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Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

A multivariate genome-wide association study identifies 203 signals associated with facial variation. These signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues.

Multiple myeloma evolves continuously. Here the authors chronologically reconstruct driver events in multiple myeloma, noting a limited repertoire of initiating driver events that shape the evolutionary trajectory of the disease.

An increase in shigellosis cases among men who have sex with men in the United Kingdom has been linked to an extensively drug-resistant strain of Shigella sonnei. In this genomic epidemiology study, the authors investigate the genetic basis, evolutionary history, and international dissemination of the outbreak strain.

Bennett et al. conducted a population-based study in adolescents and young adults with gliomas, revealing the specific molecular alterations and identifying potential subclassifications and targets.

Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.

Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.

5-Fluorouracil (5-FU) is a commonly used chemo drug to treat cancer patients. Using in vitro 5-FU treated organoids and in vivo 5-FU treated human cancer data, the authors describe a 5-FU mutational signature that is similar to COSMIC signature 17 frequently observed in untreated cancers

Cerebral malaria infection can provoke fatal neuroinflammation. Gros and colleagues identify an ubiquitin-modification axis that exacerbates neuroinflammation and that involves TRIM25 and USP15, which jointly promote type I interferon production.

The genomic features of metastatic prostate cancer are beginning to be understood. Here, the authors performed whole genome sequencing of plasma samples from these patients and found a high plasticity of the cancer genomes with newly occurring focal amplifications as a driving force in progression.

Healthy tissues from individuals with germline mutations in POLE or POLD1 show increased mutational burden, suggesting that normal cells are capable of tolerating high mutation rates.

The histone H3K4 methyltransferase SET1B is recruited to a subset of hypoxia-inducible genes by the HIF complex. Loss of SET1B reduces HIF transcriptional activity in hypoxia and impairs tumor formation in xenograft models.

The authors use three-dimensional live-cell imaging of colorectal carcinoma organoids to show that chromosomal instability is widespread. Single-cell sequencing identifies heterogeneity of copy number alterations and shows clonal evolution.

PU.1 is a master regulator of myeloid development but its role in disease-relevant neutrophils is not well known. Here, the authors look at primary neutrophils from a human population and find that genetic variants affecting binding of PU.1 are associated with cell count and disease susceptibility.

PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.

Dogs may have been domesticated much earlier than previously thought, perhaps by initially scavenging with humans. Here Zhang et al. present genetic evidence that genes positively selected during dog domestication show extensive parallelism with human analogues.

Primary immunodeficiency disorders can be used to identify key immune functions. Here, the authors identify a biallelic mutation in the gene encoding NF-κB-inducing kinase in a family suffering a range of infections, and show that it causes defects in NK and T-cell function and has broad effects on B-cell function.

A mutation in the sodium channel Nav1.9 has been identified in a family and shown to associate with cold-aggravated pain. Here, the authors characterize the electrophysiological consequences of this mutation and propose a mechanism for the pain that the individuals experience.

AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here, the authors sequence the whole exomes of 42 TGCTs, and characterize the mutational profile of this tumour type.

Paul de Bakker, Cisca Wijmenga and colleagues report on The Genome of the Netherlands Project, including whole-genome sequencing of 769 individuals of Dutch ancestry from 250 parent-offspring families and construction of a phased haplotype map. Their intermediate-coverage population sequencing data set provides a complementary resource to other publicly available data sets, including the 1000 Genomes Project.

The genetic basis of gastric cancer, the fourth most common cancer worldwide, remains poorly understood. Here, the authors sequence and analyse the exomes and transcriptomes of primary gastric tumours and cell lines, and identify a ZAK kinase isoform that may have an oncogenic role in gastric cancer.

Smoldering MM (SMM) is a premalignant stage of multiple myeloma (MM). Here the authors perform whole genome sequencing of unique paired samples of SMM progressing to MM, and show that the genomic landscape at the SMM stage is very similar to MM, but trajectories of evolution can vary from patient to patient.

