Volume 55 Issue 1, January 2023
News & Views
5-hydroxymethylcytosine stabilizes transcription by preventing aberrant initiation in gene bodies
5-hydroxymethylcytosine (5hmC) accumulates in transcribed gene regions (called ‘gene bodies’) and near enhancers, but its biological role has remained mysterious. A new study demonstrates that 5hmC serves to counteract inappropriate, spurious intragenic transcription in airway smooth muscle cells and by doing so, this DNA base functions in the prevention of chronic inflammation in the lung and an asthma-like phenotype.
Identifying type 2 diabetes risk genes by β-cell CRISPR screening
A major challenge in human genetics is the prioritization of causal genes in common complex diseases. A genome-wide CRISPR screen for intracellular insulin content in a human β-cell line has now identified a new candidate gene for type 2 diabetes, demonstrating the utility of this screening approach in β-cells.
Accounting for diversity in the design of CRISPR-based therapeutic genome editing
CRISPR cell and gene therapy have been designed largely with respect to a single reference human genome. A new study reveals how human genetic diversity could lead to off-target effects and presents a new tool to identify these risks.
Diet modulates genetic effects on longevity
It is well known that dietary composition affects lifespan, but whether the effects of diet are mediated through interactions with genetics is unknown. By careful tracking of genome-wide allele frequency in Drosophila, we identify hundreds of loci that affect longevity only in the context of a high-sugar diet.
Spatial atlas reveals insight into lung immunity
The cell types of the lung enable gas exchange and protect against infection. Our spatial atlas of the human lung and airways revealed 11 new cell types and mapped their anatomical locations. In particular, we defined the gland-associated immune niche (GAIN), which is involved in fighting respiratory infections.
DNA methylation provides molecular links underlying complex traits
We profiled human DNA methylation for 987 GTEx samples across nine tissues and characterized how genetic regulation of the methylome, compared with the transcriptome, contributes to GWAS phenotypes. This resource contributes to our understanding of molecular regulatory mechanisms in human tissues and their effects on complex traits.
Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens
High-quality multimodal single-cell, bulk and spatial genomics data are prepared from low-input, frozen needle biopsy specimens collected during routine clinical procedures.
SARS-CoV-2 diagnostic testing rates determine the sensitivity of genomic surveillance programs
The PATAT model is used to simulate SARS-CoV-2 epidemics in low- and middle-income countries, finding that diagnostic testing rates and proportions of viruses sequenced underpin timely and accurate novel variant virus detection.
Human genetic diversity alters off-target outcomes of therapeutic gene editing
CRISPRme is an off-target nomination tool that accounts for human genetic diversity. Ancestry-dependent allele-specific off-target edits can occur with therapies currently in clinical trials, highlighting the importance of genetic variation-aware assessment.
Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases
Genome-wide association studies comprising 1,091 metabolites and 309 metabolite ratios in 8,299 individuals from the Canadian Longitudinal Study on Aging provide insights into the genetic architecture of metabolites and their role in human diseases.
A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk
A genome-wide CRISPR knockout screen in the human EndoC-βH1 pancreatic beta cell line identifies 580 regulators of intracellular insulin content. Loss of CALCOCO2 perturbs insulin granule homeostasis in pancreatic beta cells.
A spatially resolved atlas of the human lung characterizes a gland-associated immune niche
Multi-omics profiling of 45 human lung samples highlights 80 different cell types along the proximal to distal axis of the lung with certain cell types showing enrichment for disease-associated genes. An immune niche for IgA-expressing plasma cells within airway submucosal glands (SMG) is also identified.
SpiceMix enables integrative single-cell spatial modeling of cell identity
SpiceMix uses latent variable modeling to infer cell identities by jointly analyzing intrinsic and spatial factors, allowing the identification of spatially variable metagenes and refined cell subtypes.
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.
Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine
Smooth muscle cell-specific knockout of Tet3 in mice leads to loss of intragenic 5-hydroxymethylcytosine, accumulation of spurious transcripts and TLR7/8-mediated lung inflammation resembling asthma in human lung samples.
DNA methylation QTL mapping across diverse human tissues provides molecular links between genetic variation and complex traits
As part of the enhanced GTEx (eGTEx) project, 987 human samples from 9 tissue types and 424 donors are assayed using DNA methylation microarrays. Colocalization of GWAS variants, eQTLs and mQTLs shows diverse links between genetic variation, molecular phenotypes and complex traits.
Dietary stress remodels the genetic architecture of lifespan variation in outbred Drosophila
An analysis of the effects of dietary stress in outbred Drosophila shows that lifespan has a polygenic architecture and is subject to environmental influence, suggesting that this context dependency is important for complex trait variation and evolution.
Dynamics of DNA hydroxymethylation and methylation during mouse embryonic and germline development
DNA 5-hydroxymethylcytosine (5hmC) is mapped in mouse preimplantation embryos, postimplantation epiblasts, primordial germ cells (PGCs) and gametes. Nlrp14 maternal depletion perturbs DNA-replication-coupled passive demethylation and impairs 5hmC deposition.
A multi-omics integrative network map of maize
An integrative network map of maize (Zea mays L.) that contains genomic, transcriptomic, translatomic and proteomic networks illustrates the landscape of molecular interactions of different functional elements and potential pathway modules in maize.
Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies
MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.