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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

Epigenetic profiles can be predictive of macrophage transcriptional responses to influenza A virus infection in individuals of European and African ancestry. Ancestry-linked epigenetic differences appear to be genetically controlled.

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.

Here, the authors report recent updates to the ENCODE data portal including a redesigned home page, an improved search interface, custom-designed pages highlighting biologically related datasets and an enhanced cart interface for data visualisation plus user-friendly data download options.

A pangenomic approach, where genome sequences are related to each other in a graph, facilitates analysis of genomic variation between individuals. Here, the authors explore the benefits of using such an approach to characterize structural variation (e.g., deletions or duplications of more than 50 base pairs) in a rare disease cohort.

Multiple alternating layers of two-dimensional materials and epilayers are grown on III–N and III–V substrates in a single growth run. Then, each epilayer is harvested by mechanical exfoliation, producing multiple freestanding membranes from a single wafer.

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

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.

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.

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.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

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.

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.

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.

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.

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.

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.

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.

Ankrd11 is a chromatin regulator that is strongly associated with KBG syndrome, a rare disorder that includes heart defects. Here they show that loss of Ankrd11 from neural crest dysregulates cardiac neural crest cell organization and crucial signaling pathways, leading to failed heart outflow tract septation and severe cardiac defects.

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.

Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.

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.

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.

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.

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.

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.

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.

Synaptotagmin 1 is involved in dopamine release. Here the authors investigate the effect of loss of Syt1 in midbrain dopaminergic neurons in mice, and find that unconditioned motor behaviour and motivation for food, are intact.

Mammals have evolved a complex set of mechanisms that maintain extracellular fluid osmolality within a narrow range to preserve cellular function. Bourque uncovers the sensory mechanisms, central pathways and peripheral responses that comprise the mammalian osmoregulatory system.

The decision to form a fruiting body have been studied extensively, however, the mechanical events that trigger the creation of multiple cell layers is poorly understood. Here the authors find M. xanthus cells adjust their reversal frequency to control mechanical stresses that triggers layer formation in the colonies.

A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.

Comparisons within the human pangenome establish that homologous regions on short arms of heterologous human acrocentric chromosomes actively recombine, leading to the high rate of Robertsonian translocation breakpoints in these regions.

The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.

Renal cancer accounts for 2.4% of all adult cancers and its incidence is increasing worldwide. Here, the authors carry out genome and transcriptome sequencing of clear cell renal cell carcinomas (ccRCCs) and highlight genomic aberrations and biological pathways underlying ccRCC tumorigenesis.

Despite initial benefits in treating HER2-positive breast cancer patients with lapatinib, resistance is prevalent. Here the authors show that lapatinib resistance can be ascribed to mTOR-mediated re-activation of ERRα and to the consequent induction of a metabolic adaptation.

Adipose tissue varies depending on localization. Vijay et al. perform single-cell RNA sequencing in multiple adipose tissue depots from obese individuals and identify distinct subpopulations of endothelial cells, immune cells and pre-adipocytes.

The results of the phase 1/2 LIBRETTO-001 clinical trial has recently established the efficacy of the RET inhibitor selpercatinib in RET-driven cancers. Here, the authors characterize the molecular determinants of response and resistance in 72 LIBRETTO-001 lung and thyroid cancer patients treated at a single site.

Constructing genome graphs directly from genome assemblies overcomes single-reference bias.