new information. Children then re-repeat the form originally targeted by the adult. With older children, adults check on intentions but less frequently, and only occasionally check on forms. Older children also re-repeat in the third turn but, like adults, add further information. For both adults and children, repeats signal attention to the other's utterances, and place the information repeated in common ground.
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Khristich, Alexandra N., and Sergei M. Mirkin. "On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability." Journal of Biological Chemistry 295, no. 13 (February 14, 2020): 4134–70. http://dx.doi.org/10.1074/jbc.rev119.007678.
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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?
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Khristich, Alexandra N., Jillian F. Armenia, Robert M. Matera, Anna A. Kolchinski, and Sergei M. Mirkin. "Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability." Proceedings of the National Academy of Sciences 117, no. 3 (January 7, 2020): 1628–37. http://dx.doi.org/10.1073/pnas.1913416117.
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Friedreich’s ataxia (FRDA) is a human hereditary disease caused by the presence of expanded (GAA)n repeats in the first intron of the FXN gene [V. Campuzano et al., Science 271, 1423–1427 (1996)]. In somatic tissues of FRDA patients, (GAA)n repeat tracts are highly unstable, with contractions more common than expansions [R. Sharma et al., Hum. Mol. Genet. 11, 2175–2187 (2002)]. Here we describe an experimental system to characterize GAA repeat contractions in yeast and to conduct a genetic analysis of this process. We found that large-scale contraction is a one-step process, resulting in a median loss of ∼60 triplet repeats. Our genetic analysis revealed that contractions occur during DNA replication, rather than by various DNA repair pathways. Repeats contract in the course of lagging-strand synthesis: The processivity subunit of DNA polymerase δ, Pol32, and the catalytic domain of Rev1, a translesion polymerase, act together in the same pathway to counteract contractions. Accumulation of single-stranded DNA (ssDNA) in the lagging-strand template greatly increases the probability that (GAA)n repeats contract, which in turn promotes repeat instability in rfa1, rad27, and dna2 mutants. Finally, by comparing contraction rates for homopurine-homopyrimidine repeats differing in their mirror symmetry, we found that contractions depend on a repeat’s triplex-forming ability. We propose that accumulation of ssDNA in the lagging-strand template fosters the formation of a triplex between the nascent and fold-back template strands of the repeat. Occasional jumps of DNA polymerase through this triplex hurdle, result in repeat contractions in the nascent lagging strand.
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An, Wenfeng, and Alice Telesnitsky. "Effects of Varying Sequence Similarity on the Frequency of Repeat Deletion during Reverse Transcription of a Human Immunodeficiency Virus Type 1 Vector." Journal of Virology 76, no. 15 (August 1, 2002): 7897–902. http://dx.doi.org/10.1128/jvi.76.15.7897-7902.2002.
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ABSTRACT Genetic recombination contributes to human immunodeficiency virus type 1 (HIV-1) diversity, with homologous recombination being more frequent than nonhomologous recombination. In this study, HIV-1-based vectors were used to assay the effects of various extents of sequence divergence on the frequency of the recombination-related property of repeat deletion. Sequence variation, similar in degree to that which differentiates natural HIV-1 isolates, was introduced by synonymous substitutions into a gene segment. Repeated copies of this segment were then introduced into assay vectors. With the use of a phenotypic screen, the deletion frequency of identical repeats was compared to the frequencies of repeats that differed in sequence by various extents. During HIV-1 reverse transcription, the deletion frequency observed with repeats that differed by 5% was 65% of that observed with identical repeats. The deletion frequency decreased to 26% for repeats that differed by 9%, and when repeats differed by 18%, the deletion frequency was about 5% of the identical repeat value. Deletion frequencies fell to less than 0.3% of identical repeat values when genetic distances of 27% or more were examined. These data argue that genetic variation is not as inhibitory to HIV-1 repeat deletion as it is to the corresponding cellular process and suggest that, for sequences that differ by about 25% or more, HIV-1 recombination directed by sequence homology may be no more frequent than that which is homology independent.
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ZHU, YONG, JOAN E. STRASSMANN, and DAVID C. QUELLER. "Insertions, substitutions, and the origin of microsatellites." Genetical Research 76, no. 3 (December 2000): 227–36. http://dx.doi.org/10.1017/s001667230000478x.
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This paper uses data from the Human Gene Mutation Database to contrast two hypotheses for the origin of short DNA repeats: substitutions and insertions that duplicate adjacent sequences. Because substitutions are much more common than insertions, they are the dominant source of new 2-repeat loci. Insertions are rarer, but over 70% of the 2–4 base insertion mutations are duplications of adjacent sequences, and over half of these generate new repeat regions. Insertions contribute fewer new repeat loci than substitutions, but their relative importance increases rapidly with repeat number so that all new 4–5-repeat mutations come from insertions, as do all 3-repeat mutations of tetranucleotide repeats. This suggests that the process of repeat duplication that dominates microsatellite evolution at high repeat numbers is also important very early in microsatellite evolution. This result sheds light on the puzzle of the origin of short tandem repeats. It also suggests that most short insertion mutations derive from a slippage-like process during replication.
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Mills, Ryan D., Terrence D. Mulhern, Heung-Chin Cheng, and Janetta G. Culvenor. "Analysis of LRRK2 accessory repeat domains: prediction of repeat length, number and sites of Parkinson's disease mutations." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1086–89. http://dx.doi.org/10.1042/bst20120088.
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Various investigators have identified the major domain organization of LRRK2 (leucine-rich repeat kinase 2), which includes a GTPase ROC (Ras of complex proteins) domain followed by a COR (C-terminal of ROC) domain and a protein kinase domain. In addition, there are four domains composed of structural repeat motifs likely to be involved in regulation and localization of this complex protein. In the present paper, we report our bioinformatic analyses of the human LRRK2 amino acid sequence to predict the repeat size, number and likely boundaries for the armadillo repeat, ankyrin repeat, the leucine-rich repeat and WD40 repeat regions of LRRK2. Homology modelling using known protein structures with similar domains was used to predict structures, exposed residues and location of mutations for these repeat regions. We predict that the armadillo repeats, ankyrin repeats and leucine-rich repeats together form an extended N-terminal flexible ‘solenoid’-like structure composed of tandem repeat modules likely to be important in anchoring to the membrane and cytoskeletal structures as well as binding to other protein ligands. Near the C-terminus of LRRK2, the WD40 repeat region is predicted to form a closed propeller structure that is important for protein complex formation.
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Munz, Stevie M. "Repeat." Departures in Critical Qualitative Research 6, no. 2 (2017): 74–75. http://dx.doi.org/10.1525/dcqr.2017.6.2.74.
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In this letter, written to my sister, I connect memories from our childhood to present-day lived experiences. By presenting my memories as fragments, I reveal them as ruptures that are layered with history and unresolved feelings. Through reflection, I show how the choices in the present repeat the history of the past. A family history tied to the military, sibling relationships, and life choices are all re-experienced.
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Borg, Anton, and Martin Svensson. "All Burglaries Are Not the Same: Predicting Near-Repeat Burglaries in Cities Using Modus Operandi." ISPRS International Journal of Geo-Information 11, no. 3 (February 23, 2022): 160. http://dx.doi.org/10.3390/ijgi11030160.
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The evidence that burglaries cluster spatio-temporally is strong. However, research is unclear on whether clustered burglaries (repeats/near-repeats) should be treated as qualitatively different crimes compared to spatio-temporally unrelated burglaries (non-repeats). This study, therefore, investigated if there were differences in modus operandi-signatures (MOs, the habits and methods employed by criminals) between near-repeat and non-repeat burglaries across 10 Swedish cities, as well as whether MO-signatures can aid in predicting if a burglary is classified as a near-repeat or a non-repeat crime. Data consisted of 5744 residential burglaries, with 137 MO features characterizing each case. Descriptive data of repeats/non-repeats is provided together with Wilcoxon tests of MO-differences between crime pairs, while logistic regressions were used to train models to predict if a crime scene was classified as a near-repeat or a non-repeat crime. Near-repeat crimes were rather stylized, showing heterogeneity in MOs across cities, but showing homogeneity within cities at the same time, as there were significant differences between near-repeat and non-repeat burglaries, including subgroups of features, such as differences in mode of entering, target selection, types of goods stolen, as well the traces that were left at the crime scene. Furthermore, using logistic regression models, it was possible to predict near-repeat and non-repeat crimes with a mean F1-score of 0.8155 (0.0866) based on the MO. Potential policy implications are discussed in terms of how data-driven procedures can facilitate analysis of spatio-temporal phenomena based on the MO-signatures of offenders, as well as how law enforcement agencies can provide differentiated advice and response when there is suspicion that a crime is part of a series as opposed to an isolated event.
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Reichen, Christian, Chaithanya Madhurantakam, Simon Hansen, Markus G. Grütter, Andreas Plückthun, and Peer R. E. Mittl. "Structures of designed armadillo-repeat proteins show propagation of inter-repeat interface effects." Acta Crystallographica Section D Structural Biology 72, no. 1 (January 1, 2016): 168–75. http://dx.doi.org/10.1107/s2059798315023116.
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The armadillo repeat serves as a scaffold for the development of modular peptide-recognition modules. In order to develop such a system, three crystal structures of designed armadillo-repeat proteins with third-generation N-caps (YIII-type), four or five internal repeats (M-type) and second-generation C-caps (AII-type) were determined at 1.8 Å (His-YIIIM4AII), 2.0 Å (His-YIIIM5AII) and 1.95 Å (YIIIM5AII) resolution and compared with those of variants with third-generation C-caps. All constructs are full consensus designs in which the internal repeats have exactly the same sequence, and hence identical conformations of the internal repeats are expected. The N-cap and internal repeats M1to M3are indeed extremely similar, but the comparison reveals structural differences in internal repeats M4and M5and the C-cap. These differences are caused by long-range effects of the C-cap, contacting molecules in the crystal, and the intrinsic design of the repeat. Unfortunately, the rigid-body movement of the C-terminal part impairs the regular arrangement of internal repeats that forms the putative peptide-binding site. The second-generation C-cap improves the packing of buried residues and thereby the stability of the protein. These considerations are useful for future improvements of an armadillo-repeat-based peptide-recognition system.
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Ida, Cristiane M., Malinda L. Butz, Patrick A. Lundquist, and D. Brian Dawson. "C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing." Neurodegenerative Diseases 18, no. 5-6 (2018): 239–53. http://dx.doi.org/10.1159/000492499.
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Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.
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Yang, Su, Huiming Yang, Luoxiu Huang, Luxiao Chen, Zhaohui Qin, Shihua Li, and Xiao-Jiang Li. "Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice." Proceedings of the National Academy of Sciences 117, no. 8 (February 6, 2020): 4411–17. http://dx.doi.org/10.1073/pnas.1919197117.
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Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.
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Smith, Kirby D., Keith E. Young, C. Conover Talbot, and Barbara J. Schmeckpeper. "Repeated DNA of the human Y chromosome." Development 101, Supplement (March 1, 1987): 77–92. http://dx.doi.org/10.1242/dev.101.supplement.77.