Chromatin accessibility is a key mediator of gene expression and mutations in chromatin modifiers are frequently seen in cancers. Here, the authors show that the chromatin accessibility regulator HMGN1 - which is frequently mutated by amplification in leukemias - acts by blocking myeloid differentiation.

SETDB1 is a histone methyltransferase and a role for the protein has been proposed in cancer. Here, the authors show that SETDB1 contributes to hepatocellular cancer by preferably forming a complex with mutant p53, resulting in di-methylation of a critical lysine residue and stabilization of the protein.

Analysis of a near-chromosomal genome assembly and transcriptome profiling of the Indian cobra identifies genes expressed in the venom glands. These data should help develop a new antivenom.

Here, the first genome-wide in vivo RNA interference screens in a mammalian animal model are reported: genes involved in normal and abnormal epithelial cell growth are studied in developing skin tissue in mouse embryos, and among the findings, β-catenin is shown to act as an antagonist to normal epithelial cell growth as well as promoting oncogene-driven growth.

Genome-wide association studies (GWAS) have revealed gene variants associated with breast cancer, but their association with breast cancer development in Latinas is not clear. Here, the authors carry out a GWAS of breast cancer in Latinas and identify a significant protective variant of Indigenous American origin in the 6q25 region.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci.

It has been previously demonstrated that some microbes are capable of extracellular electron transport through so–called nanowires or electron shuttles. Here it is demonstrated that this may be a significant process in the marine sediment.

It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.

Joint analysis of new and previously published sequencing data for primary and metastatic prostate cancers identifies new candidate driver mutations and provides insights into disease progression and potential drug targets.

Male breast cancer (MBC) is rare and largely hormonally driven. Here, the authors examine the action of steroid hormone receptors in male and female breast cancers and find gender selective hormone receptor action that associates with the survival of MBC patients.

Multiple regulatory elements distant from their targets on the linear genome can influence gene expression through chromatin looping. Here, the authors report an improved chromosome conformation capture approach that can be used to identify long-range chromatin interactions in cancer risk loci.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Zhu et al. discover that in human brain there is widespread anatomic distribution of low-frequency somatic, mosaic L1 insertions, using deep whole-genome sequencing of neuronal and glial fractions and machine-learning analysis.

Genetic elements that control inflammatory gene expression are not fully elucidated. Here the authors conduct a multi-species analysis of chromatin landscape and NF-κB binding in response to the proinflammatory cytokine TNFα, finding that conserved NF-κB bound regions are linked to enhancer activity and disease.

More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al. report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.

Analysis of DNA from ancient individuals of the Near East documents the extreme substructure among the populations which transitioned to farming, a structure that was maintained throughout the transition from hunter–gatherer to farmer but that broke down over the next five thousand years.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

The authors implement a collection of patient-derived xenograft tumors to test cancer drug responses.

The sequencing and assembly of the highly polymorphic oyster genome through a combination of short reads and fosmid pooling, complemented with extensive transcriptome analysis of development and stress response and proteome analysis of the shell, provides new insight into oyster biology and adaptation to a highly changeable environment.

Over half the world’s rivers dry periodically, yet little is known about the biological communities in dry riverbeds. This study examines biodiversity across 84 non-perennial rivers in 19 countries using DNA metabarcoding. It finds that nutrient availability, climate and biotic interactions influence the biodiversity of these dry environments.

Adrienne Flanagan and colleagues identify distinct driver mutations in H3F3A and H3F3B in chondroblastoma and giant cell tumor of bone. The mutations occur in over 90% of tumors and exhibit a high degree of tumor type specificity.

Analysis of Arctic Ocean sediment core spanning more than 50 million years identifies several key features of Arctic climate history — the revised timing of the earliest Arctic cooling events implied by this record coincides with those from Antarctica, supporting arguments that climate change is symmetric about the Earth's polar regions.

The redox transformations of sulfur mean it is a key component of global biogeochemical cycles. This Review explores the sulfur cycle over geological time, including its role during major climate perturbations, oceanic anoxic events and the evolution of life.