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The authors resolve 63 structurally diverse haplotype structures for the 22q11.2 deletion syndrome region. Deletion risk differs depending on structure; individuals of African ancestry are enriched for inverted repeats that predispose to inversion.

Guillaume Bourque and colleagues report genome-wide binding profiles of the OCT4, NANOG and CTCF proteins in human ES cells as determined by ChIP-sequencing. They find that the binding profiles of OCT4 and NANOG are different in human and mouse ES cells, and some of the differences in bound sites are due to transposable elements.

Changes in gene regulation are a major driver of human traits and disease. Here, authors develop e2MPRA, a high-throughput technology that simultaneously measures enhancer activity and associated epigenetic modifications, revealing how sequence variants influence regulatory function.

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, long-read RNA sequencing achieves accurate single-nucleotide polymorphism calling, haplotype phasing and allele-specific expression analysis.

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 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.

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.

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.

Here the authors show that REST/NRSF represses non-muscle lineage genes in muscle stem cells and progenitors, preserving their identity and differentiation capacity. Loss of REST disrupts gene silencing, impairs muscle regeneration, and leads to stem cell pool depletion.

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.

Transposable element (TE) activity affects genome structure. Here, authors present GraffiTE, a framework for analysing polymorphic TEs in long reads or assemblies. It combines state-of-the-art variant search, TE annotation, and graph-genotyping, and has proven versatile across eukaryotic models.

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.

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.

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.

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.

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 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.

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 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.

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.

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.

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.

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.

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.

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

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.

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.

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 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.

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.

DNA repair by microhomology-mediated end joining creates precise deletions based on flanking microhomologies. Here the authors use CRISPR-Cas9 to recreate pathogenic deletion mutations using existing microhomologies in the human genome identified by their program MHcut.

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.

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.

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.

Nephric duct (ND)-derived ureteric buds (UB) form the kidney collecting duct system, while ureteric tips promote nephron formation. Here the authors use single-cell RNA-seq and introduce Cluster RNA-seq to identify four progenitor populations in developing ND/UB regulated by the transcription factors Tfap2a/b and Gata3.

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.

Glioblastoma is thought to arise from neural stem cells. Here, to investigate this, the authors use single-cell RNA-sequencing to compare glioblastoma to the fetal human brain, and find a similarity between glial progenitor cells and a subpopulation of glioblastoma cells.

Ng and colleagues show that the spliceosome-associated factor SON is essential for the maintenance of pluripotency and the survival of human embryonic stem cells. Using genome-wide RNA profiling to identify SON-regulated transcripts, they find that it modulates splicing of transcripts of pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24.

Chia-Lin Wei, Yijun Ruan and colleagues used chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) to determine the CTCF-chromatin interactome in mouse embryonic stem cells.

Many transcription factors bind to regulatory DNA elements that are distant from gene promoters. These distal binding sites are thought to regulate transcription through long-range chromatin interactions, but, until now, the impact of chromatin interactions on transcription regulation has not been investigated in a genome-wide manner. A new strategy — chromatin interaction analysis by paired-end tag sequencing — is now described for the de novo detection of global chromatin interactions.

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.