In a companion paper by Koposov et al., RR Lyrae from Gaia Data Release 2 are used to demonstrate that stars in the Orphan stream have velocity vectors significantly misaligned with the stream track, ...suggesting that it has received a large gravitational perturbation from a satellite of the Milky Way. We argue that such a mismatch cannot arise due to any realistic static Milky Way potential and then explore the perturbative effects of the Large Magellanic Cloud (LMC). We find that the LMC can produce precisely, the observed motion-track mismatch and we therefore use the Orphan stream to measure the mass of the Cloud. We simultaneously fit the Milky Way and LMC potentials and infer that a total LMC mass of |$1.38^{+0.27}_{-0.24} \times 10^{11}\, \rm {M_\odot}$| is required to bend the Orphan stream, showing for the first time that the LMC has a large and measurable effect on structures orbiting the Milky Way. This has far-reaching consequences for any technique which assumes that tracers are orbiting a static Milky Way. Furthermore, we measure the Milky Way mass within 50 kpc to be |$3.80^{+0.14}_{-0.11}\times 10^{11} \, \mathrm{M}_\odot$|. Finally, we use these results to predict that, due to the reflex motion of the Milky Way in response to the LMC, the outskirts of the Milky Way’s stellar halo should exhibit a bulk, upwards motion.
Abstract
We use astrometry, broad-band photometry, and variability information from the Data Release 2 of ESA’s Gaia mission (GDR2) to identify members of the Orphan Stream (OS) across the whole sky. ...The stream is traced above and below the celestial equator and in both Galactic hemispheres, thus increasing its visible length to ∼210° equivalent to ∼150 kpc in physical extent. Taking advantage of the large number of RR Lyrae stars in the OS, we extract accurate distances and proper motions across the entire stretch of the tidal debris studied. As delineated by the GDR2 RR Lyrae, the stream exhibits two prominent twists in its shape on the sky which are accompanied by changes in the tangential motion. We complement the RR Lyrae maps with those created using GDR2 Red Giants and the DECam Legacy Survey Main Sequence Turn-Off stars. The behaviour of the OS track on the sky is consistent across all three tracers employed. We detect a strong non-zero motion in the across-stream direction for a substantial portion of the stream. Such a misalignment between the debris track and the streaming velocity cannot be reproduced in a static gravitational potential and signals an interaction with a massive perturber.
To evaluate the total number of synapses in the stratum radiatum (str rad) of the human hippocampal CA1 subfield in individuals with mild Alzheimer disease (mAD), mild cognitive impairment (MCI), or ...no cognitive impairment (NCI) and determine if synapse loss is an early event in the progression of the disease.
Short postmortem autopsy tissue was obtained, and an unbiased stereologic sampling scheme coupled with transmission electron microscopy was used to directly visualize synaptic contacts.
Individuals with mAD had fewer synapses (55%) than the other two diagnostic groups. Individuals with MCI had a mean synaptic value that was 18% lower than the NCI group mean. The total number of synapses showed a correlation with several cognitive tests including those involving both immediate and delayed recall. Total synaptic numbers showed no relationship to the subject's Braak stage or to APOE genotype. The volume of the str rad was reduced in mAD vs the other two diagnostic groups that were not different from each other.
These results strongly support the concept that synapse loss is a structural correlate involved very early in cognitive decline in mild Alzheimer disease (mAD) and supports mild cognitive impairment as a transitional stage between mAD and no cognitive impairment.
Family studies have demonstrated genetic influences on environmental exposure: the phenomenon of gene-environment correlation (rGE). A few molecular genetic studies have confirmed the results, but ...the identification of rGE in studies that measure genes and environments faces several challenges. Using examples from studies in psychology and psychiatry, we integrate the behavioral and molecular genetic literatures on rGE, describe challenges in identifying rGE and discuss the implications of molecular genetic findings of rGE for future research on gene-environment interplay and for attempts to prevent disease by reducing environmental risk exposure. Genes affect environments indirectly, via behavior and personality characteristics. Associations between individual genetic variants and behaviors are typically small in magnitude, and downstream effects on environmental risk are further attenuated by behavioral mediation. Genotype-environment associations are most likely to be detected when the environment is behaviorally modifiable and highly specified and a plausible mechanism links gene and behavior. rGEs play an important causal role in psychiatric illness. Although research efforts should concentrate on elucidating the genetic underpinnings of behavior rather than the environment itself, the identification of rGE may suggest targets for environmental intervention even in highly heritable disease. Prevention efforts must address the possibility of confounding between rGE and gene-environment interaction (G x E).
Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms ...of disease
. Many of the underlying causal variants may affect enhancers
, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types
. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.
Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of ...chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition.
A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken.
The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.
Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) ...twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.
High-intensity transcription and replication supercoil DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC ...must manage this interfering torsional stress. By comparing gene expression with the recruitment of topoisomerases and MYC to promoters, we surmised a direct association of MYC with topoisomerase 1 (TOP1) and TOP2 that was confirmed in vitro and in cells. Beyond recruiting topoisomerases, MYC directly stimulates their activities. We identify a MYC-nucleated “topoisome” complex that unites TOP1 and TOP2 and increases their levels and activities at promoters, gene bodies, and enhancers. Whether TOP2A or TOP2B is included in the topoisome is dictated by the presence of MYC versus MYCN, respectively. Thus, in vitro and in cells, MYC assembles tools that simplify DNA topology and promote genome function under high output conditions.
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•MYC manages high levels of torsional stress during transcription and replication•Both topoisomerase 1 and 2 activities are stimulated by MYC inside cells•The MYC nucleated “topoisome” harbors TOP1 and TOP2 and is activated at promoters•Inclusion of TOP2A versus TOP2B in a topoisome is decided by MYC versus MYCN, respectively
Using biochemical and genomic approaches, Das et al. demonstrate that MYC or MYCN each unite TOP1 with TOP2A or TOP2B, respectively, in a “topoisome” in which their enzymatic activities are stimulated to resolve the local and global DNA topological issues associated with high output transcription.
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