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Background: Mesorhabditis is known for its somatic genome being only a small portion of the germline genome due to programmed DNA elimination. This phenotype may be associated with the maintenance of telomeres at the ends of fragmented somatic chromosomes. Objective: To comprehensively investigate the telomeric regions of Mesorhabditis nematodes at the sequence level, we endeavored to collect a Mesorhabditis nematode in the Republic of Korea and acquire its highly contiguous genome sequences. Methods: We isolated a Mesorhabditis nematode and assembled its 108-Mb draft genome using both 6.3 Gb (53 ×) of short-read and 3.0 Gb (25 × , N50 = 5.7 kb) of nanopore-based long-read sequencing data. Our genome assembly exhibits comparable quality to the public genome of Mesorhabditis belari in terms of contiguity and evolutionary conserved genes. Results: Unexpectedly, our Mesorhabditis genome has many more interstitial telomeric sequences (ITSs), specifically subtelomeric ones, compared to the genomes of Caenorhabditis elegans and M. belari. Moreover, several subtelomeric sequences containing ITSs had 4–26 homologous sequences, implying they are highly repetitive. Based on this highly repetitive nature, we hypothesize that subtelomeric ITSs might have accumulated through the action of transposable elements containing ITSs. Conclusions: It still remains elusive whether these ITS-containing units are associated with programmed DNA elimination, but they may facilitate new telomere formation after DNA elimination. Our genomic resources for Mesorhabditis can aid in understanding how its distinct phenotypes have evolved. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) maintain vessel tone and barrier integrity, regulate blood homeostasis, and prevent the extravasation of leukocytes under normal physiological conditions. Because of the limited lifespans and batch-to-batch differences with respect to the genetic make-up of primary ECs, established immortal EC lines are extensively used for studying endothelial biology. To address this issue, the immortal endothelial cell line EA.hy926 was developed by fusing primary human umbilical vein endothelial cells (HUVECs) with human lung carcinoma A549 cells. EA.hy926 cells share a number of similar endothelial properties with HUVECs and are considered the immortal counterpart to primary HUVECs. However, the cytogenetic integrity of EA.hy926 cells is not fully elucidated. We characterized EA.hy926 cells with conventional G-banding and molecular cytogenetic techniques such as spectral karyotyping and subtelomeric fluorescence in situ hybridization. Cytogenetic analysis revealed an array of numerical and stable structural chromosomal rearrangements including one deletion, one duplication, one isochromosome, seven simple translocations, and five complex translocations in Ea.hy926 cells. These findings will advance comprehension of EA.hy926 cell biology and augment future endothelial studies, specifically in comparison studies between HUVECs and EA.hy926 cells. [ABSTRACT FROM AUTHOR]

Background: The genomic region that lies between the telomere and chromosome body, termed the subtelomere, is heterochromatic, repeat-rich, and frequently undergoes rearrangement. Within this region, large-scale structural changes enable gene diversification, and, as such, large multicopy gene families are often found at the subtelomere. In some parasites, genes associated with proliferation, invasion, and survival are often found in these regions, where they benefit from the subtelomere's highly plastic, rapidly changing nature. The increasing availability of complete (or near complete) parasite genomes provides an opportunity to investigate these typically poorly defined and overlooked genomic regions and potentially reveal relevant gene families necessary for the parasite's lifestyle. Results: Using the latest chromosome-scale genome assembly and hallmark repeat richness observed at chromosome termini, we have identified and characterised the subtelomeres of Schistosoma mansoni, a metazoan parasitic flatworm that infects over 250 million people worldwide. Approximately 12% of the S. mansoni genome is classified as subtelomeric, and, in line with other organisms, we find these regions to be gene-poor but rich in transposable elements. We find that S. mansoni subtelomeres have undergone extensive interchromosomal recombination and that these sites disproportionately contribute to the 2.3% of the genome derived from segmental duplications. This recombination has led to the expansion of subtelomeric gene clusters containing 103 genes, including the immunomodulatory annexins and other gene families with unknown roles. The largest of these is a 49-copy plexin domain-containing protein cluster, exclusively expressed in the tegument—the tissue located at the host-parasite physical interface—of intramolluscan life stages. Conclusions: We propose that subtelomeric regions act as a genomic playground for trial-and-error of gene duplication and subsequent divergence. Owing to the importance of subtelomeric genes in other parasites, gene families implicated in this subtelomeric expansion within S. mansoni warrant further characterisation for a potential role in parasitism. [ABSTRACT FROM AUTHOR]

The telomerase mechanism and telomeric motifs are vital for maintaining chromosome integrity. Their functions are conserved in eukaryotic organisms; therefore, it is not surprising that the structure of telomeric motifs is stable. For example, the TTAGG motif persists for hundreds of millions of years in most insects and other arthropods. Here we describe bursts of high diversity of telomeric motifs that have evolved independently in pentatomomorphic bugs (Hemiptera, Pentatomomorpha) and several lineages of parasitic and stinging wasps and bees (Hymenoptera, Apocrita). We show that in most insects, the telomeric DNA sequence is not just a collection of short repeats, but a very long array consisting of (TTAGG)n (or other motifs such as TTGGG, TCAGG, TCTGGG, TTAGGGATGG, TTAGGGGTGG, TTAGGGTGGT, TTAGGTCTGGG, TTAGGTTGGGG, TTAGGTTTGGG and TTGGGTCTGGG), regularly and specifically interrupted by the insertion of non-long terminal repeat (non-LTR) retrotransposons of the TRAS and SART families. Long (173–381 bp) repeats were found at chromosome ends in flies of the families Syrphidae and Tachinidae (Diptera). We hypothesize that the balance of telomerase-dependent machinery and telomerase-independent mechanisms (such as SART and TRAS transpositions) maintains telomeres in many insects. We also discuss how shifting this balance can lead to an increased variability of telomeric motifs and to their complete disappearance. [ABSTRACT FROM AUTHOR]

Eukaryotes have linear chromosomes with domains called telomeres at both ends. The telomere DNA consists of a simple tandem repeat sequence, and multiple telomere-binding proteins including the shelterin complex maintain chromosome-end structures and regulate various biological reactions, such as protection of chromosome ends and control of telomere DNA length. On the other hand, subtelomeres, which are located adjacent to telomeres, contain a complex mosaic of multiple common segmental sequences and a variety of gene sequences. This review focused on roles of the subtelomeric chromatin and DNA structures in the fission yeast Schizosaccharomyces pombe. The fission yeast subtelomeres form three distinct chromatin structures; one is the shelterin complex, which is localized not only at the telomeres but also at the telomere-proximal regions of subtelomeres to form transcriptionally repressive chromatin structures. The others are heterochromatin and knob, which have repressive effects in gene expression, but the subtelomeres are equipped with a mechanism that prevents these condensed chromatin structures from invading adjacent euchromatin regions. On the other hand, recombination reactions within or near subtelomeric sequences allow chromosomes to be circularized, enabling cells to survive in telomere shortening. Furthermore, DNA structures of the subtelomeres are more variable than other chromosomal regions, which may have contributed to biological diversity and evolution while changing gene expression and chromatin structures. [ABSTRACT FROM AUTHOR]

Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation. Indeed, the subtelomeres containing these derepressed genes are enriched in factors of polycomb repression (EZH2 and H3K27me3), insulation (CTCF and MAZ), and cohesion (RAD21 and SMC3) while being associated with the open A‐type chromatin compartment. These findings unveil that the subtelomere transcriptome associated with senescence is determined in a chromosome‐end‐specific manner according to the type of higher‐order chromatin structure. [ABSTRACT FROM AUTHOR]

In Saccharomyces cerevisiae, a heterochromatin-like chromatin structure called the silencing region is present at the telomere as a complex of Sir2, Sir3, and Sir4. Although spreading of the silencing region is blocked by histone acetylase-mediated boundary formation, the details of the factors and mechanisms involved in the spread and formation of the boundary at each telomere are unknown. Here, we show that Spt3 and Spt8 block the spread of the silencing regions. Spt3 and Spt8 are members of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, which has histone acetyltransferase activity. We performed microarray analysis of the transcriptome of spt3Δ and spt8Δ strains and RT-qPCR analysis of the transcript levels of genes from the subtelomeric region in mutants in which the interaction of Spt3 with TATA-binding protein (TBP) is altered. The results not only indicated that both Spt3 and Spt8 are involved in TBP-mediated boundary formation on the right arm of chromosome III, but also that boundary formation in this region is DNA sequence independent. Although both Spt3 and Spt8 interact with TBP, Spt3 had a greater effect on genome-wide transcription. Mutant analysis showed that the interaction between Spt3 and TBP plays an important role in the boundary formation. [ABSTRACT FROM AUTHOR]

A much debated question is whether aging is the cumulative consequence of degenerative factors insufficiently opposed by natural selection, or, on the contrary, an ordered process, genetically determined and regulated, modeled by natural selection, and for which the definition of phenoptotic phenomenon would be entirely appropriate. In this review, theoretical arguments and empirical data about the two hypotheses are exposed, with more evidence in support of the thesis of aging as a form of phenoptosis. However, as the thesis of aging as an adaptive and programmed phenomenon necessarily requires the existence of specific mechanisms that determine to age, such as the subtelomere–telomere theory proposed for this purpose, the evidence supporting the mechanisms described by this theory is reported. In particular, it is highlighted that the recent interpretation of the role of TERRA sequences in the context of subtelomere–telomere theory is a fundamental point in supporting the hypothesized mechanisms. Furthermore, some characteristics of the mechanisms proposed by the theory, such as epigenetic modifications in aging, gradual cell senescence, cell senescence, limits in cell duplications, and fixed size of the telomeric heterochromatin hood, are exposed in their compatibility with both the thesis of aging as phenoptotic phenomenon and the opposite thesis. In short, aging as a form of phenoptosis appears a scientifically sound hypothesis while the opposite thesis should clarify the meaning of various phenomena that appear to invalidate it. [ABSTRACT FROM AUTHOR]

Subtelomeres (ST) are chromosome regions that separate telomeres from euchromatin and play relevant roles in various biological processes of the cell. While their functions are conserved, ST structure and genetic compositions are unique to each species. This study aims to identify and characterize the subtelomeric regions of the 13 Toxoplasma gondii chromosomes of the Me49 strain. Here, STs were defined at chromosome ends based on poor gene density. The length of STs ranges from 8.1 to 232.4 kbp, with a gene density of 0.049 genes/kbp, lower than the Me49 genome (0.15 kbp). Chromatin organization showed that H3K9me3, H2A.X, and H3.3 are highly enriched near telomeres and the 5′ end of silenced genes, decaying in intensity towards euchromatin. H3K4me3 and H2A.Z/H2B.Z are shown to be enriched in the 5′ end of the ST genes. Satellite DNA was detected in almost all STs, mainly the sat350 family and a novel satellite named sat240. Beyond the STs, only short dispersed fragments of sat240 and sat350 were found. Within STs, there were 12 functional annotated genes, 59 with unknown functions (Hypothetical proteins), 15 from multigene FamB, and 13 from multigene family FamC. Some genes presented low interstrain synteny associated with the presence of satellite DNA. Orthologues of FamB and FamC were also detected in Neospora caninum and Hammondia hammondi. A re-analysis of previous transcriptomic data indicated that ST gene expression is strongly linked to the adaptation to different situations such as extracellular passage (evolve and resequencing study) and changes in metabolism (lack of acetyl-CoA cofactor). In conclusion, the ST region of the T. gondii chromosomes was defined, the STs genes were determined, and it was possible to associate them with high interstrain plasticity and a role in the adaptability of T. gondii to environmental changes. [ABSTRACT FROM AUTHOR]

The telomere theory tries to explain cellular mechanisms of aging as mainly caused by telomere shortening at each duplication. The subtelomere–telomere theory overcomes various shortcomings of telomere theory by highlighting the essential role of subtelomeric DNA in aging mechanisms. The present work illustrates and deepens the correspondence between assumptions and implications of subtelomere–telomere theory and experimental results. In particular, it is investigated the evidence regarding the relationships between aging and (i) epigenetic modifications; (ii) oxidation and inflammation; (iii) telomere protection; (iv) telomeric heterochromatin hood; (v) gradual cell senescence; (vi) cell senescence; and (vii) organism decline with telomere shortening. The evidence appears broadly in accordance or at least compatible with the description and implications of the subtelomere–telomere theory. In short, phenomena of cellular aging, by which the senescence of the whole organism is determined in various ways, appear substantially dependent on epigenetic modifications regulated by the subtelomere–telomere–telomeric hood–telomerase system. These phenomena appear to be not random, inevitable, and irreversible but rather induced and regulated by genetically determined mechanisms, and modifiable and reversible by appropriate methods. All this supports the thesis that aging is a genetically programmed and regulated phenoptotic phenomenon and is against the opposite thesis of aging as caused by random and inevitable degenerative factors. [ABSTRACT FROM AUTHOR]

Bambara groundnut (Vigna subterranea L. Verdc.) is an un-derutilized minor legume crop with climate resilience and great potential use in world agriculture. This study aimed to cytogenetically characterize the genome and chromosome properties of Bambara groundnut. We cloned, sequenced, and mapped a 50-bp centromere-specific tandem repeat on all chromosomes. In addition, a 400-bp subtelomeric repeat was discovered and mapped on a single pair of chromosomes. A Bambara groundnut karyotype was constructed using these novel repeats along with ribosomal RNA genes (45S and 5S) and telomeric DNA sequences. This study provides the first analysis of the genome and chromosome properties of Bambara groundnut. We discuss our findings in relation to genetic improvement of Bambara groundnut and centromere evolution in legume species. [ABSTRACT FROM AUTHOR]

