Search

A challenge for testing mechanisms of past climate change is the precise correlation of palaeoclimate records. Here, through climate modelling and the alignment of terrestrial, ice and marine ¹⁴C and ¹⁰Be records, the authors show that Southern Ocean freshwater hosing can trigger global change.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

A study of 17,152 patients with cancer identified pathogenic germline variants in cancer predisposition genes. Although tumors showed biallelic inactivation for high-penetrance genes, this was not the case in most patients with pathogenic variants in low-penetrance genes, suggesting alternative routes to tumorigenesis.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.

Ian Tomlinson and colleagues report the identification of germline variants in POLE and POLD1 that are susceptibility alleles for colorectal cancer. POLE and POLD1 encode DNA polymerases that function in DNA replication.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

Analysis of genomic data from 981 colorectal cancers from participants in 11 countries reveals variations in mutational signatures of microsatellite-stable cancers that are dependent on geographical origin and age at which the cancer was diagnosed.

It is unclear whether species’ responses to climate change tend to be adaptive or sufficient to keep up with climate change. Here, Radchuk et al. perform a meta-analysis showing that in birds phenology has advanced adaptively in some species, though not all the way to the new optima.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

This study demonstrates that 16p11.2 hemideletion, a genetic deletion linked to neurodevelopmental disorders, affects male and female mice differently, altering specific striatal neuronal circuits and driving sex-specific behavioral changes.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Mutations in the mismatch repair (MMR) genes are associated with an increased risk of developing colorectal cancer (CRC). In this Review, the authors outline the MMR system and describe how defective MMR impacts on the management of CRC. The authors also discuss how targeting these mutations can be exploited in the development of novel therapeutic strategies.

Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.

A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

12,13-diHOME produced by the gut microbiome promotes an asthma-like immunophenotype in the lungs of a murine experimental model. Accordingly, the metabolite is elevated in neonates who developed asthma during childhood, potentially providing a biomarker for early risk prediction and a novel therapeutic target.

The BabyScreen+ study offered genomic screening to 1,000 newborns in Australia, and showed that the approach is feasible and positively received by families, leading to molecular diagnoses in 1.6% of babies.

Community microattribution review of the evidence for colon cancer risk conferred by constitutional variants in MLH1, MSH2, MSH6 and PMS2 has resulted in the reclassification of two-thirds of the variants reported in existing databases and led to clinical recommendations for the interpretation of 1,370 variants that do not result in obvious protein truncation.

The integration of DNA methylation profiling and targeted sequencing with neuropathology improves the diagnostic accuracy of central nervous system tumors in a population-based cohort of more than 1,200 newly diagnosed pediatric patients.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

An ultrastrong exciton–polariton coupling in two-dimensional excitonic mithrene with a large refractive index and a large oscillator strength of its primary exciton is reported, enabling the formation of self-hybridized exciton–polaritons with Rabi splitting of >600 meV.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Elevated body mass index is heritable and associated with many health conditions that impact morbidity and mortality. Here, the authors identify greater than 900 genetic loci for body mass index (BMI) and find over 300 diagnoses associated with increasing BMI.