Full textAbstract:
A significant fraction of the human Y chromosome is composed of DNA sequences which have homologues on the X chromosome or autosomes in humans and non-human primates. However, most human Ychromosome sequences so far examined do not have homologues on the Y chromosomes of other primates. This observation suggests that a significant proportion of the human Y chromosome is composed of sequences that have acquired their Y-chromosome association since humans diverged from other primates. More than 50 % of the human Y chromosome is composed of a variety of repeated DNAs which, with one known exception, can be distinguished from homologues elsewhere in the genome. These include the alphoid repeats, the major human SINE (Alu repeats) and several additional families of repeats which account for the majority of Y-chromosome repeated DNA. The alphoid sequences tandemly clustered near the centromere on the Y chromosome can be distinguished from those on other chromosomes by both sequence and repeat organization, while the majority of Y-chromosome Alu repeats have little homology with genomic consensus Alu sequences. In contrast, the Y-chromosome LINE repeats cannot be distinguished from LINEs found on other chromosomes. It has been proposed that both SINE and LINE repeats have been dispersed throughout the genome by mechanisms that involve RNA intermediates. The difference in the relationship of the Y-chromosome Alu and LINE repeats to their respective family members elsewhere in the genome makes it possible that their dispersal to the Y chromosome has occurred by different mechanisms or at different rates. In addition to the SINE and LINE repeats, the human Y chromosome contains a group of repeated DNA elements originally identified as 3·4 and 2·1 kb fragments in HaeIII digests of male genomic DNA. Although the 3·4 and 2·1 kb Y repeats do not crossreact, both exist as tandem clusters of alternating Yspecific and non-Y-specific sequences. The 3·4 kb Y repeats contain at least three distinct sequences with autosomal homologies interspersed in various ways with a collection of several different Yspecific repeat sequences. Individual recombinant clones derived from isolated 3·4 kb HaeIII Y fragments have been identified which do not cross-react. Thus, the 3·4 kb HaeIII Y fragments are a heterogeneous mixture of sequences which have in common the regular occurrence of HaeIII restriction sites at 3·4 kb intervals and an organization as tandem clusters at various sites along the Y-long arm. The 2·1 kb HaeIII Y fragment cross-reacts with a 1i9 kb HaeIII autosomal fragment. Both the Ychromosomal and autosomal fragments are part of tandem clusters which have a unit length of 2·4 kb. All of the 2·4 kb Y repeats are similar and contain a 1·6 kb Y-specific repeat and an 800 bp sequence which has homology with an 800 bp sequence in the autosomal 2·4 kb repeats. While this 800 bp sequence is common to both Y and autosomal 2·4 kb repeats and is associated with a single Y-specific repeat, it is associated with at least four non-cross-reacting autosome-specific sequences. Like the Y repeat, the autosomal repeats exist as tandem clusters of 2·4 kb units and are composed of an 800 bp common sequence alternating with a 1·6 kb autosome-specific sequence. Thus, in humans, the common sequence is associated with several different sequences yet always occurs as part of a tandem cluster of 2·4 kb repeats. The common and autosome-specific sequences of the 2·4 kb repeats are also present in gorillas as part of organized repeat units. However, in gorillas the two are not associated with each other. The Y-chromosome repeats described here are a heterogeneous mixture of sequences organized into specific sets of alternating Y-specific and non-Y-specific sequences. They do not have an identified function and the mechanisms by which they are generated are unknown. Nevertheless, their marked chromosomal speciticity and the regularity of the basic repeat unit in each type of repeat seem inconsistent with stochastic mechanisms of sequence diffusion between chromosomes.
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van ‘t Spijker, Heleen M., Emily E. Stackpole, Sandra Almeida, Olga Katsara, Botao Liu, Kuang Shen, Robert J. Schneider, Fen-Biao Gao, and Joel D. Richter. "Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation." RNA 28, no. 2 (November 30, 2021): 123–38. http://dx.doi.org/10.1261/rna.078963.121.
Full textAbstract:
GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G4C2) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G4C2) repeat-containing RNA is a substrate for DPR protein synthesis. (G4C2) repeat-containing RNA translation is 5′ cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G4C2) repeat-containing RNA in disease.
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Adindla, S., K. K. Inampudi, K. Guruprasad, and L. Guruprasad. "Identification and Analysis of Novel Tandem Repeats in the Cell Surface Proteins of Archaeal and Bacterial Genomes Using Computational Tools." Comparative and Functional Genomics 5, no. 1 (2004): 2–16. http://dx.doi.org/10.1002/cfg.358.
Full textAbstract:
We have identified four novel repeats and two domains in cell surface proteins encoded by theMethanosarcina acetivoransgenome and in some archaeal and bacterial genomes. The repeats correspond to a certain number of amino acid residues present in tandem in a protein sequence and each repeat is characterized by conserved sequence motifs. These correspond to: (a) a 42 amino acid (aa) residue RIVW repeat; (b) a 45 aa residue LGxL repeat; (c) a 42 aa residue LVIVD repeat; and (d) a 54 aa residue LGFP repeat. The domains correspond to a certain number of aa residues in a protein sequence that do not comprise internal repeats. These correspond to: (a) a 200 aa residue DNRLRE domain; and (b) a 70 aa residue PEGA domain. We discuss the occurrence of these repeats and domains in the different proteins and genomes analysed in this work.
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Huang, Ying, Xin Huang, Xuming Zhou, Jialin Wang, Ruidong Zhang, Futong Ma, Kaiqiang Wang, et al. "Immune activation by a multigene family of lectins with variable tandem repeats in oriental river prawn ( Macrobrachium nipponense )." Open Biology 10, no. 9 (September 2020): 200141. http://dx.doi.org/10.1098/rsob.200141.
Full textAbstract:
Genomic regions with repeated sequences are unstable and prone to rapid DNA diversification. However, the role of tandem repeats within the coding region is not fully characterized. Here, we have identified a new hypervariable C-type lectin gene family with different numbers of tandem repeats (Rlecs; R means repeat) in oriental river prawn ( Macrobrachium nipponense ) . Two types of repeat units (33 or 30 bp) are identified in the second exon, and the number of repeat units vary from 1 to 9. Rlecs can be classified into 15 types through phylogenetic analysis. The amino acid sequences in the same type of Rlec are highly conservative outside the repeat regions. The main differences among the Rlec types are evident in exon 5. A variable number of tandem repeats in Rlecs may be produced by slip mispairing during gene replication. Alternative splicing contributes to the multiplicity of forms in this lectin gene family, and different types of Rlecs vary in terms of tissue distribution, expression quantity and response to bacterial challenge. These variations suggest that Rlecs have functional diversity. The results of experiments on sugar binding, microbial inhibition and clearance, regulation of antimicrobial peptide gene expression and prophenoloxidase activation indicate that the function of Rlecs with the motif of YRSKDD in innate immunity is enhanced when the number of tandem repeats increases. Our results suggest that Rlecs undergo gene expansion through gene duplication and alternative splicing, which ultimately leads to functional diversity.