Telomeres form the ends of linear chromosomes and usually comprise protein complexes that bind to simple repeated sequence motifs that are added to the 3′ ends of DNA by the telomerase reverse transcriptase (TERT). One of the primary functions attributed to telomeres is to solve the "end-replication problem" which, if left unaddressed, would cause gradual, inexorable attrition of sequences from the chromosome ends and, eventually, loss of viability. Telomere-binding proteins also protect the chromosome from 5′ to 3′ exonuclease action, and disguise the chromosome ends from the double-strand break repair machinery whose illegitimate action potentially generates catastrophic chromosome aberrations. Telomeres are of special interest in the blast fungus, Pyricularia , because the adjacent regions are enriched in genes controlling interactions with host plants, and the chromosome ends show enhanced polymorphism and genetic instability. Previously, we showed that telomere instability in some P. oryzae strains is caused by novel retrotransposons (MoTeRs) that insert in telomere repeats, generating interstitial telomere sequences that drive frequent, break-induced rearrangements. Here, we sought to gain further insight on telomeric involvement in shaping Pyricularia genome architecture by characterizing sequence polymorphisms at chromosome ends, and surrounding internalized MoTeR loci (relics) and interstitial telomere repeats. This provided evidence that telomere dynamics have played historical, and likely ongoing, roles in shaping the Pyricularia genome. We further demonstrate that even telomeres lacking MoTeR insertions are poorly preserved, such that the telomere-adjacent sequences exhibit frequent presence/absence polymorphism, as well as exchanges with the genome interior. Using TERT knockout experiments, we characterized chromosomal responses to failed telomere maintenance which suggested that much of the MoTeR relic-/interstitial telomere-associated polymorphism could be driven by compromised telomere function. Finally, we describe three possible examples of a phenomenon known as "Adaptive Telomere Failure," where spontaneous losses of telomere maintenance drive rapid accumulation of sequence polymorphism with possible adaptive advantages. Together, our data suggest that telomere maintenance is frequently compromised in Pyricularia but the chromosome alterations resulting from telomere failure are not as catastrophic as prior research would predict, and may, in fact, be potent drivers of adaptive polymorphism. [ABSTRACT FROM AUTHOR]

Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated. [ABSTRACT FROM AUTHOR]

Genomic regions of high segmental duplication content and/or structural variation have led to gaps and misassemblies in the human reference sequence, and are refractory to assembly from whole-genome short-read datasets. Human subtelomere regions are highly enriched in both segmental duplication content and structural variations, and as a consequence are both impossible to assemble accurately and highly variable from individual to individual. Recently, we developed a pipeline for improved region-specific assembly called Regional Extension of Assemblies Using Linked-Reads (REXTAL). In this study, we evaluate REXTAL and genome-wide assembly (Supernova) approaches on 10X Genomics linked-reads data sets partitioned and barcoded using the Gel Bead in Emulsion (GEM) microfluidic method. Our results describe the accuracy and relative performance of these two approaches using the reference-based assessment module of QUAST. We show that REXTAL dramatically outperforms the Supernova whole genome assembler in subtelomeric segmental duplication regions, and results in highly accurate assemblies. Nearly all of the REXTAL “misassemblies” identified using default QUAST parameters simply pinpoint locations of tandem repeat arrays in the reference sequence where the repeat array length differs from that in the cognate REXTAL assembly by > 1000 bp. [ABSTRACT FROM AUTHOR]

Any theory suggesting an adaptive meaning for aging implicitly postulates the existence of specific mechanisms, genetically determined and modulated, causing progressive decline of an organism. According to the subtelomere–telomere theory, each telomere is covered by a hood formed in the first cell of an organism having a size preserved at each subsequent duplication. Telomere shortening, which is quantitatively different for each cell type according to the telomerase regulation, causes the hood to slide on the subtelomere repressing it by the telomeric position effect. At this point, the theory postulates existence of subtelomeric regulatory sequences, whose progressive transcriptional repression by the hood should cause cellular alterations that would be the likely determinant of aging manifestations. However, sequences with characteristics of these hypothetical sequences have already been described and documented. They are the [sub]TElomeric Repeat-containing RNA (TERRA) sequences. The repression of TERRA sequences causes progressively: (i) down- or up-regulation of many other regulatory sequences; (ii) increase in the probability of activation of cell senescence program (blockage of the ability to replicate and very significant alterations of the cellular functions). When cell senescence program has not been triggered and the repression is partial, there is a partial alteration of the cellular functions that is easily reversible by telomerase activation. Location of the extremely important sequences in chromosomal parts that are most vulnerable to repression by the telomeric hood is evolutionarily unjustifiable if aging is not considered adaptive: this location must be necessarily adaptive with the specific function of determining aging of the cell and consequently of the whole organism. [ABSTRACT FROM AUTHOR]

Background: DNA packaging into chromatin regulates all DNA-related processes and at chromosomal ends could affect both essential functions of telomeres: protection against DNA damage response and telomere replication. Despite this primordial role of chromatin, little is known about chromatin organization, and in particular about nucleosome positioning on unmodified subtelomere–telomere junctions in Saccharomyces cerevisiae. Results: By ChEC experiments and indirect end-labeling, we characterized nucleosome positioning as well as specialized protein–DNA associations on most subtelomere–telomere junctions present in budding yeast. The results show that there is a relatively large nucleosome-free region at chromosome ends. Despite the absence of sequence homologies between the two major classes of subtelomere–telomere junctions (i.e.: Y'-telomeres and X-telomeres), all analyzed subtelomere–telomere junctions show a terminal nucleosome-free region just distally from the known Rap1-covered telomeric repeats. Moreover, previous evidence suggested a telomeric chromatin fold-back structure onto subtelomeric areas that supposedly was implicated in chromosome end protection. The in vivo ChEC method used herein in conjunction with several proteins in a natural context revealed no evidence for such structures in bulk chromatin. Conclusions: Our study allows a structural definition of the chromatin found at chromosome ends in budding yeast. This definition, derived with direct in vivo approaches, includes a terminal area that is free of nucleosomes, certain positioned nucleosomes and conserved DNA-bound protein complexes. This organization of subtelomeric and telomeric areas however does not include a telomeric cis-loopback conformation. We propose that the observations on such fold-back structures may report rare and/or transient associations and not stable or constitutive structures. [ABSTRACT FROM AUTHOR]

Specificities associated with chromosomal linearity are not restricted to telomeres. Here, recent results obtained on fission and budding yeast are summarized and an attempt is made to define subtelomeres using chromatin features extending beyond the heterochromatin emanating from telomeres. Subtelomeres, the chromosome domains adjacent to telomeres, differ from the rest of the genome by their gene content, rapid evolution, and chromatin features that together contribute to organism adaptation. However, current definitions of subtelomeres are generally based on synteny and are largely gene‐centered. Taking into consideration both the peculiar gene content and dynamics as well as the chromatin properties of those domains, it is discussed how chromatin features can contribute to subtelomeric properties and functions, and play a pivotal role in the emergence of subtelomeres. [ABSTRACT FROM AUTHOR]

Background: The broad host range pathogen Sclerotinia sclerotiorum infects over 400 plant species and causes substantial yield losses in crops worldwide. Secondary metabolites are known to play important roles in the virulence of plant pathogens, but little is known about the secondary metabolite repertoire of S. sclerotiorum. In this study, we predicted secondary metabolite biosynthetic gene clusters in the genome of S. sclerotiorum and analysed their expression during infection of Brassica napus using an existing transcriptome data set. We also investigated their sequence diversity among a panel of 25 previously published S. sclerotiorum isolate genomes. Results: We identified 80 putative secondary metabolite clusters. Over half of the clusters contained at least three transcriptionally coregulated genes. Comparative genomics revealed clusters homologous to clusters in the closely related plant pathogen Botrytis cinerea for production of carotenoids, hydroxamate siderophores, DHN melanin and botcinic acid. We also identified putative phytotoxin clusters that can potentially produce the polyketide sclerin and an epipolythiodioxopiperazine. Secondary metabolite clusters were enriched in subtelomeric genomic regions, and those containing paralogues showed a particularly strong association with repeats. The positional bias we identified was borne out by intraspecific comparisons that revealed putative secondary metabolite genes suffered more presence / absence polymorphisms and exhibited a significantly higher sequence diversity than other genes. Conclusions: These data suggest that S. sclerotiorum produces numerous secondary metabolites during plant infection and that their gene clusters undergo enhanced rates of mutation, duplication and recombination in subtelomeric regions. The microevolutionary regimes leading to S. sclerotiorum secondary metabolite diversity have yet to be elucidated. Several potential phytotoxins documented in this study provide the basis for future functional analyses. [ABSTRACT FROM AUTHOR]

