Cell genomics最新文献

Yersinia pestis is the bacterium responsible for plague, one of the deadliest diseases in history. To discover human genetic determinants of Y. pestis infection, we utilized nearly 1,000 genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study. A nonsynonymous SNP, rs2282284 (N721S), in Fc receptor-like 3 (FCRL3) was associated with bacterial invasion of host cells (p = 9 × 10^-8). Overexpressed FCRL3 facilitated attachment and invasion of Y. pestis and colocalized with Y. pestis at attachment sites. These properties were variably conserved across the FCRL family, revealing an immunoglobulin-like domain and signaling motifs shared by FCRL3 and FCRL5 to be necessary for attachment and invasion. Direct binding to FCRL5 extracellular domain was confirmed, and B cells (the primary cells that express FCRLs) were preferentially invaded by Y. pestis. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.

Cell deconvolution estimates cell type proportions from bulk omics data, enabling insights into tissue microenvironments and disease. However, practical applications are often hindered by batch effects between bulk data and referenced single-cell data, a challenge that is frequently overlooked. To address this discrepancy, we developed OmicsTweezer, a distribution-independent cell deconvolution model. By integrating optimal transport with deep learning, OmicsTweezer aligns simulated and real data in a shared latent space, effectively mitigating data shifts and inter-omics distribution differences. OmicsTweezer is versatile, capable of deconvolving bulk RNA-seq, bulk proteomics, and spatial transcriptomics. Extensive evaluations on simulated and real-world datasets demonstrate its robustness and accuracy. Furthermore, applications in prostate and colon cancer showcase OmicsTweezer's ability to identify biologically meaningful cell types. As a unified deconvolution framework for multi-omics data, OmicsTweezer offers an efficient and powerful tool for studying disease microenvironments.

The soybean is a critical source of vegetable protein, but its proteome remains undercharacterized. Here, we quantify 12,855 proteins across 14 soybean organs using 4D data-independent acquisition mass spectrometry (4D-DIA-MS), creating the most extensive soybean proteome dataset to date. Organ-specific protein expression and co-expression analyses highlight functional specificity with significant differences in protein-transcript abundance across organs. We also map N⁶-methyladenosine (m⁶A) modifications, identifying their key role in post-transcriptional protein regulation. Integrative analysis of the proteome and m⁶A methylome identifies a novel regulator in m⁶A methylation. This comprehensive proteomic and m⁶A landscape advances our understanding of soybean biology and provides a valuable resource for crop improvement.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 10^-8) from a large-scale genome-wide association study (GWAS). Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.

The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.

Wild boars exhibit genetic and phenotypic diversity shaped by migrations and local adaptations. Their expansion across Eurasia, especially in Central Asia, remains underexplored. Here, we present newly sequenced whole-genome data of 47 wild boars from Eastern Asia, Central Asia, and Europe, combined with 49 existing genomes, creating a comprehensive dataset of 96 individuals. Our analyses show that Asian wild boars and Southeast Asian Suids split ∼3.6 million years ago (mya), with Central Asian and Southern Chinese ancestors diverging ∼1.8 mya. The split between Central Asian and European-Near East ancestors occurred ∼0.9 mya, followed by a European-Near East divergence ∼0.6 mya. We identify signatures of local adaptation in Central Asian populations, including two positively selected variants in LPIN1, associated with lipid metabolism, and a missense mutation in ALPK2, linked to meat traits. These findings provide insights into wild boar dispersal and adaptation and shed light on domestic pig breeding.

Epigenome-wide association studies (EWASs) are transforming our understanding of the interplay between epigenetics and complex human traits. We introduce the methylation screening array (MSA) to enable scalable and quantitative screening of trait-associated DNA cytosine modifications in large human populations. The MSA integrates EWASs and cell-type-linked methylation signatures, covering diverse traits and diseases. Using the MSA to profile the ternary-code DNA methylations-dissecting 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and unmodified cytosine-revealed a previously unappreciated role of 5hmC in mediating human trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5mCs in defining epigenetic cell identities. In-depth analyses highlighted the cell-type context of EWAS and genome-wide association study (GWAS) hits. Targeting aging, we uncovered shared and tissue-specific 5hmC aging dynamics and tissue-specific rates of mitotic hyper- and hypomethylation. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.

Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific expression/splicing quantitative trait loci (e/sQTLs) were detected pre- and post-intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with genome-wide association study (GWAS) identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

Young human de novo genes, recently emerging from non-coding regions, are expected to contribute to human-specific traits and diseases. However, systematic explorations of this connection have been lacking. Here, we report 37 recently originated de novo genes in humans, with their evolution and characteristics defined within an updated genomic context. The expression of these genes is significantly upregulated and temporospatially expanded in tumors, partially associated with extrachromosomal DNA amplification. Depletion of 57.1% of these genes suppresses tumor cell proliferation, underscoring their roles in tumorigenesis. As a proof of concept, we developed mRNA vaccines expressing ELFN1-AS1 and TYMSOS-young genes specifically expressed during early development but reactivated exclusively in tumors. In humanized mice, these vaccines triggered specific T cell activation and inhibited tumor growth. The antigens derived from these genes are immunogenic and capable of eliciting antigen-specific T cell activation in colorectal cancer patients. These findings underscore young human de novo genes as neoantigens in cancer immunotherapy.

The cell cycle is a fundamental process in eukaryotic biology and is accordingly controlled by a highly conserved core signaling cascade. However, whether recently evolved proteins also influence this process is unclear. Here, we systematically map the influence of evolutionarily recent transcription factors (TFs) on human cell cycle progression. We find that the genomic targets of select young TFs, many of which belong to the rapidly evolving Krüppel-associated box zinc-finger protein (KZFP) family, exhibit synchronized cell cycle expression. Systematic perturbation studies reveal that silencing recent TFs disrupts normal cell cycle progression, which we experimentally confirm for ZNF519, a simian-restricted KZFP. Furthermore, we show that the therian-specific KZFP ZNF274 sets the cell cycle expression and replication timing of hundreds of clustered genes, many of which are KZFPs. These findings highlight an underappreciated level of lineage specificity in cell cycle regulation.