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Sipahi, Hülya, Ayşen Yumurtaci, and Zafer Mert. "Development of novel markers, using computationally extracted classi type EST-SSRs, in wheat leaf rust fungus Puccinia triticina." Genetika 47, no. 3 (2015): 917–26. http://dx.doi.org/10.2298/gensr1503917s.
Full textAbstract:
This study focused on the development of EST-simple sequence repeats markers and the detection of their transferability and their utility for evaluating wheat leaf rust pathogen diversity. A total of 44,407 publicly available EST sequences derived from Puccinia triticina were computationally mined. Di-nucleotide repeat density covered the vast majority of assembled ESTs (45%). The tri-repeat motif (TCT) and penta-repeat motif (TTCTT) were the most repeated motif. A set of 103 Class I type sequences containing simple sequence repeats were further analyzed by BLASTX similarity. Nineteen primer pairs flanking regions of EST-SSRs were designed. Of the 19 primer pairs tested, 10 successfully amplified fragments. Their polymorphism was evaluated with 8 Puccinia triticina (Pt) single-uredinal isolates collected from the different regions of Turkey. These newly developed EST-SSR primer pairs can be implicated as stable markers for pathogen diversity analysis. It was also shown that some leaf rust EST-SSR markers were capable of cross-amplification in P. graminis f. sp. tritici.
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Brouwer, Judith Rixt, Aline Huguet, Annie Nicole, Arnold Munnich, and Geneviève Gourdon. "Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus." Journal of Nucleic Acids 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/567435.
Full textAbstract:
An expanded CTG-repeat in the 3′ UTR of theDMPKgene is responsible for myotonic dystrophy type I (DM1). Somatic and intergenerational instability cause the disease to become more severe during life and in subsequent generations. Evidence is accumulating that trinucleotide repeat instability and disease progression involve aberrant chromatin dynamics. We explored the chromatin environment in relation to expanded CTG-repeat tracts in hearts from transgenic mice carrying the DM1 locus with different repeat lengths. Using bisulfite sequencing we detected abundant CpG methylation in the regions flanking the expanded CTG-repeat. CpG methylation was postulated to affect CTCF binding but we found that CTCF binding is not affected by CTG-repeat length in our transgenic mice. We detected significantly decreasedDMPKsense andSIX5transcript expression levels in mice with expanded CTG-repeats. Expression of the DM1 antisense transcript was barely affected by CTG-repeat expansion. In line with altered gene expression, ChIP studies revealed a locally less active chromatin conformation around the expanded CTG-repeat, namely, decreased enrichment of active histone mark H3K9/14Ac and increased H3K9Me3 enrichment (repressive chromatin mark). We also observed binding of PCNA around the repeats, a candidate that could launch chromatin remodelling cascades at expanded repeats, ultimately affecting gene transcription and repeat instability.
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Quan, Lihong, and Jinlong Ma. "A study of repeat-formatted repair initiations in Mandarin Chinese conversation." Chinese Language and Discourse 10, no. 2 (December 31, 2019): 158–86. http://dx.doi.org/10.1075/cld.18014.qua.
Full textAbstract:
Abstract Using the methodology of Conversation Analysis (or CA), this study examines three types of other-initiated repair initiators (henceforth OIs) that repeats some element in the trouble-source (henceforth repeats) in Chinese conversation: repeats suffixed with question particles ma (吗), repeats suffixed with question particles a (啊), and question-intonated repeats. It attempts to explore the differences between these typical formats, in terms of their forms/functions and the epistemic stance of the speaker who initiates repair. The main research findings indicate that question-intonated repeat implements an understanding check while repeat suffixed with question particles (ma or a) tends to serve different functions, in that, ma-suffixed repeat is inquiry-implicated while a-suffixed repeat contributes to constructing surprise, (dis)agreement or (dis)belief.
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Palsbøll, Per J., Martine Bérubé, and Hanne Jørgensen. "Multiple Levels of Single-Strand Slippage at Cetacean Tri- and Tetranucleotide Repeat Microsatellite Loci." Genetics 151, no. 1 (January 1, 1999): 285–96. http://dx.doi.org/10.1093/genetics/151.1.285.
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Abstract Between three and six tri- and tetranucleotide repeat microsatellite loci were analyzed in 3720 samples collected from four different species of baleen whales. Ten of the 18 species/locus combinations had imperfect allele arrays, i.e., some alleles differed in length by other than simple integer multiples of the basic repeat length. The estimate of the average number of alleles and heterozygosity was higher at loci with imperfect allele arrays relative to those with perfect allele arrays. Nucleotide sequences of 23 different alleles at one tetranucleotide repeat microsatellite locus in fin whales, Balaenoptera physalus, and humpback whales, Megaptera novaeangliae, revealed sequence changes including perfect repeats only, multiple repeats, and partial repeats. The relative rate of the latter two categories of mutation was estimated at 0.024 of the mutation rate involving perfect repeats only. It is hypothesized that single-strand slippage of partial repeats may provide a mechanism for counteracting the continuous expansion of microsatellite loci, which is the logical consequence of recent reports demonstrating directional mutations. Partial-repeat mutations introduce imperfections in the repeat array, which subsequently could reduce the rate of single-strand slippage. Limited computer simulations confirmed this predicted effect of partial-repeat mutations.