This model also shows how telomere proteins might be available to evolve new protein-protein or nucleic acid-protein interactions and act as a key factor allowing telomere flexibility and adaptability. However, more detailed observations reveals that telomere structure and function can be very dynamic and flexible, as documented by frequent evolutionary novelties in plant telomere motifs or telomerase-independent telomere maintenance pathways in numerous insects ([17]; [19]; [8]; [22]; [7]). Further, changes in the composition of telomere sequences or telomere maintenance activity are found as a part of telomere adaptive response to environmental or physiological stress exposure ([1]; [14]). Keywords: telomere; telomerase; stress response; subtelomere; alternative pathway EN telomere telomerase stress response subtelomere alternative pathway 1 3 3 10/06/21 20211004 NES 211004 Telomeres are key structures for chromosome end capping and concurrently one of the key factors that guard the stability and integrity of the whole genome ([3]). [Extracted from the article]

The limited availability of data on somatic gene evolution in breast cancer is challenging item to apply an appropriate clinical management for each individual. As human subtelomeric sequences are diverse‐prone and variable, they can be considered as hot spots for analysis of the health or disease status. We compared the hybridization signals of subtelomeric sequences in normal cells with those in auxiliary lymph nodes (ALNs) isolated from a single patient. Distinct signal intensities were found in all chromosomes: weak (5, 6, 9–12, and 16–19), medium (1, 5–9, 19, and X), and strong (2, 5, 9, 10, 16, and 18) intensities. Signal intensities in the patient's ALN and lymphocytes were higher than in normal tissues. The absence and presence of one or more hybridization signals and the presence of signals in the p and q arms were also variable. Whereas chromosomes 2, 3, 5, 7, 8, 10, 16, 18, 20, and X showed three hybridization spots, chromosomes 1, 4, 9, 12, 17, and 18–19 presented a reduced signal in the ALN and lymphocytes. In addition, signal intensity in the p arm was higher than in the q arm in most patients' chromosomes. Therefore, we propose that subtelomeric hybridization be followed periodically in individuals with breast neoplasm to provide specific patterns. Such profiling could be considered as a prediction marker throughout the patients' life. Together with the Ki67, cyclin D1, and cyclin E expression profiles, the subtelomeric hybridization profile could provide complementary information for cancer management. [ABSTRACT FROM AUTHOR]

The theories interpreting senescence as a phenomenon favored by natural selection require the existence of specific, genetically determined and regulated mechanisms that cause a progressive age-related increase in mortality. The mechanisms defined in the subtelomere–telomere theory suggest that progressive slackening of cell turnover and decline in cellular functions are determined by the subtelomere–telomere–telomerase system, which causes a progressive "atrophic syndrome" in all organs and tissues. If the mechanisms underlying aging-related dysfunctions are similar and having the same origin, it could be hypothesized that equal interventions could produce similar effects. This article reviews the consequences of some factors (diabetes, obesity/dyslipidemia, hypertension, smoking, moderate use and abuse of alcohol) and classes of drugs [statins, angiotensin-converting enzyme (ACE) inhibitors, sartans] in accelerating and anticipating or in counteracting the process of aging. The evidence is compatible with the programmed aging paradigm and the mechanisms defined by the subtelomere–telomere theory but it has no obvious discriminating value against the theories of non-programmed aging paradigm. However, the existence of mechanisms, determined by the subtelomere–telomere–telomerase system and causing a progressive age-related decline in fitness through gradual cell senescence and cell senescence, is not justifiable without an evolutionary motivation. Their existence is expected by the programmed aging paradigm, while is incompatible with the opposite paradigm. [ABSTRACT FROM AUTHOR]

Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disorder, which is characteristic of a severe impairment of immunity. In the genetic aspect, ICF is featured with mutations primarily located in the specific genes (DNMT3B for ICF1, ZBTB24 for ICF2, CDCA7 for ICF3, and HELLS for ICF4). The subtelomeric region is defined as 500 kb at the terminal of each autosomal arm. And subtelomeric DNA fragments can partially regulate key biological activities, including chromosome movement and localization in the nucleus. In this review, we updated and summarized gene mutations in ICF based on the previous review. In addition, we focused on the correlation between subtelomeric DNA methylation and ICF. The relationship between subtelomeric methylation and telomere length in ICF was also summarized. [ABSTRACT FROM AUTHOR]

Dalmatian pyrethrum (Tanacetum cinerariifolium (Trevir.) Sch. Bip.), a plant species endemic to the east Adriatic coast, is used worldwide for production of the organic insecticide, pyrethrin. Most studies concerning Dalmatian pyrethrum have focused on its morphological and biochemical traits relevant for breeding. However, little is known about the chromosomal evolution and genome organization of this species. Our study aims are to identify, classify, and characterize repetitive DNA in the T. cinerariifolium genome using clustering analysis of a low coverage genomic dataset. Repetitive DNA represents about 71.63% of the genome. T. cinerariifolium exhibits linked 5S and 35S rDNA configuration (L-type). FISH reveals amplification of interstitial telomeric repeats (ITRs) in T. cinerariifolium. Of the three newly identified satellite DNA families, TcSAT1 and TcSAT2 are located subterminally on most of T. cinerariifolium chromosomes, while TcSAT3 family is located intercalary within the longer arm of two chromosome pairs. FISH reveals high levels of polymorphism of the TcSAT1 and TcSAT2 sites by comparative screening of 28 individuals. TcSAT2 is more variable than TcSAT1 regarding the number and position of FISH signals. Altogether, our data highlights the dynamic nature of DNA sequences associated with subtelomeres in T. cinerariifolium and suggests that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes. [ABSTRACT FROM AUTHOR]

Cell senescence is an artificially reversible condition activated by various factors and characterized by replicative senescence and typical general alteration of cell functions, including extra-cellular secretion. The number of senescent cells increases with age and contributes strongly to the manifestations of aging. For these reasons, research is under way to obtain "senolytic" compounds, defined as drugs that eliminate senescent cells and therefore reduce aging-associated decay, as already shown in some experiments on animal models. This objective is analyzed in the context of the programmed aging paradigm, as described by the mechanisms of the subtelomere-telomere theory. In this regard, positive effects of the elimination of senescent cells and limits of this method are discussed. For comparison, positive effects and limits of telomerase activation are also analyzed, as well of the combined action of the two methods and the possible association of opportune gene modifications. Ethical issues associated with the use of these methods are outlined. [ABSTRACT FROM AUTHOR]

