Genomics, proteomics & bioinformatics最新文献

Human populations have substantial genetic diversity, but the extent of epigenetic diversity remains unclear, as population-specific DNA methylation (DNAm) has only been studied for ∼3.0% of CpGs. This study quantifies DNAm using whole-genome bisulfite sequencing (WGBS) and analyzes it alongside whole-genome genotype data to reveal a comprehensive picture of population-specific DNAm. Using a "co-methylated region" (CMR) approach, 36,657 CMRs were identified in 62 lymphoblastoid B cell line (LCL) WGBS samples, with validation in array data sets from 326 LCL samples. Between individuals of European and African ancestry, 101 CMRs exhibited population-specific DNAm patterns (Pop-CMRs), including 91 Pop-CMRs not found in previous investigations, which spanned genes (e.g., CCDC42, GYPE, MAP3K20, and OBI1) related to diseases (e.g., malaria infection and diabetes) with different prevalence and incidence rates between populations. Over half of the Pop-CMRs were asscoated with genetic variants, displaying population-specific allele frequencies and primarily mapping to genes involved in metabolic and infectious processes. Additionally, subsets of Pop-CMRs could be applicable in East Asian populations and peripheral blood-based tissues. This study provides insights into DNAm differences across the genome between populations and explores their associations with genetic variants and biological relevance, advancing our understanding of epigenetic roles in population specificity.

Neoantigens are classified into canonical and noncanonical types. Noncanonical neoantigens include those derived from noncoding regions, transposable elements (TE), and intron retention events, and they have recently gained considerable attention in cancer immunity. In this study, we focused on neoantigens presented by HLA class I molecules, which are central to CD8+ T cell-mediated immune responses. We curated 39,347 non-redundant neoantigen-HLA pairs from 14 immunopeptidomes studies, by analyzing unique features and differences across various sources of neoantigens. This knowledge enabled us to develop machine learning models for the prediction of different types of neoantigens. Our data and models are available at a public portal (https://ngdc.cncb.ac.cn/neoatlas) to facilitate broad access and future research. This resource offers advanced functionalities, including integration with epigenome browsers which allow easy navigation of epigenomic datasets to support and confirm the expression of neoantigens. We further demonstrate that combining our database with mass spectrometry analysis can identify noncanonical neoantigens. The resource we constructed holds significant value and promise for the development of neoantigen-based vaccines. All data, machine learning models, and analytical tools are freely available at the NeoAtlas-Tumor portal (https://ngdc.cncb.ac.cn/neoatlas).

We conducted a comprehensive genetic investigation of obesity in a cohort of 93,673 Korean individuals, categorized by body mass index and waist circumference using Korean-specific and international criteria. To explore the genetic architecture of obesity and its related comorbidities, we performed genome-wide association studies and constructed polygenic risk scores (PRSs) using both conventional single-trait and advanced multiple-trait models, including the PRSsum approach. Our analyses identified genome-wide significant loci and demonstrated higher heritability for general obesity than for abdominal obesity, and for moderate obesity than for severe obesity. East Asian populations showed stronger genetic correlations between abdominal obesity and obesity-related diseases. Both single-trait and multiple-trait PRSs stratified individuals by risk, with low PRS individuals exhibiting reduced risk for obesity, hypertension, and type 2 diabetes, while high PRS individuals displayed elevated risk, particularly under the multiple-trait model. Interaction and mediation analyses revealed distinct genetic pathways through which obesity contributes to disease development. Collectively, our findings revealed key loci and shared genetic mechanisms linking obesity and its comorbidities in the Korean population. These insights highlight the value of multiple-trait PRS models and underscore the importance of ancestry-specific genetic research for addressing the obesity epidemic.