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Jasinska, Anna J., Piotr Kozlowski, and Wlodzimierz J. Krzyzosiak. "Expression characteristics of triplet repeat-containing RNAs and triplet repeat-interacting proteins in human tissues." Acta Biochimica Polonica 55, no. 1 (January 30, 2008): 1–8. http://dx.doi.org/10.18388/abp.2008_3090.
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Numerous human transcripts contain tandem repeats of trinucleotide motifs, the function of which remains unknown. In this study we used the available gene expression EST data to characterize the abundance of a large group of these transcripts in different tissues and determine the mRNAs which had the highest contribution to the observed levels of transcripts containing different types of the CNG repeats. A more extensive characteristics was performed for transcripts containing the CUG repeats, and those encoding the repeat-binding proteins. The scarcity of double-stranded CUG repeats as well as various proportions of the single-stranded and double-stranded CUG repeat-binding proteins were revealed in the studied transcriptomes. The observed correlated levels of transcripts containing single-stranded CUG repeats and of proteins binding single-stranded CUG repeats may imply that in addition to transcripts which only provide binding sites for these proteins there may be a substantial portion of the transcripts whose metabolism is directly regulated by such proteins. Our results showing a highly variable composition of triplet repeat-containing transcripts and their interacting proteins in different tissues may contribute to a better understanding of the mechanism of RNA-mediated pathogenesis in triplet repeat expansion diseases.
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Jarjanazi, Hamdi, Hong Li, Irene L. Andrulis, and Hilmi Ozcelik. "Genome Wide Screening of CAG Trinucleotide Repeat Lengths in Breast Cancer." Disease Markers 22, no. 5-6 (2006): 343–49. http://dx.doi.org/10.1155/2006/951857.
Full textAbstract:
Trinucleotide repeat sequences are widely present in the human genome. The expansion of CAG repeats have been studied very extensively, and shown to be the causative mechanism of more than 40 neuromuscular and neurodegenerative diseases. In the present study, we performed a genome wide screening of CAG repeat expansions in non-neoplastic tissues of 212 breast cancer cases and 196 healthy population controls using the Repeat Expansion Detection (RED) method. Distribution of CAG repeat lengths in cases was not significantly different from controls. However, dramatically expanded CAG repeats were detected in 2.4% (n= 5) of breast cancer cases where no repeats of similar size were detected in any of the healthy population controls. Although this trend shows only borderline significance (p= 0.06), this finding suggests a potential involvement of CAG repeat expansion in breast cancer susceptibility. These repeats may potentially affect the function of cancer predisposition genes, with a similar mechanism as in neurodegenerative and neuromuscular disorders.
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Falistocco, E., V. Passeri, and G. Marconi. "Investigations of 5S rDNA of Vitis vinifera L.: sequence analysis and physical mapping." Genome 50, no. 10 (October 2007): 927–38. http://dx.doi.org/10.1139/g07-070.
Full textAbstract:
Here we report the first results of a study of 5S rDNA of Vitis vinifera . 5S rDNA sequences from seven genotypes were amplified by PCR, cloned, and sequenced. Three types of repeats were found. Two variants, denominated long repeat and short repeat, appeared to be the main components of the 5S rDNA of this species, since they were found in all genotypes analyzed. They differed markedly from each other in both the length and the nucleotide composition of the spacers. The third variant, classified as DEL short repeat, differs from the short repeat owing to a large deletion in the spacer region. It appears to be the most recent repeat type, since it was identified in only one genotype. The organization of the 5S rDNA repeat unit variants was investigated by amplifying the genomic DNA with primers designed on the sequence of the long and short spacers. The PCR-amplified fragments showed that the long repeat is associated with the other two repeats, indicating that in V. vinifera different repeat units coexist within the same tandem array. FISH analysis demonstrated that 5S rRNA genes are localized at a single locus. The variability of 5S rDNA repeats is discussed in relation to the putative allopolyploid origin of V. vinifera.
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Wan, Hua, Shan Chang, Jian-ping Hu, Xu-hong Tian, and Mei-hua Wang. "Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study." BioMed Research International 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/8036450.
Full textAbstract:
TAL effectors (TALEs) contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat. The structural stability analysis indicates that the modeled system is more stable than the nonmodeled system. Based on the principle component analysis, it is found that the AvrBs3 increases its structural compactness in the presence of the last half repeat. The comparison of DNA groove parameters of the two systems implies that the last half repeat also causes the change of DNA major groove binding efficiency. The following calculation of hydrogen bond reveals that, by stabilizing the phosphate binding with DNA at the C-terminus, the last half repeat helps to adopt a compact conformation at the protein-DNA interface. It further mediates more contacts between TAL repeats and DNA nucleotide bases. Finally, we suggest that the last half repeat is required for the high-efficient recognition of DNA by TALE.
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Stabach, Paul R., Ivana Simonović, Miranda A. Ranieri, Michael S. Aboodi, Thomas A. Steitz, Miljan Simonović, and Jon S. Morrow. "The structure of the ankyrin-binding site of β-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties." Blood 113, no. 22 (May 28, 2009): 5377–84. http://dx.doi.org/10.1182/blood-2008-10-184291.
Full textAbstract:
Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability. Repeats 14 and 15 of βI-spectrin are crucial for ankyrin recognition, yet the way spectrin binds ankyrin while preserving its repeat structure is unknown. We have solved the crystal structure of the βI-spectrin 14,15 di-repeat unit to 2.1 Å resolution and found 14 residues critical for ankyrin binding that map to the end of the helix C of repeat 14, the linker region, and the B-C loop of repeat 15. The tilt (64°) across the 14,15 linker is greater than in any published di-repeat structure, suggesting that the relative positioning of the two repeats is important for ankyrin binding. We propose that a lack of structural constraints on linker and inter-helix loops allows proteins containing spectrin-like di-repeats to evolve diverse but specific ligand-recognition sites without compromising the structure of the repeat unit. The linker regions between repeats are thus critical determinants of both spectrin's flexibility and polyfunctionality. The putative coupling of flexibility and ligand binding suggests a mechanism by which spectrin might participate in mechanosensory regulation.
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Han, S. W., T. Y. Kim, K. W. Lee, D. Y. Oh, S. H. Lee, D. W. Kim, D. H. Chung, S. A. Im, D. S. Heo, and Y. J. Bang. "EGFR mutation and intron 1 CA repeat polymorphism as predictive markers of gefitinib responsiveness in non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7173. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7173.
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7173 Background: EGFR mutation is significantly associated with objective response and prolonged survival in NSCLC patients treated with gefitinib. However, presence of mutant nonresponses and nonmutant responses mandates investigation of other molecular markers for more effective prediction of gefitinib sensitivity in NSCLC. It is unclear whether low CA repeat number in EGFR intron 1 has such a predictive role. Methods: Advanced NSCLC patients received gefitinib 250mg/day. EGFR mutation in exons 18 - 21 were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. Number of CA repeat in intron 1 of EGFR was determined by GeneScan with tumoral DNA. Baseline characteristics, mutational status, CA repeat number and efficacy of gefitinib were analyzed in respect to each other. Results: To date, 73 patients were evaluable for EGFR mutation, CA repeat and gefitinib responsiveness. 14 patients (19.2%) harbored EGFR mutation (7 deletion in exon 19, 4 L858R, 1 L861Q, 1 G719A, and 1 insertion in exon 20). Most common CA repeat genotype was 20/20 repeat (31 patients) followed by 16/20 repeat (15 patients). Patients were classified as having either low CA repeat (sum of both allele ≤ 37 repeats) or high CA repeat (≥ 38 repeats). 34 patients (46.6%) had low repeat, whereas 39 patients (53.4%) had high repeat. Patients with EGFR mutation showed better objective response (response rate [RR] 57.1% vs. 10.2% in wild type [WT], p < 0.001), time-to-progression (TTP) (p = 0.031, median 5.1 vs. 1.9 months in WT), and overall survival (OS) (p = 0.051, median14.5 vs. 7.4 months in WT). In the whole study population, low CA repeat was not associated with RR (p = 0.38), TTP (p = 0.15), or OS (p = 0.51). However, in the 59 patients without an EGFR mutation, patients with low CA repeat tended to have better objective response (RR 17.2% [5/29] in low repeat vs. 3.3% [1/30] in high repeat, p = 0.10) and significantly better TTP (p = 0.019, median 2.2 months in low repeat vs. 1.2 months in high repeat). Conclusions: Our results suggest that low number of CA repeats in EGFR intron 1 may have possible role in prediction of gefitinib responsiveness when analyzed together with EGFR mutational status. [Table: see text]
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Su, Xiaofeng A., and Catherine H. Freudenreich. "Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences 114, no. 40 (September 18, 2017): E8392—E8401. http://dx.doi.org/10.1073/pnas.1711283114.
Full textAbstract:
CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies. Deletion of yeast cytosine deaminase Fcy1 significantly decreased the rate of CAG repeat fragility and contractions in the rnh1Δrnh201Δ background, indicating that Fcy1-mediated deamination is one cause of breakage and contractions in the presence of R-loops. Furthermore, base excision repair (BER) is responsible for causing CAG repeat contractions downstream of Fcy1, but not fragility. The Rad1/XPF and Rad2/XPG nucleases were also important in protecting against contractions, but through BER rather than nucleotide excision repair. Surprisingly, the MutLγ (Mlh1/Mlh3) endonuclease caused R-loop–dependent CAG fragility, defining an alternative function for this complex. These findings provide evidence that breakage at expanded CAG repeats occurs due to R-loop formation and reveal two mechanisms for CAG repeat instability: one mediated by cytosine deamination of DNA engaged in R-loops and the other by MutLγ cleavage. Since disease-causing CAG repeats occur in transcribed regions, our results suggest that R-loop–mediated fragility is a mechanism that could cause DNA damage and repeat-length changes in human cells.
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Franck, Jens P. C., and Jonathan M. Wright. "Conservation of a satellite DNA sequence (SATB) in the tilapiine and haplochromine genome (Pisces: Cichlidae)." Genome 36, no. 1 (February 1, 1993): 187–94. http://dx.doi.org/10.1139/g93-025.
Full textAbstract:
We have cloned and sequenced a 1900-bp EcoRI fragment (SATB) from the tilapiine fish Oreochromis niloticus. The SATB sequence is highly reiterated in the tilapiine genome and organized in long tandem arrays. A 760-bp HindIII fragment, an internal component of SATB, has also been cloned and sequenced from the related tilapiine species Oreochromis hornorum. Hybridization of the radiolabeled 760-bp HindIII repeat detected the presence of the SATB repeat in the genomes of several tilapiine species as well as the haplochromine species Haplochromis (Protomelas) similis. The 760-bp HindIII fragment did not hybridize to genomic DNA of Etroplus maculatus (an Asian cichlid) or to that of Cichlasoma meeki (a South American cichlid). The SATB repeat sequence is 56% AT and constitutes 0.2–5% of the tilapiine genome depending on the species examined. Four imperfect 21-bp direct repeat sequences are present within the cloned 1900-bp EcoRI repeat. Alignment of the four direct repeats from the O. niloticus cloned 1900-bp DNA and the two homologous direct repeats from the O. hornorum 760-bp HindIII repeat revealed a core motif of 11 bp that exhibits 100% sequence identity between all of the direct repeats. The conservation of this motif in the SATB repeat suggests that this sequence may be under selective constraint.Key words: satellite DNA, Cichlidae, direct repeats.
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Bowman, Robert R., Wei-Shau Hu, and Vinay K. Pathak. "Relative Rates of Retroviral Reverse Transcriptase Template Switching during RNA- and DNA-Dependent DNA Synthesis." Journal of Virology 72, no. 6 (June 1, 1998): 5198–206. http://dx.doi.org/10.1128/jvi.72.6.5198-5206.1998.