Telomeres serve as protective caps that help the cell differentiate between the naturally occurring ends of chromosomes and double-stranded breaks. When telomere capping function becomes compromised, chromosome ends are subjected to elevated rates of chromosome alterations. These effects can be particularly dramatic in the telomere-adjacent subtelomeric region. While the catastrophic impact of severe telomere dysfunction on genome stability has been well documented, the adaptive telomere failure hypothesis considers an alternative role telomere dysfunction may play in adaptive evolution. This hypothesis suggests that low levels of telomere failure, induced by certain environmental stresses, can lead to elevated subtelomeric recombination. Mutational loss, duplication, or modification of subtelomeric contingency genes could ultimately facilitate adaptation by generating novel mutants better able to survive environmental stress. In this perspective, we discuss recent work that examined mild telomere dysfunction and its role in altering the adaptive potential of subtelomeric genes. [ABSTRACT FROM AUTHOR]

Subtelomeres of most eukaryotes contain fast-evolving genes usually involved in adaptive processes. In common bean (Phaseolus vulgaris), the Co-2 anthracnose resistance (R) locus corresponds to a cluster of nucleotide-binding-site leucine-richrepeat (NL) encoding sequences, the prevalent class of plant R genes. To study the recent evolution of this R gene cluster, we used a combination of sequence, genetic and cytogenetic comparative analyses between common bean genotypes from two distinct gene pools (Andean and Mesoamerican) that diverged 0.165 million years ago. Co-2 is a large subtelomeric cluster on chromosome 11 comprising from 32 (Mesoamerican) to 52 (Andean) NL sequences embedded within khipu satellite repeats. Since the recent split between Andean and Mesoamerican gene pools, the Co-2 cluster has experienced numerous gene-pool specific NL losses, leading to distinct NL repertoires. The high proportion of solo-LTR retrotransposons indicates that the Co-2 cluster is located in a hot spot of unequal intra-strand homologous recombination. Furthermore, we observe large segmental duplications involving both Non-Homologous End Joining and Homologous Recombination double-strand break repair pathways. Finally, the identification of a Mesoamerican-specific subtelomeric sequence reveals frequent interchromosomal recombinations between common bean subtelomeres. Altogether, our results highlight that common bean subtelomeres are hot spots of recombination and favor the rapid evolution of R genes. We propose that chromosome ends could act as R gene incubators in many plant genomes. [ABSTRACT FROM AUTHOR]

R‐loops (RLs) are three‐stranded nucleic acid structures that contain a DNA:RNA hybrid and a displaced DNA strand. Genomic regions with GC skew and a G‐rich transcript are particularly prone to form RLs. RLs play important physiological roles in cells; however, when present at abnormally high levels, they may threaten genome stability. The perfect GC skew of telomeric repeats and the discovery of telomeric repeat‐containing RNA (TERRA), a long noncoding transcript that consists of the G‐rich telomeric sequence, make telomeric sequences the perfect candidates for generating RLs. Indeed, in the past 5 years, telomere R‐loops (TRLs) have been demonstrated in Saccharomyces cerevisiae, Trypanosoma brucei, and human cells. The presence of TRLs in normal human cells that transcribe low levels of TERRA, suggests a physiological role for these nucleic structures in telomere maintenance. Abnormally enhanced TERRA transcription, as found in several human pathological conditions, leads to high TRL levels and various cellular outcomes, depending on the recombinogenic capabilities of the cells. Study of TRLs in various organisms highlights the necessity for tight regulation of these structures, which can switch from beneficial to detrimental under different conditions. Here, we review the current state of knowledge on TRLs, describe several means by which TRLs are regulated, and discuss how findings from yeast are relevant to human pathological scenarios in which TRLs are deregulated. [ABSTRACT FROM AUTHOR]

Efficient replication of terminal DNA is crucial to maintain telomere stability. In fission yeast, Taz1 and the Stn1-Ten1 (ST) complex play prominent roles in DNA-ends replication. However, their function remains elusive. Here, we have analyzed genome-wide replication and show that ST does not affect genome-wide replication but is crucial for the efficient replication of a subtelomeric region called STE3-2. We further show that, when ST function is compromised, a homologous recombination (HR)-based fork restart mechanism becomes necessary for STE3-2 stability. While both Taz1 and Stn1 bind to STE3-2, we find that the STE3-2 replication function of ST is independent of Taz1 but relies on its association with the shelterin proteins Pot1-Tpz1-Poz1. Finally, we demonstrate that the firing of an origin normally inhibited by Rif1 can circumvent the replication defect of subtelomeres when ST function is compromised. Our results help illuminate why fission yeast telomeres are terminal fragile sites. [Display omitted] • Stn1-Ten1 is crucial for replication of a hard-to-replicate subtelomeric region • Taz1 and Stn1-Ten1 bind to this hard-to-replicate subtelomeric region • Stn1-Ten1 function relies on its association with Pot1-Tpz1-Poz1 but not Taz1 • An HR-based fork restart mechanism occurs when Stn1 is dysfunctional Vaurs et al. show that the Stn1-Ten1 complex is crucial for efficient replication of the subtelomeric STE3-2 region. While both Taz1 and Stn1-Ten1 bind STE3-2, Stn1-Ten1 function is independent of Taz1 but relies on Pot1-Tpz1-Poz1. With dysfunctional Stn1, an HR-based fork restart mechanism becomes necessary for STE3-2 replication. [ABSTRACT FROM AUTHOR]

The programmed aging paradigm interprets aging as a function favored by natural selection at a supra-individual level. This function is implemented, according to the telomere theory, through mechanisms that operate through the subtelomere-telomere-telomerase system. After reviewing some necessary technical and ethical reservations and providing a concise description of aging mechanisms, this work considers interventions that could lead to the control of some highly disabling characteristics of aging, such as Alzheimer's and Parkinson's syndromes and age-related macular degeneration, and afterwards to a full control of aging up to a condition equivalent to that of the species defined as 'with negligible senescence'. The various steps needed for the development of such interventions are described along general lines. [ABSTRACT FROM AUTHOR]

Background: Telomeres play an important role in cancer progression. Recently it has been shown that subtelomeric methylation negatively regulates telomere length in various diseases, including cancers. Here, we evaluated the influence of subtelomeric methylation in telomere dysfunction in gallbladder cancer (GBC), and whether this dysfunction is affected by the presence of gallstones. Methods: Relative telomere length and subtelomeric methylation levels were assessed using monochrome multiplex quantitative polymerase chain reaction and bisulfite sequencing, respectively, in different gallbladder tissue types including different grades of GBC, gallstones and adjacent non‐tumor. Results: We found telomere length to shorten significantly in overall GBC, but specifically in early grade cancer. We also found D4Z4 and DNF92 subtelomeric sequences to be hypermethylated and hypomethylated, respectively, in GBC; however, their methylation levels differed significantly, only in early grade cancer. We could not find any specific correlation between subtelomeric methylation and telomere length in GBC. Interestingly, telomere length and subtelomeric methylation differed significantly in GBC without gallstones but not in GBC with gallstones. Conclusions: This study, thus, suggests that telomere dysfunction and changes in methylation levels may occur earlier in the progression of GBC, while the presence of gallstones may have no influence on telomere length as well as on methylation levels. Highlight Poojary and colleagues show that dysfunction of telomere and subtelomeric methylation may occur earlier in the progression of gallbladder cancer, while the presence of gallstones may have no effect on telomere length as well as on methylation levels, suggesting different etiologies for cancer due to gallstones and cancer without gallstones. [ABSTRACT FROM AUTHOR]

