Technical Report
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Open Access
Featured
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Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification
BEAN is a Bayesian approach for analyzing base editing screens with improved effect size quantification and variant classification. Applied to low-density lipoprotein (LDL)-associated common variants and saturation base editing of LDLR, BEAN identifies new LDL uptake genes and offers insights into variant structure–pathogenicity mechanisms.
- Jayoung Ryu
- , Sam Barkal
- & Luca Pinello
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Article |
A spatiotemporal atlas of cholestatic injury and repair in mice
A comprehensive time series characterization of a mouse model of cholestatic liver injury with spatial enhanced resolution omics sequencing and single-cell RNA sequencing identifies zonal responses to insult, such as cholangiocyte signaling recruiting lipid-associated macrophages.
- Baihua Wu
- , Xinyi Shentu
- & Lijian Hui
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Article
| Open Access
Protein-altering variants at copy number-variable regions influence diverse human phenotypes
Incorporating protein-altering copy number variants ascertained from UK Biobank whole-exome sequencing data into analyses of rare predicted loss-of-function variants identifies complex trait associations not detectable using standard analysis methods.
- Margaux L. A. Hujoel
- , Robert E. Handsaker
- & Po-Ru Loh
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Article
| Open Access
A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast
Single-cell RNA sequencing analysis of over 800,000 human adult breast cells from 55 female donors identifies 41 cell subtypes and highlights age- and parity-dependent effects. Samples from healthy women with germline mutations in BRCA1 or BRCA2 showed signs of T cell exhaustion.
- Austin D. Reed
- , Sara Pensa
- & Walid T. Khaled
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Article
| Open Access
BANKSY unifies cell typing and tissue domain segmentation for scalable spatial omics data analysis
BANKSY is an algorithm with R and Python implementations that identifies both cell types and tissue domains from spatially resolved omics data by incorporating spatial kernels capturing microenvironmental information. It is applicable to a range of technologies and is scalable to millions of cells.
- Vipul Singhal
- , Nigel Chou
- & Shyam Prabhakar
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Technical Report
| Open Access
Accurate and sensitive mutational signature analysis with MuSiCal
MuSiCal is a mutational signature analysis tool combining minimum-volume nonnegative matrix factorization with other algorithmic innovations. Applied to PCAWG data, MuSiCal gives more accurate results, including resolving ambiguous flat signatures.
- Hu Jin
- , Doga C. Gulhan
- & Peter J. Park
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Article
| Open Access
Large-scale gene expression alterations introduced by structural variation drive morphotype diversification in Brassica oleracea
De novo genome assemblies of 22 Brassica oleracea accessions and pan-genome analyses highlight the effects of structural variations on gene expression and their contributions to morphotype diversification.
- Xing Li
- , Yong Wang
- & Feng Cheng
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Technical Report
| Open Access
Adjusting for genetic confounders in transcriptome-wide association studies improves discovery of risk genes of complex traits
Causal-TWAS (cTWAS) is a statistical framework that adjusts for genetic confounders in transcriptome-wide association studies. Application of cTWAS on common traits leads to reliable detection of candidate causal genes.
- Siming Zhao
- , Wesley Crouse
- & Xin He
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Technical Report
| Open Access
Public platform with 39,472 exome control samples enables association studies without genotype sharing
A new method allows selection of matched controls from an external pool of samples without genotype sharing. This method has been implemented in an online repository containing 39,472 exome sequencing controls that can be used for association analyses.
- Mykyta Artomov
- , Alexander A. Loboda
- & Mark J. Daly
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Article
| Open Access
Computational prediction and experimental validation identify functionally conserved lncRNAs from zebrafish to human
A new computational method coupled with a CRISPR–Cas12a screen identifies human long noncoding RNAs (lncRNAs) that lead to cell proliferation defects, which can be rescued by zebrafish homologs. Knockdown of four zebrafish lncRNAs that perturb embryonic development can be rescued by human homologs.
- Wenze Huang
- , Tuanlin Xiong
- & Qiangfeng Cliff Zhang
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Editorial |
A call for spatial omics submissions
The field of spatial omics is developing rapidly, with a potentially transformative effect across many areas of biology. Nature Genetics invites authors to submit papers that use these techniques to answer questions of broad interest to researchers working in genetics and genomics.
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News & Views |
Cell perturbation and lasers illuminate the genetics of latent blood cell traits
A new study combining experimental treatments of human blood cells from thousands of individuals with flow-cytometry-based phenotyping and then genome-wide association analyses identifies genetic loci associated with non-resting cell states. Integrating the results with disease association signals yields insights into the underlying biology.
- Andrew D. Johnson
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Article
| Open Access
Accurate detection of identity-by-descent segments in human ancient DNA
ancIBD identifies identity-by-descent regions in ancient DNA using a hidden Markov model optimized for these low-coverage data. Analysis of 4,248 individuals demonstrates that ancIBD can identify up to sixth-degree relatives and provides genealogical insights into ancient populations.
