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

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

Mononuclear and dinuclear complexes with a [Ru(tBu2PCH2CH2PtBu2)(CO)] core.

Thermolysis of solid [Ru(d(t)bpe)(CO)2Cl2](2, d(t)bpe =(t)Bu2PCH2CH2P(t)Bu2) under vacuum affords the five-coordinate complex [Ru(d(t)bpe)(CO)Cl2] (4), which was shown by X-ray crystallography to contain a weak remote agostic interaction. In solution, 4 can be readily trapped by CO, CH3CN or water to give [Ru(d(t)bpe)(CO)(L)Cl2](L = CO, 2; L = CH3CN, 6; L = H2O, 7). Reaction of 4 with AgOTf/H2O yields the tris-aqua complex [Ru(d(t)bpe)(CO)(H2O)3](OTf)2 (8), which has been structurally characterised and probed in solution by pulsed-gradient spin echo (PGSE) NMR spectroscopy. The water ligands in 8 are labile and easily substituted to give [Ru(d(t)bpe)(CO)(NCCH3)3](OTf)2 (10) and [Ru(d(t)bpe)(CO)(DMSO)3](OTf)2 (11). In the presence of CO, the tris-aqua complex undergoes water-gas shift chemistry with formation of the cationic hydride species [Ru(d(t)bpe)(CO)3H](OTf) (12) and CO2. X-Ray crystal structures of complexes 2, 4, 6, 8 and 11-12 are reported along with those for [{Ru(d(t)bpe)(CO)}2(mu-Cl)2(mu-OTf)](OTf) (3), [{Ru(d(t)bpe)(CO)}2(mu-Cl)3][Ru(d(t)bpe)(CO)Cl3](5) and [Ru(d(t)bpe)(CO)(H2O)2(OTf)](OTf)(9)

ddRAD sequencing-based identification of genomic boundaries and permeability in Quercus ilex and Q. suber hybrids

Hybridization and its relevance is a hot topic in ecology and evolutionary biology. Interspecific gene flow may play a key role in species adaptation to environmental change, as well as in the survival of endangered populations. Despite the fact that hybridization is quite common in plants, many hybridizing species, such as Quercus spp., maintain their integrity, while precise determination of genomic boundaries between species remains elusive. Novel high throughput sequencing techniques have opened up new perspectives in the comparative analysis of genomes and in the study of historical and current interspecific gene flow. In this work, we applied ddRADseq technique and developed an ad hoc bioinformatics pipeline for the study of ongoing hybridization between two relevant Mediterranean oaks, Q. ilex and Q. suber. We adopted a local scale approach, analyzing adult hybrids (sensu lato) identified in a mixed stand and their open-pollinated progenies. We have identified up to 9,435 markers across the genome and have estimated individual introgression levels in adults and seedlings. Estimated contribution of Q. suber to the genome is higher, on average, in hybrid progenies than in hybrid adults, suggesting preferential backcrossing with this parental species, maybe followed by selection during juvenile stages against individuals with higher Q. suber genomic contribution. Most discriminating markers seem to be scattered throughout the genome, suggesting that a large number of small genomic regions underlie boundaries between these species. A noticeable proportion of the markers (26%) showed allelic frequencies in adult hybrids very similar to one of the parental species, and very different from the other; a finding that seems relevant for understanding the hybridization process and the occurrence of adaptive introgression. Candidate marker databases developed in this study constitute a valuable resource to design large scale re-sequencing experiments in Mediterranean sclerophyllous oak species and could provide insight in species boundaries and on adaptive introgression between Q. suber and Q. ilex. © Copyright © 2020 López de Heredia, Mora-Márquez, Goicoechea, Guillardín-Calvo, Simeone and Soto.This work was funded by the projects AGL2015-67495-C2-2-R (Spanish Ministry of Economy and Competitiveness) and PID2019-110330GB-C22 (Spanish Ministry of Science and Innovation)

Herschel observations of ortho- and para-oxidaniumyl (H2O+) in spiral arm clouds toward Sagittarius B2(M) *,**

H2O+ has been observed in its ortho- and para- states toward the massive star forming core Sgr B2(M), located close to the Galactic center. The observations show absorption in all spiral arm clouds between the Sun and Sgr B2. The average o/p ratio of H2O+ in most velocity intervals is 4.8, which corresponds to a nuclear spin temperature of 21 K. The relationship of this spin temperature to the formation temperature and current physical temperature of the gas hosting H2O+ is discussed, but no firm conclusion is reached. In the velocity interval 0–60 km s-1, an ortho/para ratio of below unity is found, but if this is due to an artifact of contamination by other species or real is not clear

Detection of OH+ and H2O+ towards Orion KL

We report observations of the reactive molecular ions OH+, H2O+, and H3O+ towards Orion KL with Herschel/HIFI. All three N = 1-0 fine-structure transitions of OH+ at 909, 971, and 1033 GHz and both fine-structure components of the doublet ortho-H2O+ 111–000 transition at 1115 and 1139 GHz were detected; an upper limit was obtained for H3O+. OH+ and H2O+ are observed purely in absorption, showing a narrow component at the source velocity of 9 km s-1, and a broad blueshifted absorption similar to that reported recently for HF and para-H218O, and attributed to the low velocity outflow of Orion KL. We estimate column densities of OH+ and H2O+ for the 9 km s-1 component of 9 ± 3 × 1012 cm-2 and 7 ± 2 × 1012 cm-2, and those in the outflow of 1.9 ± 0.7 × 1013 cm-2 and 1.0 ± 0.3 × 1013 cm-2. Upper limits of 2.4 × 1012 cm-2 and 8.7 × 1012 cm-2 were derived for the column densities of ortho and para-H3O+ from transitions near 985 and 1657 GHz. The column densities of the three ions are up to an order of magnitude lower than those obtained from recent observations of W31C and W49N. The comparatively low column densities may be explained by a higher gas density despite the assumption of a very high ionization rate