Biology subjects

Jones, M. J.

Publications and source records attributed to Jones, M. J..

18 recordsLinked to original sources

bioRxiv2026

Prenatal diet buffers infant epigenetic changes linked to pollution and transient wheeze

Prenatal air pollution exposure is associated with childhood asthma, particularly among biological males. The mechanisms remain unclear, but may involve lasting epigenetic changes, such DNA methylation (DNAm), that occur during gestation in response to oxidative stress and inflammation. Higher maternal intake of "protective" micronutrients, like antioxidants, could buffer pollution-induced oxidative stress and inflammation to mitigate potentially adverse DNAm differences contributing to asthma. Using data from 515 CANDLE participants, we examined associations between prenatal NO2, PM2.5, and PM10 and cord blood DNAm, evaluated DNAm mediation of pollution associations with childhood wheeze phenotypes (transient, persistent, and late-onset), and assessed buffering of DNAm by maternal polyunsaturated fatty acid, vitamin C, or folate intake, and overall diet quality measured by the Alternative Healthy Eating Index-Pregnancy (AHEI-P). We identified 19, seven, and five regional DNAm differences associated NO2, PM2.5, and PM10. Mediation analyses suggested a role for HLA-DPA1/DPB1 DNAm in NO2 and PM2.5 associations with transient wheeze. To assess buffering, we fit pollutant-by-diet interaction models, defining buffering as an interaction opposite in sign to the main pollutant effect. One or more micronutrients or AHEI-P attenuated pollutant effects at 16 of 19 NO2-associated DMRs, including HLA-DPA1/DPB1, and all PM2.5- and PM10-associated DMRs. However, attenuation of HLA-DPA1/DPB1 DNAm did not significantly reduce the indirect effect of NO2 on transient wheeze. In sex-stratified analyses, biological males exhibited lower PM2.5-associated DNAm in SERPINB9, a gene linked to lung function. These findings suggest prenatal air pollution alters DNAm, which may contribute to transient wheeze, with some differences partially buffered by maternal diet. Significance StatementPrenatal air pollution exposure contributes to child wheeze and asthma, potentially through the oxidative stress response and subsequent changes to infant DNA methylomes. Here, we used data from the CANDLE cohort to identify cord blood DNAm differences associated with NO2, PM2.5, or PM10. We examined if any alterations mediated the relationship between prenatal air pollution exposures and transient, persistent, or late-onset wheeze at age 4 to 6 years. Some of these DNAm differences appeared to be at least partially buffered by maternal micronutrients and/or overall diet quality.

genomics↗

bioRxiv2024

Differential roles of cyclin-CDK1 complexes in cell migration and invasion

Two key hallmarks of cancer are dysregulated proliferation and metastasis, which are co- ordinated at the single cell level by regulation of cell-cycle progression and invasive cell migration respectively. We have previously described a central role for CDK1 at the nexus of adhesion signalling and cell cycle progression, demonstrating that CDK1 has a non-canonical role in regulating integrin adhesion complexes and in the migration of cancer cells in 3D interstitial matrix. Here we show that the CDK1 binding partners cyclinB1 and cyclinA2 also have roles in cell migration and invasion in both cancer and non-transformed cells. CyclinB1 plays a key role in RhoA activation to promote rear retraction in a membrane tension dependent manner, while cyclinA2 has a general role in promoting motility. Knockdown of either cyclin significantly perturbs migration with contrasting phenotypes, while knockdown of both together has an additive effect which arrests both migration and division. We find that the cell migration specific role of CDK1 is independent of cell-cycle phase, with inhibition or knockdown of CDK1 perturbing migration in G0/G1 arrested cells, while CDK1-cyclin expression correlates strongly with invasive potential of bladder cancer cell lines. Our findings therefore describe how cyclin-CDK1 complexes orchestrate migration as well as division of cells and that cyclinA2-CDK1 and cyclinB1-CDK1 complexes play distinct roles in motility. Furthermore, these findings suggest that targeting CDK1 signalling in aggressive and invasive tumours may have an unexpected dual potential to combat metastasis in addition to proliferation.

cell biology↗

bioRxiv2024

Mechanism by which Aurora B inhibitors promotes RB and p53-dependent senescence.

Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether this is a source of increased chemotherapy resistance and aggressive disease, or a benign or even favorable outcome. We have used Aurora B kinase (AURKB) inhibitors that efficiently promote polyploidy in many cell types to investigate the fate of polyploid cells. We demonstrate AURKB inhibitor treatment of cells that have loss of RB and p53 function causes them to become hyper-polyploid, undergoing continuous rounds of growth, replication and failed mitosis/cytokinesis (endomitosis), whereas RB and p53 functional cells will eventually exit the cell cycle. These hyper-polyploid cells (>4n DNA content) are viable and undergo continuous endomitotic cycles, but have lost the ability to form viable colonies in vitro or form tumours in vivo. Investigation of mitosis in these cells revealed that centrosome duplication remained coupled to DNA replication, with the hyper-polyploid cells containing high numbers of centrosome that were capable of supporting functional mitotic spindle poles, but these failed to progress to anaphase/telophase structures even when AURKB inhibitor was removed after 2-3 days. However, when AURKB inhibitor was removed after 1 day and cells had failed a single cytokinesis to become tetraploid, they retained long term colony forming ability. Collectively, these findings demonstrate that tetraploidy is well tolerated by tumour cells but higher ploidy states are incompatible with long term proliferative potential.

cell biology↗

bioRxiv2024

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both basal and induced mitophagy. Disruption of the phosphatase activity of PPTC7 is not required for BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-NIX/BNIP3 and PPTC7-FBXL4 interactions and their disruption interferes with both NIX/BNIP3 degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts NIX/BNIP3-induced mitophagy.

cell biology↗

bioRxiv2024

Climate change, age acceleration, and the erosion of fitness in polar bears

Climate change is increasingly disrupting evolved life history strategies and reducing population viability in wild species. Using estimates of epigenetic age acceleration, a cellular biomarker of lifetime stress and the expression of age-related phenotypes, we found that polar bears aged approximately one year faster for each degree of warming since the 1960s. Age acceleration was also associated with reproducing early in life, linking this cellular process to well-established life history theory. However, we found evidence for the erosion of fitness as epigenetic aging accelerated and temperatures increased. Finally, using a large pedigree, we found adaptive potential in our study population was approximately zero. Global temperatures will soon reach the levels of warming currently experienced by Arctic species, which could impose widespread physiological costs and limit adaptive capacities worldwide.

ecology↗

bioRxiv2023

Epigenetic clocks, sex markers, and age-class diagnostics in three harvested large mammals

The development of epigenetic clocks, or the DNA methylation-based inference of age, is an emerging tool for ageing in free ranging populations. In this study, we developed epigenetic clocks for three species of large mammals that are the focus of extensive management throughout their range: white-tailed deer, black bear, and mountain goat. We quantified differential DNA methylation patterns at over 30,000 cytosine-guanine sites (CpGs) from tissue samples (N=141) of all three species. We used a penalized regression model (elastic net) to build highly explanatory (black bear r = 0.95; white-tailed deer r = 0.99; mountain goat r = 0.97) and robust (black bear Median Absolute Error or MAE = 1.33; white-tailed deer MAE = 0.29; mountain goat MAE = 0.61) models of age (clocks). We also characterized individual CpG sites within each species that demonstrated clear differences in methylation levels between age classes and sex, which can be used to develop a suite of accessible diagnostic markers. Our results demonstrate promising tools for the large-scale estimation of age in wild animals, which have the potential to contribute to wildlife monitoring by providing easily obtainable representations of age structure in managed populations.

