Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

Draft genome of the mountain pine beetle, Dendroctonus ponderosae Hopkins, a major forest pest

Background: The mountain pine beetle, 'Dendroctonus ponderosae' Hopkins, is the most serious insect pest of western North American pine forests. A recent outbreak destroyed more than 15 million hectares of pine forests, with major environmental effects on forest health, and economic effects on the forest industry. The outbreak has in part been driven by climate change, and will contribute to increased carbon emissions through decaying forests. Results: We developed a genome sequence resource for the mountain pine beetle to better understand the unique aspects of this insect's biology. A draft 'de novo' genome sequence was assembled from paired-end, shortread sequences from an individual field-collected male pupa, and scaffolded using mate-paired, short-read genomic sequences from pooled field-collected pupae, paired-end short-insert whole-transcriptome shotgun sequencing reads of mRNA from adult beetle tissues, and paired-end Sanger EST sequences from various life stages. We describe the cytochrome P450, glutathione S-transferase, and plant cell wall-degrading enzyme gene families important to the survival of the mountain pine beetle in its harsh and nutrient-poor host environment, and examine genome-wide single-nucleotide polymorphism variation. A horizontally transferred bacterial sucrose-6- phosphate hydrolase was evident in the genome, and its tissue-specific transcription suggests a functional role for this beetle. Conclusions: Despite Coleoptera being the largest insect order with over 400,000 described species, including many agricultural and forest pest species, this is only the second genome sequence reported in Coleoptera, and will provide an important resource for the Curculionoidea and other insects

Draft genome of the mountain pine beetle, Dendroctonus ponderosae Hopkins, a major forest pest

Background: The mountain pine beetle, Dendroctonus ponderosae Hopkins, is the most serious insect pest of western North American pine forests. A recent outbreak destroyed more than 15 million hectares of pine forests, with major environmental effects on forest health, and economic effects on the forest industry. The outbreak has in part been driven by climate change, and will contribute to increased carbon emissions through decaying forests. Results We developed a genome sequence resource for the mountain pine beetle to better understand the unique aspects of this insect's biology. A draft de novo genome sequence was assembled from paired-end, short-read sequences from an individual field-collected male pupa, and scaffolded using mate-paired, short-read genomic sequences from pooled field-collected pupae, paired-end short-insert whole-transcriptome shotgun sequencing reads of mRNA from adult beetle tissues, and paired-end Sanger EST sequences from various life stages. We describe the cytochrome P450, glutathione S-transferase, and plant cell wall-degrading enzyme gene families important to the survival of the mountain pine beetle in its harsh and nutrient-poor host environment, and examine genome-wide single-nucleotide polymorphism variation. A horizontally transferred bacterial sucrose-6-phosphate hydrolase was evident in the genome, and its tissue-specific transcription suggests a functional role for this beetle. Conclusions Despite Coleoptera being the largest insect order with over 400,000 described species, including many agricultural and forest pest species, this is only the second genome sequence reported in Coleoptera, and will provide an important resource for the Curculionoidea and other insects.Medical Genetics, Department ofMedicine, Faculty ofNon UBCReviewedFacult

A Single-chord Stellar Occultation by the Extreme Trans-Neptunian Object (541132) Leleākūhonua

A stellar occultation by the extreme large-perihelion trans-Neptunian object (541132) Leleākūhonua (also known by the provisional designation of 2015 TG387) was predicted by the Lucky Star project and observed with the Research and Education Collaborative Occultation Network on 2018 October 20 UT. A single detection and a nearby nondetection provide constraints for the size and albedo. When a circular profile is assumed, the radius is r = 110+14-10 km, corresponding to a geometric albedo Pv = 0.21+0.03-0.05, for an adopted absolute magnitude of HV = 5.6, typical of other objects in dynamically similar orbits. The occultation also provides a high-precision astrometric constraint

The Sizes and Albedos of Centaurs 2014 YY 49_{49} and 2013 NL 24_{24} from Stellar Occultation Measurements by RECON

In 2019, the Research and Education Collaborative Occultation Network (RECON) obtained multiple-chord occultation measurements of two centaur objects: 2014 YY$_{49}$ on 2019 January 28 and 2013 NL$_{24}$ on 2019 September 4. RECON is a citizen-science telescope network designed to observe high-uncertainty occultations by outer solar system objects. Adopting circular models for the object profiles, we derive a radius $r=16^{+2}_{-1}$km and a geometric albedo $p_V=0.13^{+0.015}_{-0.024}$ for 2014 YY$_{49}$, and a radius $r=66 ^{+5}_{-5}$km and geometric albedo $p_V = 0.045^{+0.006}_{-0.008}$ for 2013 NL$_{24}$. To the precision of these measurements, no atmosphere or rings are detected for either object. The two objects measured here are among the smallest distant objects measured with the stellar occultation technique. In addition to these geometric constraints, the occultation measurements provide astrometric constraints for these two centaurs at a higher precision than has been feasible by direct imaging. To supplement the occultation results, we also present an analysis of color photometry from the Pan-STARRS surveys to constrain the rotational light curve amplitudes and spectral colors of these two centaurs. We recommend that future work focus on photometry to more deliberately constrain the objects' colors and light curve amplitudes, and on follow-on occultation efforts informed by this astrometry