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Polymorphisms in the non-coding genome affect genetic circuits and result in variable immune responses across individuals. Here we report a genetic circuit involving a long non-coding RNA (lncRNA) that spatially coordinates chromatin contacts to control pro- and anti-inflammatory gene expression and shape immune responses of healthy individuals to pathogens or vaccination.
EasySci, a scalable single-cell profiling technique, uncovered over 300 mammalian brain cell states, revealing molecular features and dynamics of rare cell states linked to aging and Alzheimer’s disease. This work offers insights into cell states that expand (rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia, and oligodendrocytes) or are depleted (neuronal progenitors, neuroblasts and committed oligodendrocyte precursors) during normal and pathological aging.
Combined analysis of genome-wide association studies and epigenetic data has identified certain immune cell types as drivers of autoimmune disease, but current methods have not been able to pinpoint key effector immune cell states. Using single-cell data from inflammatory tissues, we identified effector cell states embedded within inflammatory tissues — including T peripheral helper cells and tissue regulatory T cells — that capture disproportionate disease heritability.
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.
Whole-genome sequencing data of individuals from the UK Biobank and Iceland and a somatic mutation barcoding strategy enabled detection of clonal hematopoiesis at scale. This comprehensive study provides insights into the epidemiology, somatic and germline genetics, and disease associations of clonal hematopoiesis.
Previous studies reported an effect of N6-methyladenosine (m6A) of super-enhancer RNAs (seRNAs) on chromatin accessibility and gene transcription. We investigated seRNA m6A levels in pancreatic ductal adenocarcinoma (PDAC) and found that aberrantly increased m6A methylation promoted local chromatin accessibility, resulting in increased transcription of oncogenes acting in PDAC progression.
We present an analysis that shows that although nearly half of the human genome comprises repetitive sequences, recombination between homologous repeats has a minor role in cancer chromosomal evolution.
Whole-exome and genome sequencing in consanguineous families with unsolved lipodystrophy identified biallelic pathogenic loss-of-function variants in the phospholipase gene PLAAT3. Multi-omics and functional analyses in human and mouse PLAAT3-deficient adipose tissue and adipose stem cells revealed an adipocyte differentiation defect that is mediated by an altered gene network downstream of the adipogenesis master regulator PPARγ.
We developed a computational, age-dependent topic model to identify longitudinal comorbidity patterns from hospital diagnosis data. The inferred comorbidity patterns are robust across UK and US populations and identify disease subtypes with distinct genetic profiles.
Genome-wide association analyses of placental weight identify 40 association signals, partially overlapping with birth weight genetics. We find parent-of-origin effects and connections to placental development and morphology, and transport of amino acids and antibodies. Mendelian randomization reveals a fetal contribution to preeclampsia and implicates fetal insulin in the regulation of placental growth.
Polygenic risk scores (PRSs) are increasingly able to predict complex traits; however, they perform suboptimally in populations not of European ancestry. We present CT-SLEB, a powerful method that enables the calculation of PRSs from multi-ancestry samples and provides insights into the opportunities and challenges of enhancing polygenic risk prediction across populations of diverse ancestry.
Genetic studies have associated thousands of non-coding variants with Alzheimer’s disease (AD), yet the functions of these variants remain elusive. We conducted cell-type-specific genetic fine mapping of AD variants and performed extensive functional characterization to unravel the causal variants that contribute to transcriptional regulation and ADrelated phenotypes in microglia.
We re-sequenced and phenotyped 2,839 rice hybrid cultivars and 9,839 F2 individuals from elite hybrids. Based on the dataset, the genetic improvement during rice hybrid breeding was investigated, and the genetic basis underlying strong heterosis was quantitatively evaluated. Furthermore, a genomic selection model was constructed to optimize heterotic combinations.
Using data from the UK Biobank, we reveal the roles of selection and mutation in shaping the genetic diversity of mosaic chromosomal alterations in healthy blood.
Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.
Through whole-genome sequencing of single molecules of circulating cell-free DNA, we found that tumor-derived mutations in cancer genomes are associated with regions of late replication timing and other chromatin features. These genome-wide analyses identified altered regional mutation profiles in people with cancer that distinguished them from people without cancer and reflected tumor burden during therapy.
Matched single-cell transcriptomic and epigenomic profiles obtained from human scalp reveal gene regulatory maps of diverse cell types in the hair follicle niche. Integrating these data with existing genome-wide association studies enabled prioritization of cell types, genes, and causal variants implicated in the pathobiology of androgenetic alopecia, eczema, and other complex traits.
How the chromatin states of transposable elements (TEs) are controlled in development and disease is unclear. We present CARGO-BioID, a CRISPR-based proteomic approach to identify TE-associated proteins, and reveal an interplay between RNA N6-methyladenosine (m6A) and DNA methylation that is crucial for regulating TE activation and human embryonic stem cell (hESC) fate.
Cross-ancestry genome-wide association meta-analyses of neuroimaging genetics data from European and East Asian populations identified 339 genetic variant–hippocampal volumetric trait associations (23 new). Further cross-ancestry analyses revealed similar genetic effects on hippocampal volumetric traits between ancestries, with improved fine-mapping precision and predictive accuracy of polygenic scores in the under-represented East Asian population.
An extra copy of a chromosome region that includes four genes encoding interferon receptors contributes to immune dysregulation, heart malformations, developmental delays, cognitive deficits and craniofacial abnormalities in a mouse model of Down syndrome.