genomics↗

bioRxiv2023

Novel DNA methylation changes in mouse lungs associated with heavy smoking

Smoking is a potent cause of asthma, chronic obstructive pulmonary disease (COPD) and many other health defects, and changes in DNA methylation (DNAm) have been identified as a potential link between smoking and these health outcomes. However, most links between smoking and DNAm have been made using blood and other easily accessible tissues in humans, while evidence from more directly affected tissues such as the lungs is greatly lacking. Here, we identified DNAm patterns which are altered by smoking directly in the lungs. We used a well-established mouse model to measure the effects of heavy smoking first on lung phenotype immediately after smoking and then after a period of smoking cessation. Next, we determined whether our mouse model could recapitulate previous DNAm patterns observed in smoking humans by measuring DNAm at a candidate gene responsive to cigarette smoke (CS), Cyp1a1. Finally we carried out epigenome-wide DNAm analyses using the newly released Illumina mouse methylation microarrays. Our results recapitulate some of the phenotypes and DNAm patterns observed in human studies but reveal 32 differentially methylated genes specific to the lungs which have not been previously associated with smoking. The affected genes are known to be involved in nicotine dependency, tumorigenesis and metastasis, immune cell dysfunction, lung function decline, and COPD. This research emphasizes the need to study CS-mediated DNAm signatures in directly affected tissues like the lungs, as that may be essential in understanding mechanisms underlying CS-mediated health outcomes.

molecular biology↗

bioRxiv2023

Jamestown Canyon Virus is transmissible by Aedes aegypti and is only moderately blocked by Wolbachia co-infection

Jamestown Canyon Virus (JCV), a negative-sense arbovirus, is increasingly common in the upper Midwest of the USA. Transmitted by a range of mosquito genera, JCV has at its primary amplifying host, white-tailed deer. Aedes aegypti is the major transmitter globally of the positive-sense viruses dengue (DENV), Zika, chikungunya, and Yellow Fever. Ae. aegyptis distribution, once confined to the tropics, is expanding, in part due to climate change. Wolbachia, an insect endosymbiont, limits the replication of co-infecting viruses inside insects. The release and spread of the symbiont into Ae. aegypti populations has been effective in reducing transmission of dengue and other viruses to humans. The mechanism of Wolbachia-mediated viral blocking in vectors is still poorly understood, however. Here we explored JCV infection potential in Ae. aegypti, the nature of the vectors immune response, and interactions with Wolbachia infection. We show that Ae. aegypti is highly competent for JCV, growing to substantial loads and rapidly reaching the saliva after an infectious blood meal. The mosquito immune system responds with strong induction of RNAi and JAK/STAT. Neither the direct effect of viral infection nor the energetic investment in immunity appears to affect mosquito longevity. Wolbachia infection blocked JCV only in the early stages of infection. Wolbachia-induced immunity was small compared to that of JCV, suggesting innate immune priming does not likely explain blocking. We propose two models to explain why Wolbachias blocking of negative-sense viruses like JCV may be less than that of positive-sense viruses, relating to the slowdown of host protein synthesis and the triggering of interferon-like factors like Vago. In conclusion, we highlight the risk for increased human disease with the predicted future overlap of Ae. aegypti and JCV ranges. We suggest that with moderate Wolbachia-mediated blocking and distinct biology, negative-sense viruses represent a fruitful comparator model to other viruses for understanding blocking mechanisms in mosquitoes. Author SummaryJamestown Canyon Virus (JCV), a newly emerging virus in North America, causes disease when it spills out of its wild mammal hosts into human populations via the bite of infected mosquitoes. We show that the mosquito Aedes aegypti, known for transmitting many viral pathogens to humans globally, and whose distribution is creeping northward in the USA toward regions where JCV is present, is likely able to transmit the virus. Wolbachia is an endosymbiotic bacterium being released in wild mosquito populations of mosquitoes because it limits the replication of human viruses inside the mosquito, limiting their transmission to humans. We show that Wolbachia has a limited ability to control the replication of JCV, which is likely because Wolbachia-induced antiviral response is quite weak, and unique aspects of negative-sense virus biology make them less susceptible to blocking. Our findings suggest that JCV may serve as a comparative model to positive-sense viruses like dengue in dissecting the mechanism of Wolbachia-mediated virus blocking. It also warns that shifting mosquito distributions, as expected under a changing climate, could bring JCV and Aedes mosquitoes into greater contact, potentially increasing the incidence of JCV in humans.

