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Enhancers for endodermal organs are primed at the chromatin level prior to lineage induction by FOXA pioneer transcription factors; how pervasive this is, is not well known. Here the authors show that only a small subset of organ-specific enhancers are bound and primed by FOXA prior to lineage induction, whereas the majority do not undergo chromatin priming and engage FOXA upon lineage induction.

Comprehensive spatial multiomic profiling of high-grade meningiomas identifies intratumor and primary–recurrence subclonal heterogeneity. Cell line models recapitulating intratumor heterogeneity show differential sensitivity in drug screens.

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.

It's a bit of a shock.

Overexpression of c-MYC regulates tumor metabolism in pancreatic ductal adenocarcinoma (PDAC). Here the authors identify ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target of PDAC.

Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.

Cistrome-wide association study (CWAS) is an approach for nominating variants that impact traits through effects on chromatin state. CWAS performed on 307 prostate cistromes identifies candidate loci for prostate cancer and androgen-related traits.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Erik Ingelsson and colleagues report a large-scale genome-wide meta-analysis for associations to the extremes of anthropometric traits, including body mass index, height, waist-to-hip ratio and clinical obesity. They identify four loci newly associated with height and seven loci newly associated with clinical obesity and find overlap in the genetic structure and distribution of variants identified for these extremes of the trait distributions and for the general population.

Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.

We present the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference.

Hess and colleagues perform metabolic screens in B cells from patients with primary antibody deficiency and find that germline mutations in the succinate dehydrogenase subunit SDHA drive the expression of the cytokine IL-6 in patients with persistent polyclonal B cell lymphocytosis.

Genome-wide analyses of ancient DNA from individuals from California and Mexico shed light on the spread of Mexican ancestry to California and how it correlates with linguistic flow.

Pervasive transcription of the human genome generates an abundance of RNAs that must be processed and degraded by the nuclear RNA exosome. Here the authors show that polyA polymerase gamma (PAPγ) associates with PAXT providing key insights into the direct targeting of PROMPT ncRNAs by PAXT at their genomic sites.

ABCC9 encodes the SUR2 subunit of K_ATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of K_ATP channel function.

Combined genomic and transcriptomic approaches identify the landscape of extrachromosomal circular DNA in neuroblastoma and reveal that extrachromosomal circular DNA is a major source of somatic rearrangements.

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

A patient with newly diagnosed glioblastoma was safely treated with neoadjuvant nivolumab, relatlimab and ipilimumab before maximal resection, with comprehensive immune profiling showing the induction of overall immune activation early during treatment. The patient had no definitive evidence of recurrence at 17 months after treatment.

Serotonin has a role in ependymoma tumorigenesis through modifying histones and thereby regulating key transcription factors and activating specific oncogenic transcriptional networks in brain cells.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

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.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

In ancient cultures without a writing system, it is difficult to infer the basis of status and rank. Here the authors analyse ancient DNA from nine presumed elite individuals buried successively over a 300-year period at Chaco Canyon, and show evidence of matrilineal relationships.

The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.

Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here the authors analyse the genomes, exomes and transcriptomes of 37 such tumours and identify genetic alterations whose nature, timing and potential interactions are key events with prognostic significance in pediatric adrenocortical tumorigenesis.

2- arachidonoylglycerol (2-AG), an abundant endocannabinoid in the brain, regulates diverse neural functions. Here, the authors identified four loss-of-function mutations in dicylglycerol lipase β (DAGLB) from six patients with early onset Parkinsonism. In mice, loss of DAGLB in dopamine neurons reduced neuronal activity and impaired locomotor function and augmentation of 2-AG levels boosted neuronal activity and rescued locomotor deficits.

DMRT transcription factors, key regulators of metazoan sexual development, use a unique DNA binding mode critical for male-to-female sex reversal in humans.

Diurnal and seasonal rhythms modulate brain function, but we do not know the genomic basis for these rhythms. Here, Limet al. show diurnal and seasonal rhythms of gene expression in the human brain, their relationship to histone acetylation and DNA methylation, and their disruption in Alzheimer’s disease.

Using whole-genome and single-cell RNA sequencing data of patients with multiple myeloma treated with carfilzomib, lenalidomide, dexamethasone and daratumumab, Maura et al. identify distinct genomic drivers and microenvironment changes affecting outcome.

Candida albicans is an opportunistic fungus primarily affecting immunocompromised patients. Here, the authors identify a novel mechanism of host immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.

Androgen receptor (AR) is the critical driver of nearly all prostate cancer. The authors show that AR activation causes specific pre-existing chromatin loops to increase contact frequency with target promoters and drive transcription.

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.

Cutaneous gamma-delta T cell lymphomas are rare but aggressive cancers. Here, by DNA, RNA and T cell receptor sequencing, the authors elucidate the molecular ontogeny by revising the cell of origin and identifying potentially targetable mutations.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Fluorescence-activated nuclear sorting combined with deep profiling shows that Huntington’s disease repeat expansions arise in specific cell types and are associated with elevated MSH2 and MSH3, which promote expansions in vitro by inhibiting excision of CAG slip-outs by FAN1.

POU2AF2 is a co-activator of POU2F3 in normal and neoplastic tuft cells, such as small cell lung cancer. Here, the authors report that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements.

The evolutionary trajectory of avian sex chromosomes may be more intricate than previously understood. In this study, sequencing and analysis of the neo-sex chromosomes and genome of the Crested Ibis suggests a multidirectional evolution of sex chromosomes in core waterbirds.

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.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Christopher Haiman, Bogdan Pasaniuc, David Reich and colleagues report a major role for low-frequency variation in the risk for prostate cancer. They show that alleles with >1% minor allele frequency contribute an order of magnitude more to risk for prostate cancer than these alleles do to overall genetic variation.

Genome-wide analyses identify variants in B3GALT5 and ST6GAL1 associated with influenza susceptibility. Knockdown of ST6GAL1 in cell culture reduces influenza infectivity, likely by interfering with the glycoprotein modifications required for viral entry.

Malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division.

Variant detection in problematic genes is facilitated with a curated benchmark.