Chromatin structure and evolution in the human genome

<p>Abstract</p> <p>Background</p> <p>Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.</p> <p>Results</p> <p>In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.</p> <p>Conclusion</p> <p>We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.</p

Site‐specific inhibition of the thalamic reticular nucleus induces distinct modulations in sleep architecture

The thalamic reticular nucleus (TRN) is crucial for the modulation of sleep-related oscillations. The caudal and rostral subpopulations of the TRN exert diverse activities, which arise from their interconnectivity with all thalamic nuclei, as well as other brain regions. Despite the recent characterization of the functional and genetic heterogeneity of the TRN, the implications of this heterogeneity for sleep regulation have not been assessed. Here, using a combination of optogenetics and electrophysiology in C57BL/6 mice, we demonstrate that caudal and rostral TRN modulations are associated with changes in cortical alpha and delta oscillations, and have distinct effects on sleep stability. Tonic silencing of the rostral TRN elongates sleep episodes, while tonic silencing of the caudal TRN fragments sleep. Overall, we show evidence of distinct roles exerted by the rostral and caudal TRN in sleep regulation and oscillatory activity

Star Formation at 4<z<64 < z < 6 From the Spitzer Large Area Survey with Hyper-Suprime-Cam (SPLASH)

Using the first 50% of data collected for the Spitzer Large Area Survey with Hyper-Suprime-Cam (SPLASH) observations on the 1.8 deg$^2$ Cosmological Evolution Survey (COSMOS) we estimate the masses and star formation rates of 3398 $M_*>10^{10}M_\odot$ star-forming galaxies at $4 < z < 6$ with a substantial population up to $M_* \gtrsim 10^{11.5} M_\odot$. We find that the strong correlation between stellar mass and star formation rate seen at lower redshift (the "main sequence" of star-forming galaxies) extends to $z\sim6$. The observed relation and scatter is consistent with a continued increase in star formation rate at fixed mass in line with extrapolations from lower-redshift observations. It is difficult to explain this continued correlation, especially for the most massive systems, unless the most massive galaxies are forming stars near their Eddington-limited rate from their first collapse. Furthermore, we find no evidence for moderate quenching at higher masses, indicating quenching either has not occurred prior to $z \sim 6$ or else occurs rapidly, so that few galaxies are visible in transition between star-forming and quenched.Comment: ApJL, accepte

Project BRAHSS: behavioural response of Australian humpback whales to seismic surveys.

BRAHSS is a major project aimed at understanding how humpback whales respond to noise, particularly from seismic air gun arrays. It also aims to infer the longer term biological significance of the responses from the results and knowledge of normal behaviour. The aim is to provide the information that will allow seismic surveys to be conducted efficiently with minimal impact on whales. It also includes a study of the response to ramp-up in sound level. Ramp-up is widely used at the start of operations as a mitigation measure intended to cause whales to move away, but there is little information to show that it is effective. BRAHSS involves four experiments with migrating humpback whales off the east and west coasts of Australia with noise exposures ranging from a single air gun to a full seismic array. Two major experiments have been completed off the east coast, the second involving 70 scientists. Whale movements were tracked using theodolites on two high points ashore and behavioural observations were made from these points and from three small vessels and the source vessel. Vocalising whales were tracked underwater with an array of hydrophones. These and other moored acoustic receivers recorded the sound field at several points throughout the area. Tags (DTAGs) were attached to whales with suction caps for periods of several hours. Observations and measurements during the experiments include the wide range of variables likely to affect whale response and sufficient acoustic measurements to characterise the sound field throughout the area. The remaining two experiments will be conducted further off shore off the west coast in 2013 and 2014

A measurement of the millimetre emission and the Sunyaev-Zel'dovich effect associated with low-frequency radio sources

We present a statistical analysis of the millimetre-wavelength properties of 1.4GHz-selected sources and a detection of the Sunyaev–Zel’dovich (SZ) effect associated with the haloes that host them. We stack data at 148, 218 and 277GHz from the Atacama Cosmology Telescope at the positions of a large sample of radio AGN selected at 1.4GHz. The thermal SZ effect associated with the haloes that host the AGN is detected at the 5σ level through its spectral signature, representing a statistical detection of the SZ effect in some of the lowest mass haloes (average M 200 ≈ 10 13 M. h −1 70 ) studied to date. The relation between the SZ effect and mass (based on weak lensing measurements of radio galaxies) is consistent with that measured by Planck for local bright galaxies. In the context of galaxy evolution models, this study confirms that galaxies with radio AGN also typically support hot gaseous haloes. Adding Herschel observations allows us to show that the SZ signal is not significantly contaminated by dust emission. Finally, we analyse the contribution of radio sources to the angular power spectrum of the cosmic microwave background

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk

The Australia Telescope Large Area Survey: Spectroscopic catalogue and radio luminosity functions

The Australia Telescope Large Area Survey (ATLAS) has surveyed 7 square degrees of sky around the Chandra Deep Field South and the European Large Area ISO Survey-South 1 fields at 1.4 GHz. ATLAS aims to reach a uniform sensitivity of 10 μJy beam−1 rms over the entire region with first data release currently reaching ∼ 30 μJy beam−1 rms. Here we present 466 new spectroscopic redshifts for radio sources in ATLAS as part of our optical follow-up programme. Of the 466 radio sources with new spectroscopic redshifts, 142 have star-forming optical spectra, 282 show evidence for active galactic nuclei (AGN) in their optical spectra, 10 have stellar spectra and 32 have spectra revealing redshifts, but with insufficient features to classify. We compare our spectroscopic classifications with two mid-infrared diagnostics and find them to be in broad agreement. We also construct the radio luminosity function for star-forming galaxies to z = 0.5 and for AGN to z = 0.8. The radio luminosity function for star-forming galaxies appears to be in good agreement with previous studies. The radio luminosity function for AGN appears higher than previous studies of the local AGN radio luminosity function. We explore the possibility of evolution, cosmic variance and classification techniques affecting the AGN radio luminosity function. ATLAS is a pathfinder for the forthcoming Evolution Map of the Universe (EMU) survey and the data presented in this paper will be used to guide EMU's survey design and early science papers

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis