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Accounting for errors arising from different high-throughput sequencing platforms and those arising from the approaches used to call variants are at the center of a controversy in RNA editing.

Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

cis-RNA editing quantitative trait loci, which are associated with immunogenic double-stranded RNAs, underlie genome-wide association study variants in common autoimmune and inflammatory diseases.

The authors show that rare genetic variants contribute to large gene expression changes across diverse human tissues and provide an integrative method for interpretation of rare variants in individual genomes.

Multiple transcriptome approaches, including single-cell sequencing, demonstrate that escape from X chromosome inactivation is widespread and occasionally variable between cells, chromosomes, and tissues, resulting in sex-biased expression of at least 60 genes and potentially contributing to sex-specific differences in health and disease.

ADAR1-mediating RNA editing enables the cell to distinguish between endogenous and viral RNA. Li and Walkley review findings from human and mouse genetics that have revealed the mechanisms of ADAR1-mediated RNA editing, which are now providing insights for the development of potential therapies that target these mechanisms.

Human RNA editing enzymes ADAR1 and ADAR2 are required for innate immune functions and neurological functions, respectively. Here, the authors show that Drosophila Adar has both innate immune and brain functions, despite being the homolog of mammalian ADAR2.

Ball et al. exploit next-generation sequencing to detect methylation across the human genome. A targeted approach uses padlock probes and bisulfite-treated DNA, whereas an untargeted method relies on the methylation-sensitive restriction enzyme HpaII.

The RNA sequence and secondary structure regulate RNA editing by ADAR. Here the authors employ a CRISPR/Cas9-mediated saturation mutagenesis and machine learning to predict RNA editing efficiency of specific substrates.

Adenosine-to-inosine (A-to-I) RNA editing plays an important role in neurological functions. Here, by a quantitative trait loci (QTL) mapping approach in 131 Drosophila melanogasterstrains, the authors identify 545 QTLs associated with differences in RNA editing.

Padlock probes, synthesized in large scale on programmable microarrays, capture expressed single-nucleotide polymorphisms for high-throughput sequencing in this method for RNA allelotyping. The approach combines the sensitivity of digital expression measurements with the efficiency of targeted resequencing to quantify allele specific gene expression in various tissues across several individuals.

A computational framework is reported for the accurate and sensitive identification of RNA editing sites from whole-genome DNA and RNA sequences from the same individual.

Environmental adaptation is generally studied at the genomic level, but it may also be driven by transcriptional processes. Here, the authors investigate variation in gene expression and RNA editing across diverging populations of Drosophila melanogaster from two microclimates.

RNA base editing enables a precise, reversible and doseable change of genetic information. Here, authors propose base editing as a method to control post-translational modifications via removal of regulatory phosphorylation and acetylation sites, applying the approach to modulation of the JAK/STAT pathway via editing of wildtype alleles.

For allele-specific expression and RNA editing studies, targeted RNA sequencing using microfluidic multiplexed PCR (mmPCR-seq) gives robust high-throughput measurements of allelic ratios across the dynamic range of gene expression, even for low-quantity or low-quality RNA.

Highly accurate and sensitive predictions of RNA editing sites can be obtained using RNA sequencing data from multiple individuals or species, without relying on matched genomic DNA sequence. Reanalyzing existing RNA sequencing data in this way greatly expands the catalog of human protein recoding events.

Optimized guide RNAs improve RNA editing with endogenous enzymes.

Breen et al. map RNA editing profiles in cortical samples from individuals with schizophrenia and controls, and find links between altered RNA editing in glutamatergic and postsynaptic density genes and schizophrenia genetic risk architecture.

Brain enriched RNA editing of Adenosine-to-Inosine (A-to-I) increases the amount of information encoded in the genome and diversifies the transcriptome. Here the authors discuss how recent technological and analytical developments may facilitate the discovery of RNA editing sites and the understanding of their functions and regulation.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

In vivo screening of pro-metastatic factors in a genetically engineered mouse model of lung cancer uncovered the CD109–JAK–STAT3 axis as a key contributor of metastatic dissemination of lung cancer cells. Activation of this pathway predicts poor outcome in patients with cancer, and its pharmacological inhibition dramatically reduces the metastatic ability of tumor cells, suggesting that it might be an effective intervention in patients.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

Fusion of a guide RNA directly to an adenosine deaminase via a SNAP-tag allows for precise and efficient RNA editing.

Endogenous RNAs are edited using antisense oligos that recruit endogenous RNA-editing enzymes.

Hunter Fraser and colleagues generate atlases of imprinted gene expression across many mouse and human tissues. They find that imprinted genes are enriched for co-expression in pairs of maternally and paternally expressed genes, consistent with an evolutionary signature of parental conflict.

Long DNA molecules, such as those encoding genes, can be assembled from short oligonucleotides created on a microarray. Kosuri et al. improve the fidelity and scalability of this process, enabling synthesis of 40 antibody fragments having repetitive regions and other challenging sequence features.

Genetic variants have been associated with myriad molecular phenotypes that provide new insight into the range of mechanisms underlying genetic traits and diseases. Identifying any particular genetic variant's cascade of effects, from molecule to individual, requires assaying multiple layers of molecular complexity. We introduce the Enhancing GTEx (eGTEx) project that extends the GTEx project to combine gene expression with additional intermediate molecular measurements on the same tissues to provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health.