Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders

Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of <1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), correlated the variants with transcriptional alterations in blood RNAseq data, and performed a case-control association study of the relevant findings in a larger cohort (394 cases and 500 controls). We found 700 differentially methylated CpGs, most of them hypomethylated in the ASD group (83.9%), with cis-acting expression changes at 7.6% of locations. Relevant findings included: (1) hypomethylation caused by rare genetic variants (meSNVs) at six loci (ERMN, USP24, METTL21C, PDE10A, STX16 and DBT) significantly associated with ASD (q-value <0.05); and (2) clustered epimutations associated to transcriptional changes in single-ASD patients (n = 4). All meSNVs and clustered epimutations were inherited from unaffected parents. Resequencing of the top candidate genes also revealed a significant load of deleterious mutations affecting ERMN in ASD compared with controls. Our data indicate that inherited methylation alterations detectable in blood DNA, due to either genetic or epigenetic defects, can affect gene expression and contribute to ASD susceptibility most likely in an additive manner, and implicate ERMN as a novel ASD gene

High-precision 41K/39K measurements by MC-ICP-MS indicate terrestrial variability of δ41K

Potassium is a major component in continental crust, the fourth-most abundant cation in seawater, and a key element in biological processes. Until recently, difficulties with existing analytical techniques hindered our ability to identify natural isotopic variability of potassium isotopes in terrestrial materials. However, measurement precision has greatly improved, and a range of K isotopic compositions has now been demonstrated in natural samples. In this study, we present a new technique for high-precision measurement of K isotopic ratios using high-resolution, cold plasma multi-collector mass spectrometry. We apply this technique to demonstrate natural variability in the ratio of 41K to 39K in a diverse group of geological and biological samples, including silicate and evaporite minerals, seawater, and plant and animal tissues. The total range in 41K/39K ratios is ca. 2.6‰, with a long-term external reproducibility of 0.17‰ (2σ, N=108). Seawater and seawater-derived evaporite minerals are systematically enriched in 41K compared to silicate minerals by ca. 0.6‰, a result consistent with recent findings (1, 2). Although our average bulk- silicate Earth value (-0.54‰) is indistinguishable from previously published values, we find systematic δ41K variability in some high-temperature sample suites, particularly those with evidence for the presence of fluids. The δ41K values of biological samples span a range of ca. 1.2‰ between terrestrial mammals, plants, and marine organisms. Implications of terrestrial K isotope variability for the atomic weight of K and K-based geochronology are discussed. Our results indicate that high-precision measurements of stable K isotopes, made using commercially available mass spectrometers, can provide unique insights into the chemistry of potassium in geological and biological systems

Using Y-Chromosomal Haplogroups in Genetic Association Studies and Suggested Implications

Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6537 males from two epidemiological cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 5080; 816 Y-DNA SNPs) and the 1958 Birth Cohort (n = 1457; 1849 Y-DNA SNPs), and studied the robust associations between 32 SNPs and body mass index (BMI), including SNPs in or near Fat Mass and Obesity-associated protein (FTO) which yield the strongest effects. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or SNP association by Y-DNA structure. Further studies using other traits, phenome-wide association studies (PheWAS), other haplogroups and/or autosomal SNPs are required to test the generalisability and utility of this approach.</p

UBVRIz Light Curves of 51 Type II Supernovae

We present a compilation of UBV RIz light curves of 51 type II supernovae discovered during the course of four different surveys during 1986 to 2003: the Cerro Tololo Supernova Survey, the Calan/Tololo Supernova Program (C&T), the Supernova Optical and Infrared Survey (SOIRS), and the Carnegie Type II Supernova Survey (CATS). The photometry is based on template-subtracted images to eliminate any potential host galaxy light contamination, and calibrated from foreground stars. This work presents these photometric data, studies the color evolution using different bands, and explores the relation between the magnitude at maximum brightness and the brightness decline parameter (s) from maximum light through the end of the recombination phase. This parameter is found to be shallower for redder bands and appears to have the best correlation in the B band. In addition, it also correlates with the plateau duration, being thus shorter (longer) for larger (smaller) s values.Comment: 110 pages, 9 Figures, 6 Tables, accepted in A

Latitudinal Variations in Methane Abundance, Aerosol Opacity and Aerosol Scattering Efficiency in Neptune's Atmosphere Determined From VLT/MUSE

