Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels.
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ABSTRACT:
SUBMITTER: McKennan C
PROVIDER: S-EPMC8143220 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. RESULTS:Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36?weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18?weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. CONCLUSIONS:Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways. TRIAL REGISTRATION:Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.
| S-EPMC7193358 | biostudies-literature
Project description:Molecular catch bonds are ubiquitous in biology and essential for processes like leucocyte extravasion1 and cellular mechanosensing2. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this feature provides 'strength on demand3', thus enabling cells to increase rigidity under stress1,4-6. However, catch bonds are often weaker than slip bonds because they have cryptic binding sites that are usually buried7,8. Here we show that catch bonds render reconstituted cytoskeletal actin networks stronger than slip bonds, even though the individual bonds are weaker. Simulations show that slip bonds remain trapped in stress-free areas, whereas weak binding allows catch bonds to mitigate crack initiation by moving to high-tension areas. This 'dissociation on demand' explains how cells combine mechanical strength with the adaptability required for shape change, and is relevant to diseases where catch bonding is compromised7,9, including focal segmental glomerulosclerosis10 caused by the α-actinin-4 mutant studied here. We surmise that catch bonds are the key to create life-like materials.
| S-EPMC7613626 | biostudies-literature
Project description:Impulsivity is an endophenotype found in many psychiatric disorders including substance use disorders, pathological gambling, and attention deficit hyperactivity disorder. Two behavioral features often considered in impulsive behavior are behavioral inhibition (impulsive action) and delayed gratification (impulsive choice). However, the extent to which these behavioral constructs represent distinct facets of behavior with discrete biological bases is unclear. To test the hypothesis that impulsive action and impulsive choice represent statistically independent behavioral constructs in mice, we collected behavioral measures of impulsivity in a single cohort of mice using well-validated operant behavioral paradigms. Mice with manipulation of serotonin 1B receptor (5-HT1BR) expression were included as a model of disordered impulsivity. A factor analysis was used to characterize correlations between the measures of impulsivity and to identify covariates. Using two approaches, we dissociated impulsive action from impulsive choice. First, the absence of 5-HT1BRs caused increased impulsive action, but not impulsive choice. Second, based on an exploratory factor analysis, a two-factor model described the data well, with measures of impulsive action and choice separating into two independent factors. A multiple-indicator multiple-causes analysis showed that 5-HT1BR expression and sex were significant covariates of impulsivity. Males displayed increased impulsivity in both dimensions, whereas 5-HT1BR expression was a predictor of increased impulsive action only. These data support the conclusion that impulsive action and impulsive choice are distinct behavioral phenotypes with dissociable biological influences that can be modeled in mice. Our work may help inform better classification, diagnosis, and treatment of psychiatric disorders, which present with disordered impulsivity.
| S-EPMC5437890 | biostudies-other
Project description:Sandeels are an ecologically important group of fishes; they are a key part of the food chain serving as food for marine mammals, seabirds and fish. Sandeels are further targeted by a large industrial fishery, which has led to concern about ecosystem effects. In the North Sea, the lesser sandeel Ammodytes marinus is by far the most prevalent species of sandeel in the fishery. Management of sandeel in the North Sea plus the Kattegat is currently divided into seven geographical areas, based on subtle differences in demography, population dynamics and results from simulations of larval dispersal. However, little is known about the underlying genetic population structure. In this study, we used 2,522 SNPs derived from restriction site-associated DNA sequencing (RADseq) typed in 429 fish representing four main sandeel management areas. Our main results showed (a) a lack of a clear spatially defined genetic structure across the majority of genetic markers and (b) the existence of a group of at least 13 SNPs under strong linkage disequilibrium which together separate North Sea sandeel into three haplotype clusters, suggestive of one or more structural variants in the genome. Analyses of the spatial distribution of these putative structural variants suggest at least partial reproductive isolation of sandeel in the western management area along the Scottish coast, supporting a separate management. Our results highlight the importance of the application of a large number of markers to be able to detect weak patterns of differentiation. This study contributes to increasing the genetic knowledge of this important exploited species, and results can be used to improve our understanding of population dynamics and stock structure.
| S-EPMC6976957 | biostudies-literature
Project description:The extent of dispersal by pelagic larvae in marine environments, including coral reefs, is central for understanding local population dynamics and designing sustainable marine reserves. We present here the first example of a clear stepping-stone genetic structure throughout the Caribbean basin for a common coral reef species, the French grunt (Haemulon flavolineatum). Analysis of microsatellite DNA markers indicated that French grunt population structure may be characterized by overlapping populations throughout the Caribbean, influenced by independent population dynamics but with no fixed geographical boundaries. In addition, different spatial genetic patterns were found in different oceanographic regions. A second species, the bluehead wrasse (Thalassoma bifasciatum), has a much longer pelagic larval duration than French grunts and showed no explicit spatial pattern of genetic variation. This finding is concordant with the hypothesis of a positive relationship between larval dispersal and duration in the plankton. While the magnitude of the genetic signal of population structure in French grunts was very low (F(ST) approximately 0.003), the pattern of isolation-by-distance throughout the Caribbean indicated considerable population structure with important ecological and conservation significance.