Human herpesvirus-6A and B (HHV-6A, HHV-6B) have recently defined endogenous genomes, resulting from integration into the germline: chromosomally-integrated "CiHHV-6A/B". These affect approximately 1.0% of human populations, giving potential for virus gene expression in every cell. We previously showed that CiHHV-6A was more divergent than CiHHV-6B by examining four genes in 44 European CiHHV-6A/B cardiac/haematology patients. There was evidence for gene expression/reactivation, implying functional non-defective genomes. Tofurther define the relationship between HHV-6A and CiHHV-6A we used next-generation sequencing to characterize genomes from three CiHHV-6A cardiac patients. Comparisons to known exogenous HHV-6A showed CiHHV-6A genomes formed a separate clade; including all 85 non-interrupted genes and necessary cis-acting signals for reactivation as infectious virus. Greater single nucleotide polymorphism (SNP) density was defined in 16 genes and the direct repeats (DR) terminal regions. Using these SNPs, deep sequencing analyses demonstrated superinfection with exogenous HHV-6A in two of the CiHHV-6A patients with recurrent cardiac disease. Characterisation of the integration sites in twelve patients identified the human chromosome 17p subtelomere as a prevalent site, which had specific repeat structures and phylogenetically related CiHHV-6A coding sequences indicating common ancestral origins. Overall CiHHV-6A genomes were similar, but distinct from known exogenous HHV-6A virus, and have the capacity to reactivate as emerging virus infections. [ABSTRACT FROM AUTHOR]

Background: The microsporidian Encephalitozoon cuniculi is an obligate intracellular eukaryotic pathogen with a small nuclear genome (2.9 Mbp) consisting of 11 chromosomes. Although each chromosome end is known to contain a single rDNA unit, the incomplete assembly of subtelomeric regions following sequencing of the genome identified only 3 of the 22 expected rDNA units. While chromosome end assembly remains a difficult process in most eukaryotic genomes, it is of significant importance for pathogens because these regions encode factors important for virulence and host evasion. Results: Here we report the first complete assembly of E. cuniculi chromosome ends, and describe a novel mosaic structure of segmental duplications (EXT repeats) in these regions. EXT repeats range in size between 3.5 and 23.8 kbp and contain four multigene families encoding membrane associated proteins. Twenty-one recombination sites were identified in the sub-terminal region of E. cuniculi chromosomes. Our analysis suggests that these sites contribute to the diversity of chromosome ends organization through Double Strand Break repair mechanisms. The region containing EXT repeats at chromosome extremities can be differentiated based on gene composition, GC content, recombination sites density and chromosome landscape. Conclusion: Together this study provides the complete structure of the chromosome ends of E. cuniculi GB-M1, and identifies important factors, which could play a major role in parasite diversity and host-parasite interactions. Comparison with other eukaryotic genomes suggests that terminal regions could be distinguished precisely based on gene content, genetic instability and base composition biais. The diversity of processes assciated with chromosome extremities and their biological consequences, as they are presented in the present study, emphasize the fact that great effort will be necessary in the future to characterize more carefully these regions during whole genome sequencing efforts. [ABSTRACT FROM AUTHOR]

Human herpesvirus-6A and B (HHV-6A, HHV-6B) have recently defined endogenous genomes, resulting from integration into the germline: chromosomally-integrated "CiHHV-6A/B". These affect approximately 1.0% of human populations, giving potential for virus gene expression in every cell. We previously showed that CiHHV-6A was more divergent than CiHHV-6B by examining four genes in 44 European CiHHV-6A/B cardiac/haematology patients. There was evidence for gene expression/reactivation, implying functional non-defective genomes. To further define the relationship between HHV-6A and CiHHV-6A we used next-generation sequencing to characterize genomes from three CiHHV-6A cardiac patients. Comparisons to known exogenous HHV-6A showed CiHHV-6A genomes formed a separate clade; including all 85 non-interrupted genes and necessary cis-acting signals for reactivation as infectious virus. Greater single nucleotide polymorphism (SNP) density was defined in 16 genes and the direct repeats (DR) terminal regions. Using these SNPs, deep sequencing analyses demonstrated superinfection with exogenous HHV-6A in two of the CiHHV-6A patients with recurrent cardiac disease. Characterisation of the integration sites in twelve patients identified the human chromosome 17p subtelomere as a prevalent site, which had specific repeat structures and phylogenetically related CiHHV-6A coding sequences indicating common ancestral origins. Overall CiHHV-6A genomes were similar, but distinct from known exogenous HHV-6A virus, and have the capacity to reactivate as emerging virus infections. [ABSTRACT FROM AUTHOR]

Tandem repeats belong to a class of genomic repetitive elements that form arrays of head-to-tail monomers. Due to technical difficulties in sequencing and assembly of large tandem repeat arrays, it remains largely unknown by which mechanisms tandem-repeat-containing regions aid in maintenance of ordered radial genome organization during interphase. Here we analyzed spatial distribution of several types of tandem repeats in interphase nuclei of chicken MDCC-MSB1 cells and somatic tissues relative to heterochromatin compartments and nuclear center. We showed that telomere and subtelomere repeats generally localize at the nuclear or chromocenters periphery. A tandem repeat known as CNM, typical for centromere regions of gene-dense microchromosomes, forms interchromosome clusters and occupies DAPI-positive chromocenters that appear predominantly within the nuclear interior. In contrast, centromere-specific tandem repeats of the majority of gene-poor macrochromosomes are embedded into the peripheral layer of heterochromatin. Chicken chromocenters rarely comprise centromere sequences of both macro- and microchromosomes, whose territories localize in different radial nuclear zones. Possible mechanisms of observed tandem repeats positioning and its implication in highly ordered arrangement of chromosome territories in chicken interphase nucleus are discussed. [ABSTRACT FROM AUTHOR]

Transcription of tandemly repetitive DNA in embryogenesis seems to be of special interest due to a crucial role of non-coding RNAs in many aspects of development. However, only a few data are available on tandem repeats transcription at subtelomere regions of chromosomes during vertebrate embryogenesis. To reduce this gap, we examined stage and tissue-specific pattern of subtelomeric PO41 (pattern of 41 bp) tandem repeat transcription during embryogenesis of chicken ( Gallus gallus domesticus). Using whole-mount RNA fluorescent in situ hybridization and reverse transcription PCR with specific primers, we demonstrated that both strands of PO41 repeat are transcribed at each of the studied stages of chicken embryo development: from 7-8 HH to 20 HH stages. Subtelomere-derived transcripts localize in the nuclei of all cell types and throughout the all embryonic bodies: head, somites, tail, wings and buds. In embryo-dividing cells and cultured embryonic fibroblasts, PO41 RNAs envelop terminal regions of chromosomes. PO41-containing RNAs are predominantly single-stranded and can be polyadenylated, indicating appearance of non-nascent form of subtelomeric transcripts. PO41 repeat RNAs represent a rare example of ubiquitously transcribed non-coding RNAs, such as Xist/XIST RNA or telomere repeat-containing RNA. Distribution of PO41 repeat transcripts at different stages of embryo development and among cell types has extremely uniform pattern, indicating on possible universal functions of PO41 non-coding RNAs. [ABSTRACT FROM AUTHOR]

