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International Journal of Molecular... Feb 2021Repetitive DNA in humans is still widely considered to be meaningless, and variations within this part of the genome are generally considered to be harmless to the... (Review)
Review
Repetitive DNA in humans is still widely considered to be meaningless, and variations within this part of the genome are generally considered to be harmless to the carrier. In contrast, for euchromatic variation, one becomes more careful in classifying inter-individual differences as meaningless and rather tends to see them as possible influencers of the so-called 'genetic background', being able to at least potentially influence disease susceptibilities. Here, the known 'bad boys' among repetitive DNAs are reviewed. Variable numbers of tandem repeats (VNTRs = micro- and minisatellites), small-scale repetitive elements (SSREs) and even chromosomal heteromorphisms (CHs) may therefore have direct or indirect influences on human diseases and susceptibilities. Summarizing this specific aspect here for the first time should contribute to stimulating more research on human repetitive DNA. It should also become clear that these kinds of studies must be done at all available levels of resolution, i.e., from the base pair to chromosomal level and, importantly, the epigenetic level, as well.
Topics: Chromosomes, Human; DNA, Satellite; Genome, Human; Humans; Microsatellite Repeats; Minisatellite Repeats; Repetitive Sequences, Nucleic Acid
PubMed: 33669810
DOI: 10.3390/ijms22042072 -
Nucleic Acids Research Nov 2023SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have...
SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of >150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.
Topics: Humans; Alu Elements; Genome, Human; Minisatellite Repeats; Retroelements; Short Interspersed Nucleotide Elements
PubMed: 37823611
DOI: 10.1093/nar/gkad821 -
BioFactors (Oxford, England) 2013Unstable repeat diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human... (Review)
Review
Unstable repeat diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly, expansion of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequences of the repeat expansions is critical to developing successful therapies for these diseases. Recent technological breakthroughs in whole genome, transcriptome and proteome analyses will almost certainly lead to new discoveries regarding the mechanisms of repeat instability, the pathogenesis of URDs, and will facilitate development of novel therapeutic approaches. The aim of this review is to give a general overview of unstable repeats diseases, highlight the complexities of these diseases, and feature the emerging discoveries in the field.
Topics: Animals; Disease; Genetic Variation; Genomic Instability; Humans; Minisatellite Repeats; Tandem Repeat Sequences; Trinucleotide Repeats
PubMed: 23233240
DOI: 10.1002/biof.1060 -
Veterinary Research Dec 2022African swine fever virus (ASFV) is a large DNA virus that infects domestic pigs with high morbidity and mortality rates. Repeat sequences, which are DNA sequence...
African swine fever virus (ASFV) is a large DNA virus that infects domestic pigs with high morbidity and mortality rates. Repeat sequences, which are DNA sequence elements that are repeated more than twice in the genome, play an important role in the ASFV genome. The majority of repeat sequences, however, have not been identified and characterized in a systematic manner. In this study, three types of repeat sequences, including microsatellites, minisatellites and short interspersed nuclear elements (SINEs), were identified in the ASFV genome, and their distribution, structure, function, and evolutionary history were investigated. Most repeat sequences were observed in noncoding regions and at the 5' end of the genome. Noncoding repeat sequences tended to form enhancers, whereas coding repeat sequences had a lower ratio of alpha-helix and beta-sheet and a higher ratio of loop structure and surface amino acids than nonrepeat sequences. In addition, the repeat sequences tended to encode penetrating and antimicrobial peptides. Further analysis of the evolution of repeat sequences revealed that the pan-repeat sequences presented an open state, showing the diversity of repeat sequences. Finally, CpG islands were observed to be negatively correlated with repeat sequence occurrences, suggesting that they may affect the generation of repeat sequences. Overall, this study emphasizes the importance of repeat sequences in ASFVs, and these results can aid in understanding the virus's function and evolution.