| S-EPMC1560316 | biostudies-literature
Project description:BackgroundThe objective of this work was to investigate the hypothesis that eukaryotic Internal Ribosome Entry Sites (IRES) lack secondary structure and to examine the generality of the hypothesis.Methodology/principal findingsIRESs of the yeast and the fruit fly are located in the 5'UTR immediately upstream of the initiation codon. The minimum folding energy (MFE) of 60 nt RNA segments immediately upstream of the initiation codons was calculated as a proxy of secondary structure stability. MFE of the reverse complements of these 60 nt segments was also calculated. The relationship between MFE and empirically determined IRES activity was investigated to test the hypothesis that strong IRES activity is associated with weak secondary structure. We show that IRES activity in the yeast and the fruit fly correlates strongly with the structural stability, with highest IRES activity found in RNA segments that exhibit the weakest secondary structure.ConclusionsWe found that a subset of eukaryotic IRESs exhibits very low secondary structure in the 5'-UTR sequences immediately upstream of the initiation codon. The consistency in results between the yeast and the fruit fly suggests a possible shared mechanism of cap-independent translation initiation that relies on an unstructured RNA segment.
| S-EPMC2607549 | biostudies-literature
Project description:Here is reported the first study of transcriptome analyses using the Illumina HiSeq 4000 platform for three kinds of wheat (G represents Strong gluten wheat, Z represents middle gluten wheat,R represents weak gluten wheat). The variation of wheat varieties with different gluten content is mainly shown in the content of gluten, flour is divided into high gluten powder ( > 30%), medium gluten powder (26%-30%) and low gluten powder ( < 20%), according to the wet gluten content. In total, over 102.6 Gb clean reads were produced and 114, 621 unigenes were assembled; more than 59,085 unigenes had at least one significant match to an existing gene model. Differentially expressed gene analysis identified 2339 and 2600 unigenes which were expressed higher or lower among strong gluten, middle gluten and weak gluten wheat. After functional annotation and classification, three dominant pathways including protein isomerase, antioxidase activity and energy metabolism, and 410 unigenes related to gluten strength polymerization of wheat were discovered. In strong-gluten wheat, low molecular weight subunit content is higher than weak-gluten wheat, and the activity of cysteine synthase and isomerase is increased, which may promote the cross-linking of low molecular weight protein to high molecular weight protein. Meanwhile, POD enzyme strengthens gluten network and CAT enzyme affects gluten polymerization, along with higher ATPase activity, which will provides energy for protein polymerization reaction in comparison of strong-gluten wheat and weak-gluten wheat. The accuracy of these RNA-seq data was validated by qRT-PCR analysis. These data will extend our knowledge of quality characteristics of wheat and provide a theoretical foundation for molecular mechanism research of wheat.
2020-09-03 | GSE122699 | GEO
Project description:BackgroundSmoking is a major cause of morbidity and mortality. Smoking-related epigenetic biomarkers may open new avenues to better quantify the adverse health effects of smoking, and to better understanding of the underlying mechanisms. We aimed to evaluate the clinical implications of F2RL3 methylation, a novel epigenetic biomarker of smoking exposure disclosed by recent genome-wide methylation studies.MethodsBlood DNA methylation at F2RL3 (also known as PAR-4) was quantified in baseline samples of 3588 participants aged 50-75 years in a large population-based prospective cohort study by MALDI-TOF mass spectrometry. Deaths were recorded during a median follow-up of 10.1 years. The associations of methylation intensity and of smoking with all-cause, cardiovascular, cancer and other mortality were assessed by Cox's proportional hazards regression, controlling for potential confounding factors.ResultsLower methylation intensity at F2RL3 was strongly associated with mortality. After adjustment for multiple covariates including smoking, hazard ratios [95% confidence interval (CI)] for death from any cause, cardiovascular disease, cancer or other causes were 2.60 (95% CI, 1.81-3.74), 2.45 (95% CI, 1.28-4.68), 2.94 (95% CI, 1.68-5.14) and 2.39 (95% CI, 1.11-5.16), respectively, in subjects in the lowest quartile of methylation intensity compared with subjects in the highest quartile. The associations with mortality outcomes were much stronger among men than among women. In addition, strong positive associations of smoking with each of the outcomes were substantially weakened, and almost disappeared when controlling for F2RL3 methylation intensity.ConclusionsF2RL3 methylation is a strong predictor of mortality, including all-cause, cardiovascular, cancer and other mortality. Systemic adverse effects of smoking may be mediated by pathways associated with F2RL3 methylation.
| S-EPMC4258765 | biostudies-literature
Project description:The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels.Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.
| S-EPMC3583143 | biostudies-literature
Project description:Understanding genetic differentiation and speciation processes in marine species with high dispersal capabilities is challenging. The Chilean dolphin, Cephalorhynchus eutropia, is the only endemic cetacean of Chile and is found in two different coastal habitats: a northern habitat with exposed coastlines, bays and estuaries from Valparaíso (33°02'S) to Chiloé (42°00'S), and a southern habitat with highly fragmented inshore coastline, channels and fjords between Chiloé and Navarino Island (55°14'S). With the aim of evaluating the potential existence of conservation units for this species, we analyzed the genetic diversity and population structure of the Chilean dolphin along its entire range. We genotyped 21 dinucleotide microsatellites for 53 skin samples collected between 1998 and 2012 (swab: n = 8, biopsy: n = 38, entanglement n = 7). Bayesian clustering and spatial model analyses identified two genetically distinct populations corresponding to the northern and southern habitats. Genetic diversity levels were similar in the two populations (He: 0.42 v/s 0.45 for southern and northern populations, respectively), while effective size population was higher in the southern area (Ne: 101 v/s 39). Genetic differentiation between these two populations was high and significant (FST = 0.15 and RST = 0.19), indicating little or no current gene flow. Because of the absence of evident geographical barriers between the northern and southern populations, we propose that genetic differentiation may reflect ecological adaptation to the different habitat conditions and resource uses. Therefore, the two genetic populations of this endemic and Near Threatened species should be considered as different conservation units with independent management strategies.
| S-EPMC4405423 | biostudies-literature