Decoding a cancer-relevant splicing decision in the RON proto-oncogene

Mutations causing aberrant splicing are frequently implicated in human diseases including cancer.

Here, we establish a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape that determines alternative splicing of exon 11 in the proto-oncogene MST1R (RON). Mathematical modelling of splicing kinetics enables us to identify more than 1000 mutations affecting RON exon 11 skipping, which corresponds to the pathological isoform RON∆165. Importantly, the effects correlate with RON alternative splicing in cancer patients bearing the same mutations. Reference

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Linking the International Wheat Genome Sequencing Consortium bread wheat reference genome sequence to wheat genetic and phenomic data

The Wheat@URGI portal has been developed to provide the international community of researchers and breeders with access to the bread wheat reference genome sequence produced by the International Wheat Genome Sequencing Consortium.

Genome browsers, BLAST, and InterMine tools have been established for in-depth exploration of the genome sequence together with additional linked datasets including physical maps, sequence variations, gene expression, and genetic and phenomic data from other international collaborative projects already stored in the GnpIS information system. Reference

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Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining

The worldwide prevalence of infections caused by antibiotic-resistant Gram-negative bacteria poses a serious threat to public health due to the limited therapeutic alternatives.

Cationic peptides represent a large family of antibiotics and have attracted interest due to their diverse chemical structures and potential for combating drug-resistant Gram-negative pathogens. Here, we analyze 7395 bacterial genomes to investigate their capacity for biosynthesis of cationic nonribosomal peptides with activity against Gram-negative bacteria. Reference

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Population genomics and morphometric assignment of western honey bees

Apis mellifera scutellata and A.m. capensis (the Cape honey bee) are western honey bee subspecies indigenous to the Republic of South Africa (RSA). Both bees are important for biological and economic reasons. First, A.m. scutellata is the invasive “African honey bee” of the Americas and exhibits a number of traits that beekeepers consider undesirable.

They swarm excessively, are prone to absconding (vacating the nest entirely), usurp other honey bee colonies, and exhibit heightened defensiveness. Second, Cape honey bees are socially parasitic bees; the workers can reproduce thelytokously. Both bees are indistinguishable visually. Therefore, we employed Genotyping-by-Sequencing (GBS), wing geometry and standard morphometric approaches to assess the genetic diversity and population structure of these bees to search for diagnostic markers that can be employed to distinguish between the two subspecies. Reference

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Copy number signatures and mutational processes in ovarian carcinoma

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers.

Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes. Reference

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QsRNA-seq: a method for high-throughput profiling and quantifying small RNAs

The ability to profile and quantify small non-coding RNAs (sRNAs), specifically microRNAs (miRNAs), using high-throughput sequencing is challenging because of their small size.

We developed QsRNA-seq, a method for preparation of sRNA libraries for high-throughput sequencing that overcomes this difficulty by enabling a gel-free separation of fragments shorter than 100 nt that differ only by 20 nt in length. The method allows the use of unique molecular identifiers for quantification and is more amenable to automation than gel-based methods. We show that QsRNA-seq gives very accurate, comprehensive, and reproducible results by looking at miRNAs in Caenorhabditis elegans embryos and larvae. Reference

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Genetic and transcriptional evolution alters cancer cell line drug response

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied.

Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Reference

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ChromTime: modeling spatio-temporal dynamics of chromatin marks

To model spatial changes of chromatin mark peaks over time we develop and apply ChromTime, a computational method that predicts peaks to be either expanding, contracting, or holding steady between time points.

Predicted expanding and contracting peaks can mark regulatory regions associated with transcription factor binding and gene expression changes. Spatial dynamics of peaks provide information about gene expression changes beyond localized signal density changes. ChromTime detects asymmetric expansions and contractions, which for some marks associate with the direction of transcription. ChromTime facilitates the analysis of time course chromatin data in a range of biological systems. Reference

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GWAS identifies multiple new loci associated with Ewing sarcoma susceptibility

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry.

Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Reference

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CTCF maintains regulatory homeostasis of cancer pathways

CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus.

In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. Reference

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FusionPathway: Prediction of pathways and therapeutic targets associated with gene fusions in cancer

Numerous gene fusions have been uncovered across multiple cancer types. Although the ability to target several of these fusions has led to the development of some successful anti-cancer drugs, most of them are not druggable.

Understanding the molecular pathways of a fusion is important in determining its function in oncogenesis and in developing therapeutic strategies for patients harboring the fusion. However, the molecular pathways have been elucidated for only a few fusions, in part because of the labor-intensive nature of the required functional assays. Therefore, we developed a domain-based network approach to infer the pathways of a fusion. Molecular interactions of a fusion are first predicted by using its protein domain composition, and its associated pathways are then inferred from these molecular interactions. We demonstrated the capabilities of this approach by primarily applying it to the well-studied BCR-ABL1 fusion. Reference

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A genome-wide siRNA screen identifies a druggable host pathway essential for the Ebola virus life cycle

The 2014–2016 Ebola virus (EBOV) outbreak in West Africa highlighted the need for improved therapeutic options against this virus.

Approaches targeting host factors/pathways essential for the virus are advantageous because they can potentially target a wide range of viruses, including newly emerging ones and because the development of resistance is less likely than when targeting the virus directly. In order to identify host factors involved in the EBOV life cycle, we performed a genome-wide siRNA screen comprising 64,755 individual siRNAs against 21,566 human genes to assess their activity in EBOV genome replication and transcription. Reference

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Exploring the OncoGenomic Landscape of cancer

The widespread incorporation of next-generation sequencing into clinical oncology has yielded an unprecedented amount of molecular data from thousands of patients.