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ABSTRACT Retroviral reverse transcriptases (RTs) frequently switch templates during DNA synthesis, which can result in mutations and recombination. The relative rates of in vivo RT template switching during RNA- and DNA-dependent DNA synthesis are unknown. To determine the relative rates of RT template switching during copying of RNA and DNA templates, we constructed spleen necrosis virus-based retroviral vectors containing a 400-bp direct repeat. The directly repeated sequences were upstream of the polypurine tract (PPT) in the RB-LLP vector; the same direct repeats flanked the PPT and attachment site (att) in the RB-LPL vector. RT template switching events could occur during either RNA- or DNA-dependent DNA synthesis and delete one copy of the direct repeat plus the intervening sequences. RB-LLP vectors that underwent direct repeat deletions during RNA- and DNA-dependent DNA synthesis generated viral DNA that could integrate into the host genome. However, any deletion of the direct repeats in the RB-LPL vector that occurred during RNA-dependent DNA synthesis resulted in deletion of the essential PPT and att site and generated a dead-end viral DNA product. Thus, only RB-LPL vectors that underwent direct repeat deletions during DNA-dependent DNA synthesis could integrate to form proviruses. The RB-LLP and RB-LPL vectors were permitted to undergo a single replication cycle, and the frequencies of direct repeat deletions were determined by PCR and Southern analysis of the resulting proviruses. A comparison of the frequency of direct repeat deletions in the RB-LLP and RB-LPL vectors indicated that the in vivo rates of RT template switching during RNA- and DNA-dependent DNA synthesis are nearly identical.
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Gorbunova, Vera, Andrei Seluanov, Vincent Dion, Zoltan Sandor, James L. Meservy, and John H. Wilson. "Selectable System for Monitoring the Instability of CTG/CAG Triplet Repeats in Mammalian Cells." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4485–93. http://dx.doi.org/10.1128/mcb.23.13.4485-4493.2003.
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ABSTRACT Despite substantial progress in understanding the mechanism by which expanded CTG/CAG trinucleotide repeats cause neurodegenerative diseases, little is known about the basis for repeat instability itself. By taking advantage of a novel phenomenon, we have developed a selectable assay to detect contractions of CTG/CAG triplets. When inserted into an intron in the APRT gene or the HPRT minigene, long tracts of CTG/CAG repeats (more than about 33 repeat units) are efficiently incorporated into mRNA as a new exon, thereby rendering the encoded protein nonfunctional, whereas short repeat tracts do not affect the phenotype. Therefore, contractions of long repeats can be monitored in large cell populations, by selecting for HPRT+ or APRT+ clones. Using this selectable system, we determined the frequency of spontaneous contractions and showed that treatments with DNA-damaging agents stimulate repeat contractions. The selectable system that we have developed provides a versatile tool for the analysis of CTG/CAG repeat instability in mammalian cells. We also discuss how the effect of long CTG/CAG repeat tracts on splicing may contribute to the progression of polyglutamine diseases.
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NYEO, SU-LONG, and JUI-PING YU. "LENGTH DISTRIBUTIONS OF SIMPLE TANDEM REPEATS IN GENOMES." Journal of Biological Systems 15, no. 03 (September 2007): 299–312. http://dx.doi.org/10.1142/s0218339007002246.
Full textAbstract:
The length distributions of simple tandem repeats in the genomes of several organisms are evaluated and found to exhibit long-range correlations in A and T nucleotide bases related repeats for most eukaryotes. In particular, the length distributions of the mononucleotide A/T repeat units have longer tails than those of the C/G repeat units. Also, the length distributions of the dinucleotide repeat unit CG show a simple monotonously fast decreasing behavior, while those of repeat units AT, AG and AC have complicated structures at larger repeat lengths, especially for human, mouse and rat chromosomes. These distributive behaviors are due to the CpG deficiency in different genomes with different methylation activities. Especially, methyltransferases in vertebrates appear to methylate specifically the cytosine in CpG dinucleotides, and the methylated cytosines is prone to mutate to thymine by spontaneous deamination. The dinucleotide CpG would gradually decay into TpG and CpA. In addition, there is a peak in the distributions of repeat unit A at repeat-repeat separation 153 nt for humans and chimpanzees. We show that the long-tail behavior of mononucleotide repeat unit A and the peak at repeat separation 153 nt are due to the interspersed repetitive DNA sequences in humans and chimpanzees.
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Matsumura, R., N. Futamura, Y. Fujimoto, S. Yanagimoto, H. Horikawa, A. Suzumura, and T. Takayanagi. "Spinocerebellar ataxia type 6." Neurology 49, no. 5 (November 1997): 1238–43. http://dx.doi.org/10.1212/wnl.49.5.1238.
Full textAbstract:
Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.
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Schaper, Elke, Andrey V. Kajava, Alain Hauser, and Maria Anisimova. "Repeat or not repeat?—Statistical validation of tandem repeat prediction in genomic sequences." Nucleic Acids Research 40, no. 20 (August 24, 2012): 10005–17. http://dx.doi.org/10.1093/nar/gks726.
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Wells, J. M., J. L. Ellingson, D. M. Catt, P. J. Berger, and K. M. Karrer. "A small family of elements with long inverted repeats is located near sites of developmentally regulated DNA rearrangement in Tetrahymena thermophila." Molecular and Cellular Biology 14, no. 9 (September 1994): 5939–49. http://dx.doi.org/10.1128/mcb.14.9.5939.
