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Long-read sequencing enables high-quality genome assemblies, but challenges remain. Here, the authors introduce Cornetto, a method that improves assembly quality, enables genome sequencing from saliva, and accurately resolves medically-relevant repetitive genes.

Any DNA sequence can be represented by a chiral partner sequence – an exact copy arranged in reverse nucleotide order. Here, the authors show that chiral DNA sequence pairs share important properties and show the utility of synthetic chiral sequences (sequins) as controls for clinical genomics.

Synthetic spike-in standards (‘sequins’), representing spliced mRNA isoforms, provide internal controls for assessing transcript assembly and quantification within and between RNA sequencing libraries. Sequins representing fused genes can be used to determine the sensitivity limit for oncogenic fusions in cancer samples.

Nanopore sequencing (ONT) has been used in SARS-CoV-2 studies, however adoption of ONT for SARS-CoV-2 surveillance has been limited due to common concerns around sequencing accuracy. Here, the authors perform a comprehensive evaluation of ONT analytical performance on 157 matched SARS-CoV-2-positive patient specimens and synthetic RNA controls.

Population-scale whole-genome sequencing across four remote Indigenous Australian communities reveals a large fraction of structural variants that are unique to these populations, emphasizing the genetic distinctiveness of and diversity among Indigenous Australians.

Samarakoon et al. present Genopo, a portable toolkit for analysis of nanopore sequencing data on Android smartphone and tablet devices. Genopo enables field-based nanopore analysis using widely accessible technology.

A significant proportion of individuals with inherited neuromuscular disease do not receive a genetic diagnosis. Here, the authors establish CCG expansions in the 5’ untranslated region of ABCD3 as a cause of oculopharyngodistal myopathy (OPDM) in individuals of European ancestry and identify increased expression of expansion-containing ABCD3 transcripts as a possible disease mechanism underlying muscle degeneration.

Synthetic DNA spike-ins that recapitulate genetic variation present in human genomes serve as quantitative and qualitative controls for genome sequencing and variant detection.

Here, the authors describe the use of synthetic DNA spike-ins, called sequins, as internal quantitative and qualitative controls throughout the sequencing workflow. They detail their application in whole-genome and targeted human genome sequencing.

Multi-omics analyses powerfully combine gene expression and translation, however no available controls can be used across these techniques. Here the authors develop pREF, a universal control construct designed for use in DNA, RNA and protein analyses.

Technical errors can hamper the interpretation of next-generation sequencing (NGS) data, which poses a major challenge for the clinical application of this technology. This Review discusses how reference standards circumvent this issue by calibrating NGS measurements and evaluating diagnostic performance of NGS-based genetic tests.

DNA methylation plays a major role in establishing cell identity, but the dynamics of DNA methylation patterns are highly variable across species. Here, the authors discover extensive DNA methylation reprogramming during embryonic development of the sea lamprey, a jawless fish with a distinctive, highly disordered methylome.

Reliable detection of mutations below 0.5% variant allele frequency remains a key challenge for circulating tumor DNA sequencing assays.

Adding library adaptors to DNA samples is an essential step in preparing samples for next-generation sequencing. Here, Gunter et al. describe the development of Control Library Adaptors (CAPTORs), that correct sequencing errors and normalise quantitative biases in Nanopore libraries.

Experiments in mice show that a LINE-1 transposable element, Lx9c11, has a functional role in immunity by negatively regulating the response to viral infection to protect the host from an over-reactive immune response.

SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use.

Standard units of measurement are required for a quantitative description of the genome. Here, the authors present a universal synthetic DNA ladder that can measure genetic abundance in next-generation sequencing libraries.

Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.

Nanopore sequencing data are rapidly analyzed with parallel data access.

Complex microbial communities pose a challenge to metagenomic analysis. Here the authors develop ‘sequins’, internal DNA standards that represent a synthetic community of artificial genomes.

Analysis of the FGF14-SCA27B repeat locus identifies a common 5′-flanking insertion that represents the major allele, is present exclusively on nonpathogenic alleles, enhances repeat stability and increases chromatin accessibility.

This Review describes tools and approaches for characterizing short tandem repeats in the human genome from whole-genome sequencing data. Furthermore, the authors discuss how these recent developments have helped to better understand the effect of short tandem repeats on human health and disease.