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A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

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.

There are limited in vitro and in vivo models to study human fetal exposure to environmental noise. Here, the authors develop a computational model to quantify fetal exposure to acoustic fields, obtaining acoustic transfer characteristics across the human audio range.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

An approach to estimate the contribution of all alleles to phenotypic variation is applied to transcription regulation using whole-genome sequencing and transcriptome data. Ultrarare variants contribute approximately 46% of cis heritability across genes.

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.

By performing a global RNA-RNA interactome analysis in hypervirulent Klebsiella pneumoniae, the authors identify the small RNA ArcZ targets many capsule genes and a key virulence factor MlaA, inhibiting Klebsiella infection and pathogenesis in mice.

White-tailed deer are an important reservoir of SARS-CoV-2 in the USA and continued monitoring of the virus in deer populations is needed. In this genomic epidemiology study from Ohio, the authors show that the virus has been introduced multiple times to deer from humans, and that it has evolved faster in deer.

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).

This study presents the genomes of 2,101 emm28 Streptococcus pyogenes invasive strains, of which 492 were transcriptionally profiled, and 50 were assessed for virulence. GWAS, eQTL analysis, and study of isogenic mutant strains identified an intergenic region that alters global transcript profiles and bacterial virulence.

Rare variant association analysis of plasma proteins using whole-genome sequencing data in 54,306 individuals in the UK Biobank demonstrates that combining both single-variant and aggregate testing will be needed for noncoding variant analysis.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

New Zealand implemented stringent COVID-19 control measures early after identification of its first case. Here, the authors perform whole genome sequencing of samples taken until 22 May 2020 and find high viral diversity indicative of multiple separate introductions and limited community transmission.

Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease.

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.

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.

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.

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

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.

Genomic analyses in individuals with index and familial intracranial aneurysms and experiments in vertebrate models identify pathogenic variants in the PPIL4 gene implicated in cerebral angiogenesis and cerebrovascular integrity, through the Wnt signaling pathway.

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.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

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.

The ability to manage ill health and care needs might be affected by who a person lives with. Here, authors show that living alone or with co-residents with multimorbidity poses additional risk for unplanned hospitalisation and care home transition beyond an individual’s characteristics.

Classification of archaeal and bacterial viruses can be automated with an algorithm that identifies relationships on the basis of shared gene content.

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.

The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of subjects with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, they found that ∼20% of schizophrenia loci have variants that may contribute to altered gene expression and liability.

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.

Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.

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.

Wolf Reik and Ian Dunham and colleagues cloned and sequenced the complete IGF2-H19 locus in tammar wallaby, a marsupial. Functional analyses revealed conservation of imprinting mechanisms, including germline DNA methylation, between marsupials and eutherians.

Convergent mutations in hot spots of the spike proteins of currently circulating SARS-CoV-2 Omicron variants increase the binding affinity for the host receptor and promote more efficient fusion with host cell membranes.

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.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

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

DADA2 is an open-source software package that denoises and removes sequencing errors from Illumina amplicon sequence data to distinguish microbial sample sequences differing by as little as a single nucleotide.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

A study shows that cross-reactivity of microbial antigens and self-antigens presented by HLA-B*27 may be important in the pathogenesis of diseases associated with HLA-B*27 and identifies the shared binding motif responsible.