Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Funding: This work was funded by a Marie Curie Career Integration Grant and by a Max Planck Research Group Grant both awarded to SCV. The work of the Newbury lab is funded by the Medical Research Council (G1000569/1 and MR/J003719/1). XSC, AG, CF and SEF were supported by the Max Planck Society. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust (090532/Z/09/Z). JH was supported by a scholarship from the Agency for Science, Technology, and Research, Singapore. The work of SDS is supported by the grant HD027802 from NIH.Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.Publisher PDFPeer reviewe

Relaxation Processes in Clouds of Trapped Bosons above the Bose-Einstein Condensation Temperature

We present a unified account of damping of low-lying collective modes and of relaxation of temperature anisotropies in a trapped Bose gas in the collisionless regime. By means of variational techniques, we show that the relaxation times for the two situations are closely related to the simplest variational estimate of the viscous relaxation time. We derive rather precise theoretical expressions for the characteristic relaxation times, and compare our results with experiment.Comment: 4 pages, revte

Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

High-resolution microwave frequency dissemination on an 86-km urban optical link

We report the first demonstration of a long-distance ultra stable frequency dissemination in the microwave range. A 9.15 GHz signal is transferred through a 86-km urban optical link with a fractional frequency stability of 1.3x10-15 at 1 s integration time and below 10-18 at one day. The optical link phase noise compensation is performed with a round-trip method. To achieve such a result we implement light polarisation scrambling and dispersion compensation. This link outperforms all the previous radiofrequency links and compares well with recently demonstrated full optical links.Comment: 11 pages, 5 figure

Long-distance frequency transfer over an urban fiber link using optical phase stabilization

We transferred the frequency of an ultra-stable laser over 86 km of urban fiber. The link is composed of two cascaded 43-km fibers connecting two laboratories, LNE-SYRTE and LPL in Paris area. In an effort to realistically demonstrate a link of 172 km without using spooled fiber extensions, we implemented a recirculation loop to double the length of the urban fiber link. The link is fed with a 1542-nm cavity stabilized fiber laser having a sub-Hz linewidth. The fiber-induced phase noise is measured and cancelled with an all fiber-based interferometer using commercial off the shelf pigtailed telecommunication components. The compensated link shows an Allan deviation of a few 10-16 at one second and a few 10-19 at 10,000 seconds

Spin-axis relaxation in spin-exchange collisions of alkali atoms

We present calculations of spin-relaxation rates of alkali-metal atoms due to the spin-axis interaction acting in binary collisions between the atoms. We show that for the high-temperature conditions of interest here, the spin relaxation rates calculated with classical-path trajectories are nearly the same as those calculated with the distorted-wave Born approximation. We compare these calculations to recent experiments that used magnetic decoupling to isolate spin relaxation due to binary collisions from that due to the formation of triplet van-der-Waals molecules. The values of the spin-axis coupling coefficients deduced from measurements of binary collision rates are consistent with those deduced from molecular decoupling experiments. All the experimental data is consistent with a simple and physically plausible scaling law for the spin-axis coupling coefficients.Comment: text+1 figur

Condensation and interaction range in harmonic boson traps: a variational approach

For a gas of N bosons interacting through a two-body Morse potential a variational bound of the free energy of a confined system is obtained. The calculation method is based on the Feynman-Kac functional projected on the symmetric representation. Within the harmonic approximation a variational estimate of the effect of the interaction range on the existence of many-particle bound states, and on the N-T phase diagram is obtained.Comment: 14 pages+4 figures, submitted to phys.rev.

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

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Feshbach resonances in rubidium 87: Precision measurement and analysis

More than 40 Feshbach resonances in rubidium 87 are observed in the magnetic field range between 0.5 and 1260 G for various spin mixtures in the lower hyperfine ground state. The Feshbach resonances are observed by monitoring the atom loss, and their positions are determined with an accuracy of 30 mG. In a detailed analysis, the resonances are identified and an improved set of model parameters for the rubidium interatomic potential is deduced. The elastic width of the broadest resonance at 1007 G is predicted to be significantly larger than the magnetic field resolution of the apparatus. This demonstrates the potential for applications based on tuning the scattering length.Comment: figure 2 corrected; minor changes in the tex