Topics: Animals; Swine; African Swine Fever Virus; Sus scrofa; Amino Acids; Antimicrobial Peptides; Minisatellite Repeats
PubMed: 36461107
DOI: 10.1186/s13567-022-01119-9 -
Molecular Pathology : MP Aug 2000Microsatellite DNA sequences consist of relatively short repeats of one to five base pair units; together with satellites and minisatellites they comprise a larger... (Review)
Review
Microsatellite DNA sequences consist of relatively short repeats of one to five base pair units; together with satellites and minisatellites they comprise a larger family known as tandemly repetitive sequences. Microsatellites are found both in prokaryotes and eukaryotes, including humans, wherein they appear scattered almost at random throughout the genome. Although in prokaryotes distinct biological functions have been demonstrated, the role of microsatellites in eukaryotes is less clear. Nevertheless, several interesting hypotheses exist suggesting that certain microsatellites may exert subtle influences on the regulation of gene expression. Although the presence of these subtle mechanisms may be beneficial to a whole population, when they go wrong, as is thought to happen in the case of human trinucleotide repeat associated diseases, such as Huntington's disease, the consequences for the individual can be fatal. Most human microsatellites probably have no biological use at all; however, they are extremely useful in such fields as forensic DNA profiling and genetic linkage analysis, which can be used to search for genes involved in a wide range of disorders. With a primary focus on humans, it is the aim of this review to present an up to date discussion, both of the biological aspects and scientific uses of microsatellite sequences. In the latter case, basic theoretical and technical points will be considered, and as such it may be of use both to laboratory and non-laboratory based readers.
Topics: Genetic Markers; Genome, Human; Humans; Microsatellite Repeats; Minisatellite Repeats
PubMed: 11040939
DOI: 10.1136/mp.53.4.177 -
Nature Communications Jul 2021Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences...
Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. In this work, we solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We develop software to build a RPGG, and use the RPGG to estimate VNTR composition with short reads. We use this to discover VNTRs with length stratified by continental population, and expression quantitative trait loci, indicating that RPGG analysis of VNTRs will be critical for future studies of diversity and disease.
Topics: Chromosome Mapping; Gene Expression Regulation; Genetic Loci; Genetic Variation; Genetics, Population; Genome, Human; Humans; Minisatellite Repeats; Nucleotide Motifs; Quantitative Trait Loci
PubMed: 34253730
DOI: 10.1038/s41467-021-24378-0 -
EMBO Reports Aug 2000It is widely accepted that the large trinucleotide repeat expansions observed in many neurological diseases occur during replication. However, genetic recombination has... (Review)
Review
It is widely accepted that the large trinucleotide repeat expansions observed in many neurological diseases occur during replication. However, genetic recombination has emerged as a major source of instability for tandem repeats, including minisatellites, and recent studies raise the possibility that it may also be responsible for trinucleotide repeat expansions. We will review data connecting tandem repeat rearrangements and recombination in humans and in eukaryotic model organisms, and discuss the possible role of recombination in trinucleotide repeat expansions in human neurological disorders.
Topics: Animals; DNA; DNA Repair; Gene Conversion; Humans; Meiosis; Minisatellite Repeats; Models, Genetic; Recombination, Genetic; Tandem Repeat Sequences; Trinucleotide Repeat Expansion
PubMed: 11265750
DOI: 10.1093/embo-reports/kvd031 -
Genome Research Dec 2007Variable tandem repeats are frequently used for genetic mapping, genotyping, and forensics studies. Moreover, variation in some repeats underlies rapidly evolving traits... (Comparative Study)
Comparative Study
Variable tandem repeats are frequently used for genetic mapping, genotyping, and forensics studies. Moreover, variation in some repeats underlies rapidly evolving traits or certain diseases. However, mutation rates vary greatly from repeat to repeat, and as a consequence, not all tandem repeats are suitable genetic markers or interesting unstable genetic modules. We developed a model, "SERV," that predicts the variability of a broad range of tandem repeats in a wide range of organisms. The nonlinear model uses three basic characteristics of the repeat (number of repeated units, unit length, and purity) to produce a numeric "VARscore" that correlates with repeat variability. SERV was experimentally validated using a large set of different artificial repeats located in the Saccharomyces cerevisiae URA3 gene. Further in silico analysis shows that SERV outperforms existing models and accurately predicts repeat variability in bacteria and eukaryotes, including plants and humans. Using SERV, we demonstrate significant enrichment of variable repeats within human genes involved in transcriptional regulation, chromatin remodeling, morphogenesis, and neurogenesis. Moreover, SERV allows identification of known and candidate genes involved in repeat-based diseases. In addition, we demonstrate the use of SERV for the selection and comparison of suitable variable repeats for genotyping and forensic purposes. Our analysis indicates that tandem repeats used for genotyping should have a VARscore between 1 and 3. SERV is publicly available from http://hulsweb1.cgr.harvard.edu/SERV/.
Topics: Animals; Genetic Variation; Heredodegenerative Disorders, Nervous System; Humans; Microsatellite Repeats; Minisatellite Repeats; Models, Genetic; Nonlinear Dynamics; Saccharomyces cerevisiae; Sequence Analysis, DNA
PubMed: 17978285
DOI: 10.1101/gr.6554007 -
Genome Research Aug 2021There are more than 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in...
There are more than 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in human evolution and genomic variation, they have yet to be studied collectively and in detail, partially owing to their large size, variability, and predominant location in noncoding regions. Here, we examine 467 VNTRs that are human-specific expansions, unique to one location in the genome, and not associated with retrotransposons. We leverage publicly available long-read genomes, including from the Human Genome Structural Variant Consortium, to ascertain the exact nucleotide composition of these VNTRs and compare their composition of alleles. We then confirm repeat unit composition in more than 3000 short-read samples from the 1000 Genomes Project. Our analysis reveals that these VNTRs contain highly structured repeat motif organization, modified by frequent deletion and duplication events. Although overall VNTR compositions tend to remain similar between 1000 Genomes Project superpopulations, we describe a notable exception with substantial differences in repeat composition (in ), as well as several VNTRs that are significantly different in length between superpopulations (in , and ). We also observe that most of these VNTRs are expanded in archaic human genomes, yet remain stable in length between single generations. Collectively, our findings indicate that repeat motif variability, repeat composition, and repeat length are all informative modalities to consider when characterizing VNTRs and their contribution to genomic variation.
Topics: Genome, Human; Genomic Structural Variation; Humans; Minisatellite Repeats; Nucleotides; Polymorphism, Genetic
PubMed: 34244228
DOI: 10.1101/gr.275560.121 -
Proceedings of the National Academy of... Aug 2011Active cigarette smoking increases oxidative damage, DNA adducts, DNA strand breaks, chromosomal aberrations, and heritable mutations in sperm. However, little is known...
Active cigarette smoking increases oxidative damage, DNA adducts, DNA strand breaks, chromosomal aberrations, and heritable mutations in sperm. However, little is known regarding the effects of second-hand smoke on the male germ line. We show here that short-term exposure to mainstream tobacco smoke or sidestream tobacco smoke (STS), the main component of second-hand smoke, induces mutations at an expanded simple tandem repeat locus (Ms6-hm) in mouse sperm. We further show that the response to STS is not linear and that, for both mainstream tobacco smoke and STS, doses that induced significant increases in expanded simple tandem repeat mutations in sperm did not increase the frequencies of micronucleated reticulocytes and erythrocytes in the bone marrow and blood of exposed mice. These data show that passive exposure to cigarette smoke can cause tandem repeat mutations in sperm under conditions that may not induce genetic damage in somatic cells. Although the relationship between noncoding tandem repeat instability and mutations in functional regions of the genome is unclear, our data suggest that paternal exposure to second-hand smoke may have reproductive consequences that go beyond the passive smoker.
Topics: Animals; Dose-Response Relationship, Drug; Erythrocytes; Male; Mice; Micronuclei, Chromosome-Defective; Micronucleus, Germline; Minisatellite Repeats; Mutagens; Mutation; Reticulocytes; Smoke; Spermatozoa; Tandem Repeat Sequences; Time Factors; Nicotiana
PubMed: 21768363
DOI: 10.1073/pnas.1106896108