We present OncoGenomic Landscapes, a framework to analyze and display thousands of cancer genomic profiles in a 2D space. Our tool allows users to rapidly assess the heterogeneity of large cohorts, enabling the comparison to other groups of patients, and using driver genes as landmarks to aid in the interpretation of the landscapes.  Reference

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Selection-driven cost-efficiency optimization of transcripts modulates gene evolutionary rate in bacteria

Most amino acids are encoded by multiple synonymous codons. However, synonymous codons are not used equally, and this biased codon use varies between different organisms. Through analysis of 1320 bacterial genomes, we show that bacterial genes are subject to multi-objective selection-driven optimization of codon use.

Here, selection acts to simultaneously decrease transcript biosynthetic cost and increase transcript translational efficiency, with highly expressed genes under the greatest selection. This optimization is not simply a consequence of the more translationally efficient codons being less expensive to synthesize.  Reference

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De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations

The human reference genome is used extensively in modern biological research. However, a single consensus representation is inadequate to provide a universal reference structure because it is a haplotype among many in the human population.

Using 10× Genomics (10×G) “Linked-Read” technology, we perform whole genome sequencing (WGS) and de novo assembly on 17 individuals across five populations. We identify 1842 breakpoint-resolved non-reference unique insertions (NUIs) that, in aggregate, add up to 2.1 Mb of so far undescribed genomic content. Among these, 64% are considered ancestral to humans since they are found in non-human primate genomes. Reference

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Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses.

Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines.  We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort).  Reference

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Extensive intraspecific gene order and gene structural variations between Mo17 and other maize genomes

Maize is an important crop with a high level of genome diversity and heterosis. The genome sequence of a typical female line, B73, was previously released.

Here, we report a de novo genome assembly of a corresponding male representative line, Mo17. More than 96.4% of the 2,183 Mb assembled genome can be accounted for by 362 scaffolds in ten pseudochromosomes with 38,620 annotated protein-coding genes. Comparative analysis revealed large gene-order and gene structural variations: approximately 10% of the annotated genes were mutually nonsyntenic, and more than 20% of the predicted genes had either large-effect mutations or large structural variations, which might cause considerable protein divergence between the two inbred lines. Reference

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Chromatin loop anchors are associated with genome instability in cancer

Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied.

Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns.  Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Reference

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Integrative omics analyses broaden treatment targets in human cancer

Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers.

To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO. Reference

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Functional characterization of enhancer evolution in the primate lineage

Enhancers play an important role in morphological evolution and speciation by controlling the spatiotemporal expression of genes. Previous efforts to understand the evolution of enhancers in primates have typically studied many enhancers at low resolution, or single enhancers at high resolution.

We identified candidate hominoid-specific liver enhancers from H3K27ac ChIP-seq data. After locating orthologs in 11 primates spanning around 40 million years, we synthesized all orthologs as well as computational reconstructions of 9 ancestral sequences for 348 active tiles of 233 putative enhancers. We concurrently tested all sequences for regulatory activity with STARR-seq in HepG2 cells.  Reference

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Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1

Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP).

Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. Reference

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Wnt evolution and function shuffling in liberal and conservative chordate genomes

What impact gene loss has on the evolution of developmental processes, and how function shuffling has affected retained genes driving essential biological processes, remain open questions in the fields of genome evolution and EvoDevo.

We conduct an exhaustive survey of Wnt genes in genomic databases, identifying 156 Wnt genes in 13 non-vertebrate chordates. This represents the most complete Wnt gene catalog of the chordate subphyla and has allowed us to resolve previous ambiguities about the orthology of many Wnt genes, including the identification of WntA for the first time in chordates. Moreover, we create the first complete expression atlas for the Wnt family during amphioxus development, providing a useful resource to investigate the evolution of Wnt expression throughout the radiation of chordates. Reference

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Predicting the clinical impact of human mutation with deep neural networks

Millions of human genomes and exomes have been sequenced, but their clinical applications remain limited due to the difficulty of distinguishing disease-causing mutations from benign genetic variation.

Here we demonstrate that common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to be systematically identified by the process of elimination. Using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy and enables the discovery of 14 new candidate genes in intellectual disability at genome-wide significance. Reference

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Gene discovery and polygenic prediction from a GWAS of educational attainment in 1.1 million individuals

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs.

For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. Reference

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Metaproteomics reveals associations between microbiome and intestinal extracellular vesicle proteins

Alterations in gut microbiota have been implicated in the pathogenesis of inflammatory bowel disease (IBD), however factors that mediate the host–microbiota interactions remain largely unknown.

Here we collected mucosal-luminal interface samples from a pediatric IBD inception cohort and characterized both the human and microbiota proteins using metaproteomics. We show that microbial proteins related to oxidative stress responses are upregulated in IBD cases compared to controls. In particular, we demonstrate that the expression of human proteins related to oxidative antimicrobial activities is increased in IBD cases and correlates with the alteration of microbial functions. Reference

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Functional and genomic analyses reveal therapeutic potential of targeting β-catenin

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease.

We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays.  Reference

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GIVE: portable genome browsers for personal websites

Growing popularity and diversity of genomic data demand portable and versatile genome browsers.

Here, we present an open source programming library called GIVE that facilitates the creation of personalized genome browsers without requiring a system administrator. By inserting HTML tags, one can add to a personal webpage interactive visualization of multiple types of genomics data, including genome annotation, “linear” quantitative data, and genome interaction data. GIVE includes a graphical interface called HUG (HTML Universal Generator) that automatically generates HTML code for displaying user chosen data, which can be copy-pasted into user’s personal website or saved and shared with collaborators. Reference

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