Full textAbstract:
Extensive DNA rearrangement occurs during the development of the somatic macronucleus from the germ line micronucleus in ciliated protozoans. The micronuclear junctions and the macronuclear product of a developmentally regulated DNA rearrangement in Tetrahymena thermophila, Tlr1, have been cloned. The intrachromosomal rearrangement joins sequences that are separated by more than 13 kb in the micronucleus with the elimination of moderately repeated micronucleus-specific DNA sequences. There is a long, 825-bp, inverted repeat near the micronuclear junctions. The inverted repeat contains two different 19-bp tandem repeats. The 19-bp repeats are associated with each other and with DNA rearrangements at seven locations in the micronuclear genome. Southern blot analysis is consistent with the occurrence of the 19-bp repeats within pairs of larger repeated sequences. Another family member was isolated. The 19-mers in that clone are also in close proximity to a rearrangement junction. We propose that the 19-mers define a small family of developmentally regulated DNA rearrangements having elements with long inverted repeats near the junction sites. We discuss the possibility that transposable elements evolve by capture of molecular machinery required for essential cellular functions.
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Wells, J. M., J. L. Ellingson, D. M. Catt, P. J. Berger, and K. M. Karrer. "A small family of elements with long inverted repeats is located near sites of developmentally regulated DNA rearrangement in Tetrahymena thermophila." Molecular and Cellular Biology 14, no. 9 (September 1994): 5939–49. http://dx.doi.org/10.1128/mcb.14.9.5939-5949.1994.
Full textAbstract:
Extensive DNA rearrangement occurs during the development of the somatic macronucleus from the germ line micronucleus in ciliated protozoans. The micronuclear junctions and the macronuclear product of a developmentally regulated DNA rearrangement in Tetrahymena thermophila, Tlr1, have been cloned. The intrachromosomal rearrangement joins sequences that are separated by more than 13 kb in the micronucleus with the elimination of moderately repeated micronucleus-specific DNA sequences. There is a long, 825-bp, inverted repeat near the micronuclear junctions. The inverted repeat contains two different 19-bp tandem repeats. The 19-bp repeats are associated with each other and with DNA rearrangements at seven locations in the micronuclear genome. Southern blot analysis is consistent with the occurrence of the 19-bp repeats within pairs of larger repeated sequences. Another family member was isolated. The 19-mers in that clone are also in close proximity to a rearrangement junction. We propose that the 19-mers define a small family of developmentally regulated DNA rearrangements having elements with long inverted repeats near the junction sites. We discuss the possibility that transposable elements evolve by capture of molecular machinery required for essential cellular functions.
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Huang, Tze-Yun, Chung-ke Chang, Ya-Fen Kao, Chih-Hao Chin, Cheng-Wei Ni, Hao-Yi Hsu, Nien-Jen Hu, et al. "Parity-dependent hairpin configurations of repetitive DNA sequence promote slippage associated with DNA expansion." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): 9535–40. http://dx.doi.org/10.1073/pnas.1708691114.
Full textAbstract:
Repetitive DNA sequences are ubiquitous in life, and changes in the number of repeats often have various physiological and pathological implications. DNA repeats are capable of interchanging between different noncanonical and canonical conformations in a dynamic fashion, causing configurational slippage that often leads to repeat expansion associated with neurological diseases. In this report, we used single-molecule spectroscopy together with biophysical analyses to demonstrate the parity-dependent hairpin structural polymorphism of TGGAA repeat DNA. We found that the DNA adopted two configurations depending on the repeat number parity (even or odd). Transitions between these two configurations were also observed for longer repeats. In addition, the ability to modulate this transition was found to be enhanced by divalent ions. Based on the atomic structure, we propose a local seeding model where the kinked GGA motifs in the stem region of TGGAA repeat DNA act as hot spots to facilitate the transition between the two configurations, which may give rise to disease-associated repeat expansion.
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Krenz, J. D., R. D. Semlitsch, H. C. Gerhardt, and P. A. Mahoney. "Isolation and characterization of simple sequence repeat loci in the gray tree frog, Hyla chrysoscelis." Genome 42, no. 4 (August 1, 1999): 676–80. http://dx.doi.org/10.1139/g98-166.
Full textAbstract:
A gray tree frog (Hyla chrysoscelis) genomic library was constructed and characterized with regard to the incidence and complexity of simple sequence repeat (SSR) loci. The partial genomic library, containing approximately 10 000 clones with an average-sized insert of 350 bp, was screened with six SSR repeat oligonucleotides (AC, AG, ACG, AGC, AAC, and AAG). Screening identified 31 unique positive clones containing 41 SSR loci. Sequences of tandemly arrayed dinucleotide repeats were more common (36 of 41) than trinucleotide repeats. Twenty-six loci were identified using the AC dinucleotide probe, while 7 loci were identified using the AG dinucleotide probe. An additional 3 AT dinucleotide loci were serendipitously identified. The AT repeats generally comprised the longest dinucleotide repeat loci. The SSR repeat loci reported here should provide potent markers for identity, parentage, and short-lineage determinations in large-scale experiments using gray tree frogs.Key words: Hyla chrysoscelis, simple sequence repeat, SSR, gray tree frog, microsatellite.
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Taylor, John S., and Felix Breden. "Slipped-Strand Mispairing at Noncontiguous Repeats in Poecilia reticulata: A Model for Minisatellite Birth." Genetics 155, no. 3 (July 1, 2000): 1313–20. http://dx.doi.org/10.1093/genetics/155.3.1313.
Full textAbstract:
Abstract The standard slipped-strand mispairing (SSM) model for the formation of variable number tandem repeats (VNTRs) proposes that a few tandem repeats, produced by chance mutations, provide the “raw material” for VNTR expansion. However, this model is unlikely to explain the formation of VNTRs with long motifs (e.g., minisatellites), because the likelihood of a tandem repeat forming by chance decreases rapidly as the length of the repeat motif increases. Phylogenetic reconstruction of the birth of a mitochondrial (mt) DNA minisatellite in guppies suggests that VNTRs with long motifs can form as a consequence of SSM at noncontiguous repeats. VNTRs formed in this manner have motifs longer than the noncontiguous repeat originally formed by chance and are flanked by one unit of the original, noncontiguous repeat. SSM at noncontiguous repeats can therefore explain the birth of VNTRs with long motifs and the “imperfect” or “short direct” repeats frequently observed adjacent to both mtDNA and nuclear VNTRs.