pathology↗

bioRxiv2023

Early life exposure to cigarette smoke is associated with lung function changes and primes gene expression and DNA methylation changes at Cyp1a1 upon exposure later in life

Prenatal and early life exposure to cigarette smoke (CS) have repeatedly been shown to induce stable, long-term changes in DNA methylation (DNAm) in offspring. It has been hypothesized that these changes might be functionally related to the known outcomes of prenatal and early life CS exposure, which include impaired lung development, altered lung function and increased risk of asthma and wheeze. However, to date, few studies have examined DNAm changes induced by prenatal CS in tissues of the lung, and even fewer have attempted to examine the specific influences of prenatal versus early postnatal exposures. Here, we have established a mouse model of CS exposure which isolates the effects of prenatal and early postnatal CS exposures in early life. We have used this model to measure the effects of prenatal and/or postnatal CS exposures on lung function and immune cell infiltration as well as DNAm and expression of Cyp1a1, a candidate gene previously observed to demonstrate DNAm differences upon CS exposure in humans. Our study revealed that exposure to CS prenatally and in the early postnatal period cause long-lasting differences in offspring lung function, gene expression and lung Cyp1a1 DNAm, which wane over time but are reestablished upon re-exposure to CS in adulthood. This study creates a testable mouse model which can be used to investigate the effects of prenatal and early postnatal CS exposures and will contribute to the design of intervention strategies to mediate these detrimental effects.

genetics↗

bioRxiv2023

Persistent DNA methylation changes associated with prenatal NO2 exposure in a Canadian prospective birth study

BackgroundAccumulating evidence suggests prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. However, it remains unclear whether prenatal DNAm alterations persist through early life. Identifying DNAm changes that persist from birth into childhood would provide greater insight into the molecular mechanisms that most likely contribute to the association of prenatal air pollution exposure with health outcomes such as atopic disease. ObjectivesThis study investigated the persistence of DNAm changes associated with prenatal NO2 exposure (a surrogate measure of traffic-related air pollution) at age one to begin characterizing which DNAm changes most likely to contribute to atopic disease. MethodsWe used an atopy-enriched subset of CHILD study participants (N=145) to identify individual and regional cord blood DNAm differences associated with prenatal NO2, followed by an investigation of persistence in age one peripheral blood. As we had repeated DNAm measures, we also isolated postnatal-specific DNAm changes and examined their association with NO2 exposure in the first year of life. MANOVA tests were used to examine the association between DNAm changes associated with NO2 and child wheeze and atopy. ResultsWe identified 24 regions of altered cord blood DNAm, with several annotated to HOX genes. Two regions annotated to MPDU1 and C5orf63 were significantly associated with age one wheeze. Further, we found the effect of prenatal NO2 exposure across CpGs within all altered regions remained similar at age one. A single region of postnatal-specific DNAm annotated to HOXB6 was associated with year one NO2 and age one atopy. DiscussionRegional cord blood DNAm changes associated with prenatal NO2 exposure persist through at least the first year of life, and some of these changes are associated with age one wheeze. The early-postnatal period remains a sensitive window to DNAm perturbations that may also influence child health.

genetics↗

bioRxiv2022

Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice

Risk factors contributing to dementia are multifactorial. Pathogens as risk factors for dementia is largely correlative with few causal relationships. Here, we demonstrate that intermittent cytomegalovirus (CMV) infection in mice, mimicking human chronic infection and reactivation/reinfection events, alters blood brain barrier (BBB) metabolic pathways. An increase in basal mitochondrial function is observed in brain microvasculature endothelial cells (BMEC) at 12 months post infection but not at earlier time points and is accompanied by elevated levels of superoxide, indicative of oxidative stress. Further, these mice score lower in cognitive assays as compared to age-matched controls. Our data show that repeated systemic infection with CMV, alters BBB metabolic function and impacts cognition. These observations provide mechanistic insights through which pathogens contribute to the progression of pathologies associated with dementia. In BriefMechanistic evidence supporting an infectious etiology of dementia (e.g. Alzheimers Disease) are poorly defined. Harrison et al., show that intermittent infection with cytomegalovirus metabolically rewires the blood brain barrier and neighboring glial cells altering their function, resulting in decreased cognitive function.