Spectral observations of Neptune made in 2019 with the Multi Unit Spectroscopic Explorer (MUSE) instrument at the Very Large Telescope (VLT) in Chile have been analyzed to determine the spatial variation of aerosol scattering properties and methane abundance in Neptune's atmosphere. The darkening of the South Polar Wave at ∼60°S, and dark spots such as the Voyager 2 Great Dark Spot is concluded to be due to a spectrally dependent darkening (λ 650 nm. We find the properties of an overlying methane/haze aerosol layer at ∼2 bar are, to first-order, invariant with latitude, while variations in the opacity of an upper tropospheric haze layer reproduce the observed reflectivity at methane-absorbing wavelengths, with higher abundances found at the equator and also in a narrow “zone” at 80°S. Finally, we find the mean abundance of methane below its condensation level to be 6%–7% at the equator reducing to ∼3% south of ∼25°S, although the absolute abundances are model dependent.We are grateful to the United Kingdom Science and Technology Facilities Council for funding this research (Irwin: ST/S000461/1, Teanby: ST/R000980/1). Glenn Orton was supported by funding to the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). Leigh Fletcher and Mike Roman were supported by a European Research Council Consolidator Grant (under the European Union's Horizon 2020 research and innovation programme, grant agreement no. 723890) at the University of Leicester. Santiago Pérez-Hoyos and Agustin Sánchez-Lavega are supported by the Spanish project PID2019-109467GB-I00 (MINECO/FEDER, UE), Elkartek21/87 KK-2021/00061 and Grupos Gobierno Vasco IT-1742-22

Variation in the SLC23A1 gene does not influence cardiometabolic outcomes to the extent expected given its association with L-ascorbic acid

Background: Observational studies showed that circulating l-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation. Objectives:We assessed the relation between l-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating l-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-l-ascorbic acid and l-ascorbic acid–outcome associations. Design: A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737). Results: With the use of a meta-analysis of observational estimates, inverse associations were shown between l-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (−0.13-SD change; 95% CI: −0.20-, −0.07-SD change; P = 0.0001) per SD increase in l-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 × 10−6) increase in l-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected. Conclusions: The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of l-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between l-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation

Genetic Variability in CLU and Its Association with Alzheimer's Disease

Background: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU.Methodology/Principal Findings: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD.Conclusions/Significance: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein

A natural little hierarchy for RS from accidental SUSY

We use supersymmetry to address the little hierarchy problem in Randall-Sundrum models by naturally generating a hierarchy between the IR scale and the electroweak scale. Supersymmetry is broken on the UV brane which triggers the stabilization of the warped extra dimension at an IR scale of order 10 TeV. The Higgs and top quark live near the IR brane whereas light fermion generations are localized towards the UV brane. Supersymmetry breaking causes the first two sparticle generations to decouple, thereby avoiding the supersymmetric flavour and CP problems, while an accidental R-symmetry protects the gaugino mass. The resulting low-energy sparticle spectrum consists of stops, gauginos and Higgsinos which are sufficient to stabilize the little hierarchy between the IR scale and the electroweak scale. Finally, the supersymmetric little hierarchy problem is ameliorated by introducing a singlet Higgs field on the IR brane.Comment: 37 pages, 3 figures; v2: minor corrections, version published in JHE

The phylogenetically-related pattern recognition receptors EFR and XA21 recruit similar immune signaling components in monocots and dicots

During plant immunity, surface-localized pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs). The transfer of PRRs between plant species is a promising strategy for engineering broad-spectrum disease resistance. Thus, there is a great interest in understanding the mechanisms of PRR-mediated resistance across different plant species. Two well-characterized plant PRRs are the leucine-rich repeat receptor kinases (LRR-RKs) EFR and XA21 from Arabidopsis thaliana (Arabidopsis) and rice, respectively. Interestingly, despite being evolutionary distant, EFR and XA21 are phylogenetically closely related and are both members of the sub-family XII of LRR-RKs that contains numerous potential PRRs. Here, we compared the ability of these related PRRs to engage immune signaling across the monocots-dicots taxonomic divide. Using chimera between Arabidopsis EFR and rice XA21, we show that the kinase domain of the rice XA21 is functional in triggering elf18-induced signaling and quantitative immunity to the bacteria Pseudomonas syringae pv. tomato (Pto) DC3000 and Agrobacterium tumefaciens in Arabidopsis. Furthermore, the EFR:XA21 chimera associates dynamically in a ligand-dependent manner with known components of the EFR complex. Conversely, EFR associates with Arabidopsis orthologues of rice XA21-interacting proteins, which appear to be involved in EFR-mediated signaling and immunity in Arabidopsis. Our work indicates the overall functional conservation of immune components acting downstream of distinct LRR-RK-type PRRs between monocots and dicots