Background Structural variants (SVs) are genetic polymorphisms including deletions, insertions, inversions, and duplications, with potential to influence traits through impacts on gene function and ex...

The authors report a meta-analysis of methylome-wide association studies, identifying 15 significant CpG sites linked to major depression, revealing associations with inflammatory markers and suggesti...

Simultaneous profiling of spatial transcriptomics (ST) and metabolomics (SM) offers a novel way to decode tissue microenvironment heterogeneity. Here, the authors present SpatialMETA, a conditional va...

The “omnigenic” hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans effects on the expression of a

A symposium for early career researchers from all disciplines of genomics and genetics to connect and share their research

Translational Psychiatry - Multivariate genome-wide association analysis of dyslexia and quantitative reading skill improves gene discovery

Author summary Some parts of proteins, known as intrinsically disordered regions, do not fold into fixed shapes. Instead, they stay flexible and play key roles in controlling how cells work, often by ...

Aleksandra Chybowska is a PhD student in Professor Riccardo Marioni’s group at the Institute of Genetics and Cancer. Here she talks about working on next-generation sequencing in epigenetic epidemiolo...

In mammalian cells, RNA species make up ∼10% of chromatin by mass and play a structural role in the nucleus by acting as scaffolds and influencing gen…

Molecular Psychiatry - Association between polygenic risk for Major Depression and brain structure in a mega-analysis of 50,975 participants across 11 studies

A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields

Integration of genome-scale data on host responses to Staphylococcus aureus identified the genes and pathways with the most cumulative evidence. This defin

Background Single base substitution (SBS) mutations, particularly C > T and T > C, are increased owing to unrepaired DNA replication errors in mismatch repair-deficient (MMRd) cancers. Excess CpG > TpG mutations have been reported in MMRd cancers defective in mismatch detection (dMutSα), but not in mismatch correction (dMutLα). Somatic CpG > TpG mutations conventionally result from unrepaired spontaneous deamination of 5’-methylcytosine throughout the cell cycle, causing T:G mismatches and signature SBS1. It has been proposed that MutSα detects those mismatches, prior to error correction by base excision repair (BER). However, other evidence appears inconsistent with that hypothesis: for example, MutSα is specifically expressed in S/G2 phases of the cell cycle, and defects in replicative DNA polymerase proofreading specifically cause excess CpG > TpG mutations in signature SBS10b. Methods We analysed mutation spectra and COSMIC mutation signatures in whole-genome sequencing data from 1803 colorectal cancers (164 dMutLα, 20 dMutSα) and 596 endometrial cancers (103 dMutLα, 9 dMutSα) from the UK 100,000 Genomes Project. We mapped each C > T mutation to its genomic features, including normal DNA methylation state, replication timing, transcription strand, and replication strand, to investigate the mechanism(s) by which these mutations arise. Results We confirmed that dMutSα tumours specifically had higher CpG > TpG burdens than dMutLα tumours. We could fully reconstitute the observed dMutSα CpG > TpG mutation spectrum by adding CpG > TpG mutations in proportion to their SBS1 activity to the dMutLα spectrum. However, other evidence indicated that the SBS1 excess in dMutSα cancers did not come from 5’-methylcytosine deamination alone: non-CpG C > T mutations were also increased in dMutSα cancers; and, in contrast to tumours deficient in BER, CpG > TpG mutations were biased to the leading DNA replication strand, at similar levels in dMutSα and dMutLα cancers, suggesting an origin in DNA replication. Other substitution mutations usually corrected by BER were not increased in dMutSα tumours. Conclusions There is a CpG > TpG and SBS1 excess specific to dMutSα MMRd tumours, consistent with previous reports, and we find a general increase in somatic C > T mutations. Contrary to some other studies, the similar leading replication strand bias in both dMutSα and dMutLα tumours indicates that at least some of the excess CpG > TpG mutations arise via DNA replication errors, and not primarily via the replication-independent deamination of 5’-methylcytosine.

Advances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-trans…

Genes & Immunity - Discovery of core genes for systemic lupus erythematosus via genome-wide aggregated trans-effects analysis

The emergence of a highly pathogenic FCoV–CCoV recombinant is responsible for a rapidly spreading outbreak of feline infectious peritonitis originating in Cyprus.

AbstractSTUDY QUESTION. What is the diagnostic yield and the pre-testicular sperm extraction (TESE) prognostic value of a non-obstructive azoospermia (NOA)

A proteogenomic study in a small Scottish cohort identifies 505 genetic loci regulating plasma protein levels. It then links 14 proteins to disease risk, such as B3GAT1 with prostate cancer and LTK with type 2 diabetes

Abstract. To complete the genome-to-phenome map, transcriptome-wide association studies (TWAS) are performed to correlate genetically predicted gene expres

Scientific Reports - Identification and replication of sex-dimorphic protein quantitative trait loci across multiple ancestries and their associations with diseases

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 a...

A single MRI scan can provide reliable estimates of human lifetime brain atrophy, helping overcome lifespan data collection challenges. This may enhance genetic studies of late-life neurodegeneration ...

While there is good reason to believe EF research has been subject to genetic confounding, the specialized samples required to test for it can be impractical for researchers. We tested one proposed a...