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The combination of massively parallel mutation enrichment and duplex sequencing allows for the tracking of up to 10,000 low-frequency mutations with up to 100-fold fewer reads per locus than conventional duplex sequencing.

MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

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.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity.

Current outcomes are reported from the ongoing National Lung Matrix Trial, an umbrella trial for the treatment of non-small-cell lung cancer in which patients are triaged according to their tumour genotype and matched with targeted therapeutic agents.

Clare Turnbull and colleagues identify three new risk loci for testicular germ cell cancer. The newly discovered risk variants reside near the telomere regulator genes TERT and ATF7IP and the sex determination gene DMRT1.

Copy number variations inferred from spatial transcriptomics data in benign and malignant tissue reveal clonal architecture at the organ-wide level.

Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Marshall et al. show that regions of the genome adopt a noncanonical Z-DNA state in the prefrontal cortex in response to fear learning and that binding of Adar1 reduces Z-DNA during extinction learning, which is required for memory flexibility.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.

Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

This study reveals how infections that increase long-term dementia risk can contribute to longitudinal brain volume loss and regulate immunological proteins in plasma, and which of these proteins may drive infection-specific neurodegeneration.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

Loss-of-function mutations in tumour suppressor genes are associated with oesophageal adenocarcinoma (EAC), but the mechanisms underlying EAC development remain unclear. Here, the authors show that EACs present a high frequency of genomic catastrophes resulting in amplification of potent oncogenes.

Comparison of multiple genome assemblies from wheat reveals extensive diversity that results from the complex breeding history of wheat and provides a basis for further potential improvements to this important food crop.

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 mechanisms of remyelination are unclear. Here, the authors develop and use two-photon apoptotic targeted ablation and show a form of rapid synchronous remyelination mediated by a distinct subset of OPCs that can occur in adult mice but not in aging.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

The function of a poorly characterized transmembrane protein, TMEM164, was annotated by integrated genetic dependency mapping, AlphaFold2 structural modeling and lipidomics as an acyltransferase that generates ferroptotic C20:4 ether phospholipids.

Using integrative multi-omics and CRISPR knock-out of all ~1,900 transcription factors, the authors identify essential transcription factors required for Neurogenin-driven differentiation of human cortical neurons.

Sequencing of the sex-determining Y chromosomes of cattle and sheep has proved difficult in the past. Using modern methods, this study presents complete T2T assemblies of these chromosomes and uncovers differences between the species that are suggestive of divergent evolutionary trajectories.

Here Liu et al. show that genome-wide redistribution of methyltransferase-like 3 and 14 transcriptionally promotes the senescence-associated secretory phenotype in an m⁶A-independent manner.

Timothy Bishop and colleagues from GenoMEL present a genome-wide association study for melanoma. They report three loci associated with susceptibility to melanoma, of which two were previously associated with pigmentation.

A chromosome-scale genome assembly of rye inbred line ‘Lo7’ provides insights into its incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution and the yield benefits of rye–wheat introgressions.

We show the evolution of a case of EGFR mutant lung cancer treated with a combination of erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine targeting somatic mutations, including EGFR exon 19 deletion.

Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.

Maternal glucose levels during pregnancy can affect the metabolic health of a developing fetus, both early on and later in life. Here, the authors reveal that genetic variants in several regulatory elements alter glucose homeostasis during pregnancy by reducing the expression of a novel hexokinase gene, HKDC1.

Gnirke et al. present a bead-based method for capturing sequences of interest in the human genome for massively parallel sequencing. Using long, biotinylated RNA probes to pull down PCR-amplified DNA fragments, they demonstrate sequencing of 2.5 Mbs of exons in 1,900 genes.

The evolutionary genetics of a keystone savannah species the blue wildebeest, and the related black wildebeest, remain largely unexplored. This study finds evidence for archaic introgression of black wildebeest to blue wildebeest and detrimental effects of human activities on migratory populations.

The transcription factor PfAP2-G is a key determinant of sexual commitment in Plasmodium falciparum. Here, Josling et al. define the transcriptional regulatory network of PfAP2-G by identifying its DNA binding sites genome-wide, which vary depending on the route of sexual conversion and rely on interactions with the PfAP2-I transcription factor.

Whole-genome sequencing of haematopoietic colonies from human fetuses reveals the somatic mutations acquired by individual progenitors, which are used as barcodes to construct a phylogenetic tree of blood development.

Many strains of Plasmodium differ in virulence, but factors that control these distinctions are not known. Here the authors comparatively map virulence loci using the offspring from a P. yoelii YM and N67 genetic cross, and identify a putative HECT E3 ubiquitin ligase that may explain the variance.

The century-scale marine sequestration flux of biogenic inorganic carbon driven by the biological pump over the whole water column may be several times higher than previous estimates.

Patrick Gaffney and colleagues perform a fine-mapping study of the TNFAIP3 region in systemic lupus erythematosus using individuals from diverse ancestral populations. They identify a putative causal variant in a region of high conservation and regulatory potential that is associated with reduced TNFAIP3 expression.

Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

The brushtail possum is a treasured Australian marsupial, but also a harmful pest introduced into New Zealand. Here, using functional genomics and a new chromosome-level genome assembly of New Zealand possums, Bond et al. quantify their genome admixture and identify unique parent-specific and weaning associated gene expression.

Helium isotopes are interesting platforms for testing the quantum properties of fluids. Here the authors demonstrate quantum one-dimensional behaviour of helium (4He) confined in nanopores by using neutron scattering.

Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.

Many babies have now been born to mothers who were exposed to SARS-CoV-2 during their pregnancy. Here the authors look at the effect of this exposure on the immunology of human neonates, showing immune changes and increased neonatal cytokine responses despite limited evidence of vertical transmission.