Background: Subtelomeres are located close to the ends of chromosomes and organized by tandemly repetitive sequences, duplicated copies of genes, pseudogenes and retrotransposons. Transcriptional activity of tandemly organized DNA at terminal chromosomal regions and the distribution of subtelomere-derived non-coding RNAs are poorly investigated. Here we aimed to analyze transcriptional activity of subtelomeric tandem repeat in somatic tissues and cultured cells of birds. We focused on tissue-specific differences of subtelomeric repeats transcription, structure of the resulting transcripts and the behavior of subtelomere-derived RNA during mitosis. Results: Transcriptional activity of short subtelomeric PO41 ("pattern of 41 bp") tandem repeat in the somatic and cultured cells of chicken (Gallus gallus domesticus) and Japanese quail (Coturnix coturnix japonica) was examined using RNA fluorescence in situ hybridization approach. We discovered transcripts from both strands of the PO41 repeat in chicken MDCCMSB1 cells as well as in chicken and Japanese quail somatic tissues: cerebellum, telencephalon, muscles, oviduct, small and large intestine. Normal somatic and transformed cells demonstrate similar distribution of PO41 repeat transcripts in interphase nuclei. We revealed one or two major foci of PO41 repeat transcripts associated with RNA polymerase II, representing nascent RNA, and dispersed PO41 repeat transcripts localized in euchromatin or interchromatin space, representing released RNA. During mitosis PO41 non-coding RNA distribute between condensed chromosomes till anaphase, when they concentrate at the cleavage plane. At telophase, clusters of PO41 RNA surround terminal regions of chromosomes. Treatments with RNases of different substrate specificity indicate that PO41 repeat transcripts are single-stranded RNAs with short double-stranded regions due to appearance of inverted repeats. Conclusion: Transcription of a subtelomeric tandem repeat in avian somatic cells is reported here for the first time. PO41 repeat transcription is conserved among Galliformes and has similar pattern in somatic tissues. We demonstrated redistribution of non-coding PO41 RNA occurring during the cell cycle. Potential regulatory role of the PO41 repeat transcripts in RNAdependent process of subtelomere heterochromatin maintenance is discussed. [ABSTRACT FROM AUTHOR]

Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Subtelomeric regions in eukaryotic organisms are known for harboring species-specific tandemly repeated satellite sequences. However, studies on the molecular organization and evolution of subtelomeric repeats are scarce, especially in plants. Khipu is a satellite DNA of 528-bp repeat unit, specific of the Phaseolus genus, with a subtelomeric distribution in common bean, P. vulgaris.To investigate the genomic organization and the evolution of khipu, we performed genome-wide analysis on the complete genome sequence of the common bean genotype G19833. We identified 2,460 khipu units located at most distal ends of the sequenced regions. Khipu units are arranged in discrete blocks of 2-55 copies and are heterogeneously distributed among the different chromosome ends of G19833 (from 0 to 555 khipus units per chromosome arm). Phylogenetically related khipu units are spread between numerous chromosome ends, suggesting frequent exchanges between non-homologous subtelomeres. However, most subclades contain numerous khipu units from only one or few chromosome ends indicating that local duplication is also driving khipu expansion. Unexpectedly, we also identified 81 khipu units located at centromeres. All the centromeric khipu units belong to a single divergent clade also comprised of a few units from several subtelomeres, suggesting that a few sequence exchanges between centromeres and subtelomeres took place in the common bean genome. The divergence and low copy number of these centromeric units from the subtelomeric units could explain why they were not detected by FISH (Fluorescence in situ Hybridization) although it can not be excluded that these centromeric units may have resulted from errors in the pseudomolecule assembly. Altogether our data highlight extensive sequence exchanges in subtelomeres between non-homologous chromosomes in common bean and confirm that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes. [ABSTRACT FROM AUTHOR]

ABSTRACT Chromosomal abnormalities involving 19p13.3 have rarely been described in the published literature. Here, we report on a girl with a pure terminal duplication of 6.1 Mb on 19p13.3, caused by an unbalanced translocation der(19)t(10;19)(qter;p13.3)dn. Her phenotype included severe psychomotor developmental delay, skeletal malformations, and a distinctive facial appearance, similar to that of a patient previously reported by Lybaek et al. [Lybaek et al. (2009); Eur J Hum Genet 17:904-910]. These results suggest that a duplication of >3 Mb at the terminus of 19p13.3 might represent a distinct chromosomal syndrome. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The strategy of antigenic variation is to present a constantly changing population phenotype that enhances parasite transmission, through evasion of immunity arising within, or existing between, host animals. Trypanosome antigenic variation occurs through spontaneous switching among members of a silent archive of many hundreds of variant surface glycoprotein ( VSG) antigen genes. As with such contingency systems in other pathogens, switching appears to be triggered through inherently unstable DNA sequences. The archive occupies subtelomeres, a genome partition that promotes hypermutagenesis and, through telomere position effects, singular expression of VSG. Trypanosome antigenic variation is augmented greatly by the formation of mosaic genes from segments of pseudo- VSG, an example of implicit genetic information. Hypermutation occurs apparently evenly across the whole archive, without direct selection on individual VSG, demonstrating second-order selection of the underlying mechanisms. Coordination of antigenic variation, and thereby transmission, occurs through networking of trypanosome traits expressed at different scales from molecules to host populations. [ABSTRACT FROM AUTHOR]

The subtelomeric regions of organisms ranging from protists to fungi undergo a much higher rate of rearrangement than is observed in the rest of the genome. While characterizing these ∼40-kb regions of the human fungal pathogen Cryptococcus neoformans, we have identified a recent gene amplification event near the right telomere of chromosome 3 that involves a gene encoding an arsenite efflux transporter (ARR3). The 3,177-bp amplicon exists in a tandem array of 2–15 copies and is present exclusively in strains with the C. neoformans var. grubii subclade VNI A5 MLST profile. Strains bearing the amplification display dramatically enhanced resistance to arsenite that correlates with the copy number of the repeat; the origin of increased resistance was verified as transport-related by functional complementation of an arsenite transporter mutant of Saccharomyces cerevisiae. Subsequent experimental evolution in the presence of increasing concentrations of arsenite yielded highly resistant strains with the ARR3 amplicon further amplified to over 50 copies, accounting for up to ∼1% of the whole genome and making the copy number of this repeat as high as that seen for the ribosomal DNA. The example described here therefore represents a rare evolutionary intermediate—an array that is currently in a state of dynamic flux, in dramatic contrast to relatively common, static relics of past tandem duplications that are unable to further amplify due to nucleotide divergence. Beyond identifying and engineering fungal isolates that are highly resistant to arsenite and describing the first reported instance of microevolution via massive gene amplification in C. neoformans, these results suggest that adaptation through gene amplification may be an important mechanism that C. neoformans employs in response to environmental stresses, perhaps including those encountered during infection. More importantly, the ARR3 array will serve as an ideal model for further molecular genetic analyses of how tandem gene duplications arise and expand. [ABSTRACT FROM PUBLISHER]

