Recent discoveries have revealed that simple repeating DNA sequences, which are known to adopt non-B DNA conformations (such as triplexes, cruciforms, slipped structures, left-handed Z-DNA and ...tetraplexes), are mutagenic. The mutagenesis is due to the non-B DNA conformation rather than to the DNA sequence
per se in the orthodox right-handed Watson-Crick B-form. The human genetic consequences of these non-B structures are ∼20 neurological diseases, ∼50 genomic disorders (caused by gross deletions, inversions, duplications and translocations), and several psychiatric diseases involving polymorphisms in simple repeating sequences. Thus, the convergence of biochemical, genetic and genomic studies has demonstrated a new paradigm implicating the non-B DNA conformations as the mutagenesis specificity determinants, not the sequences as such.
DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, ...mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSβ and the MutLα (and or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway.
Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. ...Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in two additional individuals. These recurrent mutations all occur within or in very close proximity to sites that regulate mtDNA replication, strongly implying that these variations alter the replication dynamics of the mutated mtDNA genome. These recurrent variants are all independent of each other and do not occur in the mtDNA coding regions. The most parsimonious explanation of the data is that these frequently repeated mutations experience tissue-specific positive selection, probably through replication advantage.
Friedreich ataxia, the most common inherited ataxia, is caused by the transcriptional silencing of the FXN gene, which codes for the 210 amino acid frataxin, a mitochondrial protein involved in ...iron-sulfur cluster biosynthesis. The expansion of the GAA·TTC tract in intron 1 to as many as 1700 repeats elicits the transcriptional silencing by the formation of non-B DNA structures (triplexes or sticky DNA), the formation of a persistent DNA·RNA hybrid, or heterochromatin formation. The triplex (sticky DNA) adopted by the long repeat sequence also elicits profound mutagenic, genetic instability, and recombination behaviors. Early stage therapeutic investigations involving polyamides or histone deacetylase inhibitors are being pursued. Friedreich ataxia may be one of the most thoroughly studied hereditary neurological disease from a pathophysiological standpoint.--Wells, R. D. DNA triplexes and Friedreich ataxia.
Uncertainty in comparative analyses can come from at least two sources: a) phylogenetic uncertainty in the tree topology or branch lengths, and b) uncertainty due to intraspecific variation in trait ...values, either due to measurement error or natural individual variation. Most phylogenetic comparative methods do not account for such uncertainties. Not accounting for these sources of uncertainty leads to false perceptions of precision (confidence intervals will be too narrow) and inflated significance in hypothesis testing (e.g. p-values will be too small). Although there is some application-specific software for fitting Bayesian models accounting for phylogenetic error, more general and flexible software is desirable.
We developed models to directly incorporate phylogenetic uncertainty into a range of analyses that biologists commonly perform, using a Bayesian framework and Markov Chain Monte Carlo analyses.
We demonstrate applications in linear regression, quantification of phylogenetic signal, and measurement error models. Phylogenetic uncertainty was incorporated by applying a prior distribution for the phylogeny, where this distribution consisted of the posterior tree sets from Bayesian phylogenetic tree estimation programs. The models were analysed using simulated data sets, and applied to a real data set on plant traits, from rainforest plant species in Northern Australia. Analyses were performed using the free and open source software OpenBUGS and JAGS.
Incorporating phylogenetic uncertainty through an empirical prior distribution of trees leads to more precise estimation of regression model parameters than using a single consensus tree and enables a more realistic estimation of confidence intervals. In addition, models incorporating measurement errors and/or individual variation, in one or both variables, are easily formulated in the Bayesian framework. We show that BUGS is a useful, flexible general purpose tool for phylogenetic comparative analyses, particularly for modelling in the face of phylogenetic uncertainty and accounting for measurement error or individual variation in explanatory variables. Code for all models is provided in the BUGS model description language.
Habitat loss is the primary driver of biodiversity decline worldwide, but the effects of fragmentation (the spatial arrangement of remaining habitat) are debated. We tested the hypothesis that forest ...fragmentation sensitivity-affected by avoidance of habitat edges-should be driven by historical exposure to, and therefore species' evolutionary responses to disturbance. Using a database containing 73 datasets collected worldwide (encompassing 4489 animal species), we found that the proportion of fragmentation-sensitive species was nearly three times as high in regions with low rates of historical disturbance compared with regions with high rates of disturbance (i.e., fires, glaciation, hurricanes, and deforestation). These disturbances coincide with a latitudinal gradient in which sensitivity increases sixfold at low versus high latitudes. We conclude that conservation efforts to limit edges created by fragmentation will be most important in the world's tropical forests.
Radiotherapy for prostate cancer (PCa) may cause unfavorable changes in fatigue, quality of life (QOL), and physical fitness. We report results from the Prostate Cancer Radiotherapy and Exercise ...Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue, QOL, physical fitness, body composition, prostate-specific antigen, testosterone, hemoglobin, and lipid levels in men with PCa receiving radiotherapy.
Between 2003 and 2006, we conducted a randomized controlled trial in Ottawa, Canada, where 121 PCa patients initiating radiotherapy with or without androgen deprivation therapy were randomly assigned to usual care (n = 41), resistance (n = 40), or aerobic exercise (n = 40) for 24 weeks. Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale.
The follow-up assessment rate for our primary end point of fatigue was 92.6%. Median adherence to prescribed exercise was 85.5%. Mixed-model repeated measures analyses indicated both resistance (P =.010) and aerobic exercise (P = .004) mitigated fatigue over the short term. Resistance exercise also produced longer-term improvements (P = .002). Compared with usual care, resistance training improved QOL (P = .015), aerobic fitness (P = .041), upper- (P < .001) and lower-body (P < .001) strength, and triglycerides (P = .036), while preventing an increase in body fat (P = .049). Aerobic training also improved fitness (P = .052). One serious adverse event occurred in the group that performed aerobic exercise.
In the short term, both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy. Resistance exercise generated longer-term improvements and additional benefits for QOL, strength, triglycerides, and body fat.
Opportunistic assessment of sarcopenia on CT examinations is becoming increasingly common. This study aimed to determine relationships between CT-measured skeletal muscle size and attenuation with ...1-year risk of mortality in older adults enrolled in a Medicare Shared Savings Program (MSSP).
Relationships between skeletal muscle metrics and all-cause mortality were determined in 436 participants (52% women, mean age 75 years) who had abdominopelvic CT examinations. On CT images, skeletal muscles were segmented at the level of L3 using two methods: (a) all muscles with a threshold of -29 to +150 Hounsfield units (HU), using a dedicated segmentation software, (b) left psoas muscle using a free-hand region of interest tool on a clinical workstation. Muscle cross-sectional area (CSA) and muscle attenuation were measured. Cox regression models were fit to determine the associations between muscle metrics and mortality, adjusting for age, sex, race, smoking status, cancer diagnosis, and Charlson comorbidity index.
Within 1 year of follow-up, 20.6% (90/436) participants died. In the fully-adjusted model, higher muscle index and muscle attenuation were associated with lower risk of mortality. A one-unit standard deviation (SD) increase was associated with a HR = 0.69 (95% CI = 0.49, 0.96; p = .03) for total muscle index, HR = 0.67 (95% CI = 0.49, 0.90; p < .01) for psoas muscle index, HR = 0.54 (95% CI = 0.40, 0.74; p < .01) for total muscle attenuation, and HR = 0.79 (95% CI = 0.66, 0.95; p = .01) for psoas muscle attenuation.
In older adults, higher skeletal muscle index and muscle attenuation on abdominopelvic CT examinations were associated with better survival, after adjusting for multiple risk factors.
PDF