neuroscience↗

bioRxiv2022

Alpha-mannosidase-2 modulates arbovirus infection in a pathogen- and Wolbachia-specific manner in Aedes aegypti mosquitoes

Multiple Wolbachia strains can block pathogen infection, replication, and/or transmission in Aedes aegypti mosquitoes under both laboratory and field conditions. However, Wolbachia effects on pathogens can be highly variable across systems and the factors governing this variability are not well understood. It is increasingly clear that the mosquito host is not a passive player in which Wolbachia governs pathogen transmission phenotypes; rather, the genetics of the host can significantly modulate Wolbachia-mediated pathogen blocking. Specifically, previous work linked variation in Wolbachia pathogen blocking to polymorphisms in the mosquito alpha-mannosidase 2 (Man2) gene. Here we use CRISPR-Cas9 mutagenesis to functionally test this association. We developed Man2 knockouts and examined effects on both Wolbachia and virus levels, using both dengue virus (DENV; Flaviviridae) and Mayaro virus (MAYV; Togaviridae). Wolbachia titers were significantly elevated in Man2 knockout (KO) mosquitoes, but there were complex interactions with virus infection and replication. In Wolbachia-uninfected mosquitoes, the Man2 KO mutation was associated with decreased DENV titers, but in a Wolbachia-infected background, the Man2 KO mutation significantly modulated virus blocking. In contrast, the Man2 KO mutation significantly increased MAYV replication in Wolbachia-uninfected mosquitoes and did not affect Wolbachia-mediated virus blocking. These results demonstrate that Man2 modulates arbovirus infection in Ae. aegypti mosquitoes in a pathogen- and Wolbachia-specific manner, and that Wolbachia-mediated pathogen blocking is a complex phenotype dependent on the mosquito host genotype and the pathogen. These results have significant impact for the design and use of Wolbachia-based strategies to control vector-borne pathogens.

microbiology↗

bioRxiv2020

Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate

SARS-CoV-2 has initiated a global pandemic and vaccines are being rapidly developed. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory transmission was poor to only 1/4 contact animals. To assess the durability of immunity, ferrets were re-challenged 28 or 56 days post-primary infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets against infection, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the SARS-CoV-2 USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity. ImportanceThe SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.

microbiology↗

bioRxiv2020

Low light levels increase avoidance behaviour of diurnal fish species: Implications for road culverts

Inadequately designed culverts are known to pose hydraulic barriers to fish passage, but they may also be behavioural barriers if they adversely affect light levels within them. To test this, we performed a choice experiment and quantified the amount of time individuals of four Australian fish species spent in darkened and illuminated areas of an experimental swimming fume. Behavioural responses were reflective of the species diel activity patterns; diurnal species preferred illuminated regions, while nocturnal species preferred the darkened region. We then determined a threshold light level of only ~100-200 lux (c.f. midday sunlight ~100,000 lux) was required to overcome the behavioural barrier in ~ 70% of the diurnal fish tested. Placing these threshold values into field context, 100% of culverts sampled recorded inadequate light levels. Attention is required to better understand the impacts of low light levels in culverts on fish passage and to prioritise restoration.

zoology↗

bioRxiv2019

Breaking down defenses: Quantitative analysis of malaria infection dynamics reveals distinct immune defense strategies