Abstract: A telomere is a repetitive DNA structure at chromosomal ends that stabilizes the chromosome structure and prevents harmful end-to-end recombinations. The telomere length of somatic cells becomes shorter with aging because of the 'end replication problem.' This telomere shortening is accelerated by pathophysiological conditions including daily mental stress. Living with Parkinson's disease (PD) causes physical and mental stress; therefore, the authors hypothesized that the telomere length of somatic cells was shortened excessively in patients with PD. In order to detect PD-associated somatic telomeric alterations, the telomere length and subtelomeric methylation status of peripheral leukocytes of PD patients were assessed by Southern blotting, using methylation-sensitive and -insensitive isoschizomers. The results demonstrated that the peripheral leukocytes of Japanese female patients with PD bore fewer long telomeres and a proportional increase of hypomethylated subtelomeres in short telomeres in comparison with the healthy controls. This study indicates that with the neurodegeneration associated with PD, telomeric and subtelomeric structural alterations occur. These structural telomere altertions most likely occur secondary to the acceleration of aging-associated telomeric changes and the accelerated loss of cells bearing short telomeres. [ABSTRACT FROM AUTHOR]

Telomere shortening has been reported to be related to oxidative stress (OS) associated with the aging process and aging-associated diseases, including Alzheimer's disease (AD). We measured the methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells of 34 AD patients and 49 healthy controls by a Southern blotting analysis, using methylation-sensitive and - insensitive restriction enzyme isoschizomers, MspI and HpaII. AD patients bore normal mean telomere lengths and had an unchanged distribution of the telomere length in peripheral leukocytes. However, the subtelomeres in the shortest telomeres were relatively more methylated in AD patients of both genders, compared with age-matched controls. We observed that the pathogenesis of AD was associated with the epigenetic condition of the subtelomere, but not on the overall telomere length and distribution. The relative elevation of subtelomeric methylation of short telomeres in peripheral blood leukocytes may be a characteristic of AD. This implies that leukocytes containing short telomeres with less methylated subtelomeres tend to be removed faster from the peripheral blood in AD patients. [ABSTRACT FROM AUTHOR]

Dynamics of chromosomal ends during meiosis was examined using a tetrad F population derived from a cross between Setaria and Triticum isolates of Magnaporthe oryzae. Telomeric fragments were liberated by six restriction enzymes and detected with a telomere probe. Each fragment was assigned to one of the 14 chromosomal ends using chromosome-specific markers. Size shifts and non-Mendelian segregation (4:0, 3:1, 1:3, and 0:4) were frequently observed in these telomeric fragments and were considered to be caused by deletion, insertion, point mutation, and gene conversion. Similar results were obtained in another tetrad F population derived from a cross between Oryza and Triticum isolates. These results suggest that subtelomeric regions are unstable during meiosis and are prone to various rearrangements including gene conversion. [ABSTRACT FROM AUTHOR]

Background The most prevalent type of structural variation in the human genome is represented by copy number variations that can affect transcription levels, sequence, structure and function of genes. Method In the present study, we used the multiplex ligation-dependent probe amplification (MLPA) technique and quantitative PCR for the detection of copy number variation in 132 intellectually disabled male patients with normal karyotypes and negative fragile- X-testing. Results Ten of these patients (7.6%) showed copy number variation in the subtelomeric regions, including deletions and duplications. Discussion Duplications of the SECTM1 gene, located at 17q25.3, and of the FLJ22115 gene, located at 20p13, could be associated with phenotype alterations. This study highlights the relevance in the aetiology of intellectual disability of subtelomeric rearrangements that can be screened by MLPA and other molecular techniques. [ABSTRACT FROM AUTHOR]

Satellite DNAs consist of long tandem arrays of short or large repeated sequences that form the centromeric and sometimes also subtelomeric regions of all higher eukaryote chromosomes. Telomeres and centromeres are the most important elements involved in the structure and function of chromosome. Telomeric DNA sequences are conserved among nearly all plant species. Although centromere-specific DNA sequences have been isolated in a wide range of plant species, almost no conservation was found in their DNA sequences. Here, we utilized the cassette-ligation-mediated PCR approach for cloning the sequence near the telomeric repeats of Brassica napus. Sequences analysis showed that one sequence was highly homologous to the centromeric satellite DNA sequence reported. FISH revealed that this satellite was located primarily at centromeric regions of most chromosomes, and also at some chromosome ends. The sequence was a subtelomeric satellite DNA which possessed variability in the evolution of chromosomes of Brassica species. The phylogenetic tree analysis of the satellite showed its sequence was conservative in Brassica. We discussed why the centromeric satellites appeared in the subtelomeric region. [ABSTRACT FROM AUTHOR]

The subtelomere and a portion of the associated telomeric region (together named 3RTAS) of chromosome IIIR from the Arabidopsis thaliana ecotypes Columbia (Col) and Wassilewskija (Ws) were specifically amplified by polymerase chain reaction and subsequently cloned and sequenced. The centromere-proximal portion of 3RTAS from both ecotypes contained two newly identified potential genes, one encoding the chloroplast luminal 19-kDa protein precursor and the other encoding three potential alternatively spliced CCCH-type zinc finger proteins. The telomere-proximal portion of 3RTAS from the Col ecotype contained short duplicated fragments derived from chromosomes I, II, and III, and that from the Ws ecotype contained a duplicated fragment derived from chromosome V. Each duplicated fragment has diverged somewhat in sequence from that of the ectopic template. Small patches of homologous nucleotides were found within the flanking sequences of both the duplicated fragments and the corresponding ectopic template sequences. The structural characteristics of these duplicated fragments suggest that they are filler DNAs captured by non-homologous end joining during double-strand break repair. Our characterization of 3RTAS not only filled up a gap in the chromosome IIIR sequence of A. thaliana but also identified new genes with unknown functions. [ABSTRACT FROM AUTHOR]

Abstract: Telomerase, the key enzyme essential for the maintenance of eukaryotic chromosome ends, contains a reverse transcriptase and an RNA that provides the template for the synthesis of telomeric repeats. Here, we characterize the telomerase subunits in the hemiascomycete yeast Candida glabrata. We propose a secondary structure model for the telomerase RNA that is the largest described to date. Telomerase deletion mutants show a progressive shortening of telomeres and a modest loss of viability. Frequent post-senescence survivors emerge that possess long telomeric repeat tracts. We suggest that the high telomere length heterogeneity accounts for this distinct senescence phenotype. [Copyright &y& Elsevier]

A telomere is a repetitive DNA structure capping the chromosomal ends. Telomeres stabilize the chromosome structure and prevent harmful end-to-end recombinations. The telomere length of somatic cells can be determined as the terminal restriction fragment length provided by a genomic Southern blotting analysis, and the telomere length becomes shorter at each mitotic cycle due to an “end-replication problem.” Therefore, older somatic cells, which have undergone more mitotic cycles, bear shorter telomeres. This telomere shortening is accelerated by various disease conditions. Parkinson's disease (PD) also yields telomere fragility, thus accelerating the telomere shortening of the circulating leukocytes. This study found that peripheral leukocytes of Japanese PD patients bear fewer short telomeres with constant subtelomeric methylation status in comparison with the healthy controls with increasing short telomeres and also increasing hypomethylated subtelomeres in short telomeres with aging. The correlation between the telomeric attrition and the subtelomeric methylated state in PD is herein discussed. [ABSTRACT FROM PUBLISHER]