- Harald Ringbauer
- , Yilei Huang
- & David Reich
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Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases
Genome-wide analyses of blood cell phenotypes derived from perturbations coupled with flow cytometry-based functional readouts identify loci associated with latent cellular traits, yielding insights into biological mechanisms underlying common diseases.
- Max Homilius
- , Wandi Zhu
- & Rahul C. Deo
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Research Briefing |
A biology-aware mutation rate model for human germline
We present a model to predict the chance of each possible de novo mutation in the human genome informed by recent insights into determinants of mutagenesis. Predictions were applied to refine demographic models, identify constrained genes, and uncover mutagenic effects of polymerase III transcription and transcription factor binding in testis.
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Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes
Genome-wide association analyses of magnetic resonance imaging data describe the genetic architecture of 13 cortical phenotypes at both global and regional levels, implicating neurodevelopmental and constrained genes.
- Varun Warrier
- , Eva-Maria Stauffer
- & Richard A. I. Bethlehem
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Article
| Open Access
Genome-wide prediction of disease variant effects with a deep protein language model
A modified framework leveraging a protein language model (ESM1b) is used to predict all possible 450 million missense variant effects in the human genome and shows potential for generalizing to more complex genetic variations such as indels and stop-gains.
- Nadav Brandes
- , Grant Goldman
- & Vasilis Ntranos
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SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response
SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.
- Philip Bland
- , Harry Saville
- & Rachael Natrajan
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News & Views |
RNA Pol II enters the ring of cohesin-mediated loop extrusion
The three-dimensional organization of mammalian chromosomes can regulate transcription. Whether transcription itself influences genome structure has remained a source of debate. Using sensitive genome-wide readouts, two recent studies describe the involvement of transcription on genome architecture by different mechanisms.
- Daan Noordermeer
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Article |
Potent and uniform fetal hemoglobin induction via base editing
A comparison of fetal hemoglobin gene editing strategies using human sickle cell disease donor cells and in vivo transplantation finds that adenine base editing of the –175A>G site in the γ-globin gene promoters results in durable and potent expression.
- Thiyagaraj Mayuranathan
- , Gregory A. Newby
- & Jonathan S. Yen
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Article |
G4access identifies G-quadruplexes and their associations with open chromatin and imprinting control regions
G4access is a nuclease-based method for identifying DNA G-quadruplex forming regions genome-wide in open chromatin using sequencing. Application across a range of cell types and species highlights associations of G-quadruplexes with various epigenetic and regulatory features.
- Cyril Esnault
- , Talha Magat
- & Jean-Christophe Andrau
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Technical Report |
Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments
Region Capture Micro-C (RCMC) combines MNase-based 3C with a tiling region-capture method. Profiling mouse embryonic stem cells with RCMC identifies nested microcompartments, which connect enhancers and promoters.
- Viraat Y. Goel
- , Miles K. Huseyin
- & Anders S. Hansen
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Correspondence |
Annotating and prioritizing human non-coding variants with RegulomeDB v.2
- Shengcheng Dong
- , Nanxiang Zhao
- & Benjamin C. Hitz
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| Open Access
Precise modulation of transcription factor levels identifies features underlying dosage sensitivity
SOX9 titration in neural crest cells identifies regulatory elements and genes with sensitive or buffered responses. Sensitive genes are enriched for craniofacial disorder genes phenocopying SOX9, suggesting differential sensitivity contributes to phenotypic specificity.
- Sahin Naqvi
- , Seungsoo Kim
- & Joanna Wysocka
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Article |
Thymidine nucleotide metabolism controls human telomere length
Genome-wide CRISPR screening identifies thymidine nucleotide metabolism as a key regulator of human telomere length. Thymidine supplementation promotes telomere elongation in cells derived from patients with telomere biology disorders.
- William Mannherz
- & Suneet Agarwal
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Genome-wide RNA polymerase stalling shapes the transcriptome during aging
In aging mouse livers, 40% of elongating RNA polymerases are stalled, biasing transcriptional output dependent on gene length. This transcriptional stress appears to be caused by endogenous DNA damage.
- Akos Gyenis
- , Jiang Chang
- & Joris Pothof
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News & Views |
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.
- Krishanu Saha
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Technical Report
| Open Access
Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis
Sort-assisted single-cell chromatin immunocleavage (sortChIC) combines single-cell histone modification profiling with fluorescence-activated cell sorting (FACS), enabling the study of rare cell populations. H3K4me1/H3K4me3, H3K9me3 and H3K27me3 profiling of blood suggest a model of lineage-shared repressive and cell type-specific active chromatin.
- Peter Zeller
- , Jake Yeung
- & Alexander van Oudenaarden
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