Hosts defend themselves against pathogens by mounting an immune response. Fully understanding the immune response as a driver of host disease and pathogen evolution requires a quantitative account of its impact on parasite population dynamics. Here, we use a data-driven modeling approach to quantify the birth and death processes underlying the dynamics of infections of the rodent malaria parasite, Plasmodium chabaudi, and the red blood cells (RBCs) it targets. We decompose the immune response into three components, each with a distinct effect on parasite and RBC vital rates, and quantify the relative contribution of each component to host disease and parasite density. Our analysis suggests that these components are deployed in a coordinated fashion to realize distinct resource-directed defense strategies that complement the killing of parasitized cells. Early in the infection, the host deploys a strategy reminiscent of siege and scorched-earth tactics, in which it both restricts the supply of RBCs and destroys them. Late in the infection, a juvenilization strategy, in which turnover of RBCs is accelerated, allows the host to recover from anemia while holding parasite proliferation at bay. By quantifying the impact of immunity on both parasite fitness and host disease, we reveal that phenomena often interpreted as immunopathology may in fact be beneficial to the host. Finally, we show that, across mice, the components of the host response are consistently related to each other, even when infections take qualitatively different trajectories. This suggests the existence of simple rules that govern the immune systems deployment.

ecology↗

bioRxiv2019

Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data

BackgroundUmbilical cord blood (UCB) is commonly used in epigenome-wide association studies of prenatal exposures. Accounting for cell type composition is critical in such studies as it reduces confounding due to the cell specificity of DNA methylation (DNAm). In the absence of cell sorting information, statistical methods can be applied to deconvolve heterogeneous cell mixtures. Among these methods, reference-based approaches leverage age appropriate cell-specific DNA-methylation profiles to estimate cellular composition. In UCB, four reference datasets comprising DNAm signatures profiled in purified cell populations have been published using the Illumina 450K and 850K EPIC arrays. These datasets are biologically and technically different, and currently there is no consensus on how to best apply them. Here, we systematically evaluate and compare these datasets and provide recommendations for reference-based UCB deconvolution.\n\nResultsWe first evaluated the four reference datasets to ascertain both the purity of the samples and the potential cell cross-contamination. We filtered samples and combined datasets to obtain a joint UCB reference. We selected deconvolution libraries using two different approaches: automatic selection using the top differentially methylated probes from the function pickCompProbes in minfi and a standardized library selected using the IDOL (Identifying Optimal Libraries) iterative algorithm. We compared the performance of each reference separately and in combination, using the two approaches for reference library selection, and validated the results in an independent cohort (Generation R Study, n=191) with matched FACS measured cell counts. Strict filtering and combination of the references significantly improved the accuracy and efficiency of cell type estimates. Ultimately, the IDOL library outperformed the library from the automatic selection method implemented in pickCompProbes.\n\nConclusionThese results have important implications for epigenetic studies in UCB as implementing this method will optimally reduce confounding due to cellular heterogeneity. This work provides guidelines for future reference-based UCB deconvolution and establishes a framework for combining reference datasets in other tissues.

bioinformatics↗

bioRxiv2018

Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

BackgroundEpigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).\n\nResultsWe used Akaikes information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.\n\nConclusionGenetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

genetics↗

bioRxiv2017

BECon: A tool for interpreting DNA methylation findings from blood in the context of brain

Tissue differences are one of the largest contributors to variability in the human DNA methy-lome. Despite the tissue specific nature of DNA methylation, the inaccessibility of human brain samples necessitates the frequent use of surrogate tissues such as blood, in studies of associations between DNA methylation and brain function and health. Results from studies of surrogate tissues in humans are difficult to interpret in this context, as the connection between blood-brain DNA methylation is tenuous and not well documented. Here we aimed to provide a resource to the community to aid interpretation of blood based DNA methylation results in the context of brain tissue. We used paired samples from 16 individuals from three brain regions and whole blood, run on the Illumina 450K Human Methylation Array to quantify the concordance of DNA methylation between tissues. From these data we have made available metrics on: the variability of CpGs in our blood and brain samples, the concordance of CpGs between blood and brain, and estimations of how strongly a CpG is affected by cell composition in both blood and brain through the web application BECon (Blood-Brain Epigenetic Concordance; https://redgar598.shinyapps.io/BECon/). We anticipate that BECon will enable biological interpretation of blood based human DNA methylation results, in the context of brain.

genetics↗