Uncovering the complexity of structural variants in four individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is an increasingly recognized childhood developmental disorder. Despite extensive study, causal variants and molecular diagnosis remain elusive. There is both heterogeneity of the phenotype, as well as the genetic landscape associated with phenotype, which includes both inherited and de novo mutations.

Mitogen-induced defective mitosis transforms neural progenitor cells.

Background: Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs).

Methods: Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

Background: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies.

Patients And Methods: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA.

The evolution of pre-mRNA splicing and its machinery revealed by reduced extremophilic red algae.

The Cyanidiales are a group of mostly thermophilic and acidophilic red algae that thrive near volcanic vents. Despite their phylogenetic relationship, the reduced genomes of Cyanidioschyzon merolae and Galdieria sulphuraria are strikingly different with respect to pre-mRNA splicing, a ubiquitous eukaryotic feature. Introns are rare and spliceosomal machinery is extremely reduced in C.

A community approach to the cancer-variant-interpretation bottleneck.

As guidelines, therapies, and literature on cancer variants expand, the lack of consensus variant interpretations impedes clinical applications. CIViC is a public domain, crowd-sourced, and adaptable knowledgebase of evidence for the Clinical Interpretation of Variants in Cancer, designed to reduce barriers to knowledge sharing and alleviate the variant interpretation bottleneck.

A platform for oncogenomic reporting and interpretation.

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer.

Rearrangement-mediated cis-regulatory alterations in advanced patient tumors reveal interactions with therapy.

The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1.

Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Purpose: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels.

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression.

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis.

Genome and Transcriptome Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers.

Experimental Design: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA).

In vitro modeling of glioblastoma initiation using PDGF-AA and p53-null neural progenitors.

Background: Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture.

Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments.

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined.

Relative Mutation Rates in Nucleomorph-Bearing Algae.

Chlorarachniophyte and cryptophyte algae are unique among plastid-containing species in that they have a nucleomorph genome: a compact, highly reduced nuclear genome from a photosynthetic eukaryotic endosymbiont. Despite their independent origins, the nucleomorph genomes of these two lineages have similar genomic architectures, but little is known about the evolutionary pressures impacting nucleomorph DNA, particularly how their rates of evolution compare to those of the neighboring genetic compartments (the mitochondrion, plastid, and nucleus). Here, we use synonymous substitution rates to estimate relative mutation rates in the four genomes of nucleomorph-bearing algae.

Evolution and Diversity of Pre-mRNA Splicing in Highly Reduced Nucleomorph Genomes.

Eukaryotic genes are interrupted by introns that are removed in a conserved process known as pre-mRNA splicing. Though well-studied in select model organisms, we are only beginning to understand the variation and diversity of this process across the tree of eukaryotes. We explored pre-mRNA splicing and other features of transcription in nucleomorphs, the highly reduced remnant nuclei of secondary endosymbionts.

The New Red Algal Subphylum Proteorhodophytina Comprises the Largest and Most Divergent Plastid Genomes Known.

Red algal plastid genomes are often considered ancestral and evolutionarily stable, and thus more closely resembling the last common ancestral plastid genome of all photosynthetic eukaryotes [1, 2]. However, sampling of red algal diversity is still quite limited (e.g.

Dramatically reduced spliceosome in Cyanidioschyzon merolae.

The human spliceosome is a large ribonucleoprotein complex that catalyzes pre-mRNA splicing. It consists of five snRNAs and more than 200 proteins. Because of this complexity, much work has focused on the Saccharomyces cerevisiae spliceosome, viewed as a highly simplified system with fewer than half as many splicing factors as humans.

Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs.

Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans.

Patterns of 5' untranslated region length distribution in Encephalitozoon cuniculi: implications for gene regulation and potential links between transcription and splicing.

Encephalitozoon cuniculi, a eukaryotic intracellular parasite belonging to the group Microsporidia, has a highly reduced and compacted genome. Its mRNA transcripts have been found to differ between the two life stages, the spore and meront, of the parasite. Spore transcripts generally have more transcription start sites, longer 5' untranslated regions (UTRs), and overlap more frequently with upstream genes than those of meronts.

Splicing and transcription differ between spore and intracellular life stages in the parasitic microsporidia.

Microsporidia are a diverse group of highly derived fungal relatives that are intracellular parasites of many animals. Both transcription and introns have been shown to be unusual in microsporidia: The complete genome of the human parasite Encephalitozoon cuniculi has only a few very short introns, and two distantly related microsporidian spores have been shown to harbor transcripts encoding several genes that overlap on different strands. However, microsporidia alternate between two life stages: the intracellular proliferative stage and the extracellular and largely metabolically dormant infectious spore.