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The genus Serratia includes clinically-important and diverse environmental bacteria. Here, Williams et al. assemble and analyse a representative set of 664 genomes from across the genus, including historic isolates, to provide a genome-based phylogenetic framework for a better understanding of the emergence of clinical and environmental lineages of Serratia.

A multimodal analysis of patients with 22 different immune-mediated monogenic diseases versus matched healthy controls leads to the development of the immune health metric, which could be implemented broadly to predict responses to aging, vaccination and other immune perturbations.

This study develops family-based genome-wide association study methods that maximize power in homogeneous samples through inclusion of singletons and in diverse samples by using all available parental genotypes.

Despite many common genetic variants being linked to depression, the impact of rare coding variants on depression remains largely unknown. Here, the authors perform a whole-exome sequencing study of depression, providing insights into the rare genetic architecture of depression.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Using a newly developed spatiotemporal phylogeographic path analysis method combined with phylogenetic niche modelling, the authors estimate clade-wide dispersal maps spanning the early Permian to end-Triassic periods for archosauromorph reptiles.

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.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

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).

Last year the first map of single nucleotide changes was published; now an international consortium has mapped even larger areas of differences, called copy number variants. These variants are at least 1,000-base-pair differences between individual people, and have been linked to both benign and disease-causing changes in the human genome.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Hong Kong has used an elimination strategy to control SARS-CoV-2 with stringent measures including traveller quarantine. Here, the authors show that the majority of community-acquired cases until January 2021 resulted from three importations, and that increased transmission followed prolonged periods of restrictions, likely due to adherence fatigue.

Fluorescence-labelling strategies and a suite of imaging methods are used to characterize mycobacteriophage infection in single cells and populations.

HIV infected cells persist for decades in patients under ART, but the mechanisms responsible remain unclear. Here, Reeves et al. use modeling approaches adapted from ecology to show that cellular proliferation, rather than viral replication, generates a majority of infected cells during ART.

Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.

Mathieson et al. carried out a genome-wide association study of reproductive success (number of children born) in humans, revealing the importance of diverse neuro-endocrine and behavioural factors.

An analysis of 38 ancient genomes from the aurochs, the extinct ancestor of modern cattle, provides insight into the population ancestry and domestication of this species.

The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

The identification of high-affinity molecular mimicry between the Epstein–Barr virus (EBV) transcription factor EBNA1 and the CNS protein GlialCAM provides a mechanistic link between multiple sclerosis and EBV.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Biller et al. use long-read sequencing of fractionated ocean nanoparticles, showing that extracellular vesicles and virus-like particles contain distinct pools of genetic information and thus may differentially contribute to horizontal gene transfer dynamics in the ocean.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Integrative data analysis of 1,367 human iPSC lines maps common and rare regulatory variants that colocalize with loci associated with human traits and diseases.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

The deletion and duplication of genes can be major facilitators of evolution. Here, the role of such variation was investigated in over a thousand genomes characterizing the global spread of a major fungal pathogen of wheat. The study suggests that gene loss likely facilitated the pathogen’s colonization of new continents by modulating climate tolerance and metabolic capabilities.

Using epigenome-wide mediation analyses to investigate DNA methylation as a path between adversity and depression, the authors found 31 cytosine–guanine dinucleotides (CpGs) associated with risk and 39 CpGs associated with protective effects.

Circulating tumor DNA is detected with high sensitivity and specificity using molecular barcoding and in silico error correction.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Understanding the emergence, evolution, and transmission of antibiotic resistance genes (ARGs) is essential to combat antimicrobial resistance. Here, Munk et al. analyse ARGs in hundreds of sewage samples from 101 countries and describe regional patterns, diverse genetic environments of common ARGs, and ARG-specific transmission patterns.

Application of a nanopore sequencing workflow for real-time analysis of brain tumors results in molecular classification within a 30-minute intraoperative window, followed by comprehensive profiling within 24 hours.

This study presents and validates a novel approach to reliably identify structural variations (SVs) in non-model genomes using whole genome sequencing, which was used to detect 15,483 SVs in 492 Atlantic salmon, shedding light on their roles in genome evolution and the genetic architecture of domestication.

Genomic epidemiology reveals multiple travel-related introductions of SARS-CoV-2 from mainland Europe into Scotland during the first wave of COVID-19.

Molecular networking connects molecules based on their fragment ion mass spectra (MS²), but may leave adduct species from the same molecular family separate. To address this issue, the authors develop a networking approach that fuses MS¹- and MS²-based networks and integrate it into the GNPS environment.

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.

The base-calling algorithm SNPSeeker detects single-nucleotide polymorphisms with frequencies that are below the error rate of the sequencing platform. It is thus well suited to analyze data from large pooled samples and find rare variants that may contribute to diseases or complex traits.

Aberrant changes in DNA methylation have been implicated in various neurodevelopmental disorders but remain under studied in developmental and epileptic encephalopathies. Here, the authors demonstrate the diagnostic utility of genome-wide DNA methylation analyses toward identifying molecular etiologies in developmental and epileptic encephalopathies.

Multiplayer games can be used as testbeds for the development of learning algorithms for artificial intelligence. Omidshafiei et al. show how to characterize and compare such games using a graph-based approach, generating new games that could potentially be interesting for training in a curriculum.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

The significance of translated upstream open reading frames is not well known. Here, the authors investigate genetic variants in these regions, finding that they are under high evolutionary constraint and may contribute to disease.

Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.

Vaccines against the WA1 SARS-CoV2 strain confer protection against other variants. However, the mechanisms underlying cross-protection are not fully understood. Here, the authors develop a method for rapid analysis of single B cells from patient samples and show that infection with a variant elicits convergent, public B cell responses to other variants.

Souporcell clusters single-cell RNA-seq data using genotype information without the use of a genotype reference.

Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

Spatial multi-omics methodologies are essential for capturing the molecular heterogeneity of complex biological systems. In this study, the authors introduce a multi-omics imaging workflow capable of mapping metabolite-protein interactions with spatial specificity, enabling pathway-level resolution across distinct placental tissue microenvironments.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.