The use of statins as the primary therapy for reducing low-density lipoprotein cholesterol has raised concerns regarding their potential side effects in increasing the risk of type 2 diabetes (T2D). However, the underlying mechanism remains largely unknown. In this study, we utilized multi-omics molecular signatures to unravel the etiology of statin-induced T2D. Through systematic screening of 102 gut microbial features, 40 blood metabolites, and 131 circulating proteins in East Asians and Europeans, we identified a set of blood metabolites and proteins potentially influenced by genetically proxied statin use. Notably, Mendelian randomization analyses provided evidence that elevated circulating levels of gastric inhibitory polypeptide (GIP) were associated with an increased risk of T2D. This association between genetically proxied statin use and GIP was consistently observed across East Asian and European populations, highlighting the pivotal role of GIP in modulating the risks of statin-induced T2D. Furthermore, this study establishes an extensive atlas of multi-omics molecular signatures associated with statin-induced T2D, offering valuable insights for prioritizing intervention targets.

The ultimate goal of a genome-wide association study (GWAS) is to translate its discoveries into clinical practice. To explore the clinical use of GWAS findings in the bone field, we conducted a GWAS of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 91 unique and independent loci were identified for 11 DXA-derived BMD traits and fractures, including five novel loci (harboring the genes ABCA1, CHSY1, CYP24A1, SWAP70, and PAX1) for six BMD traits. These loci exhibited evidence of association in both males and females, which could serve as independent replication. We demonstrated that each polygenic risk score (PRS) was independently associated with fracture risk. Although incorporating multiple PRSs (ie, metaPRS) with clinical risk factors from the Fracture Risk Assessment Tool exhibited the highest predictive performance, the improvement was modest in fracture prediction. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. Finally, by integrating gene expression and GWAS datasets, we prioritized genes (e.g., ESR1 and SREBF1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed a new genetic basis for BMD and its clinical relevance to fracture prediction. More importantly, it is suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implies the potential repurposing of drugs (e.g., the n-3 PUFA supplement) for the prevention of osteoporosis.

Tumor heterogeneity and the suppressive microenvironment are key challenges that limit the effectiveness of cancer treatment. In this study, we systematically elucidated the molecular characteristics and mechanisms underlying the suppressive immune microenvironment via a combination of single-cell RNA sequencing, spatial transcriptomics, and metabolomics for a series of human esophageal squamous cell carcinoma (ESCC) and matched nontumor tissues. We found that COL17A1+ epithelial cells presented greater malignancy, characterized by triglyceride (TG) and phosphocholine (PC) accumulation. We also identified a tumor-specific POSTN+ fibroblast subgroup. We found a unique epithelial-fibroblast niche with low infiltration of effector immune cells and substantial enrichment of lipids, composed of POSTN+ fibroblasts and COL17A1+ epithelial cells, where their crosstalk contributed to tumor progression. We confirmed that the INHBA/TP63 axis played a key role in mediating the regulation of COL17A1+ tumor cells by POSTN+ fibroblasts. Our findings provide new insights into the characteristics of the tumor microenvironment and the crosstalk between tumor and fibroblasts, offering valuable multiomics data resources for elucidating tumor progression mechanisms.

Subjective cognitive decline (SCD) is widely regarded as a potential preclinical stage of Alzheimer's disease (AD), yet its genetic basis remains poorly understood. To address this gap, we investigated genetic biomarkers associated with SCD using whole-genome sequencing (WGS) in 10,763 Chinese participants from the Healthy Zhejiang One Million People Cohort (HOPE Cohort). The discovery stage included 9284 samples, with 1479 samples used for validation. Using a two-stage design, we systematically investigated both common and rare variants associated with SCD. In rare variant analyses, we identified and replicated an association between the upstream region of SEPHS2 and SCD. SEPHS2 is involved in selenophosphate synthesis, and a Mendelian randomization analysis reveals that its expression levels in both blood and brain cerebellum are associated with AD. Additionally, we identified CLVS2, which encodes a protein primarily expressed in neuronal cells, as a potential regulator for SCD based on missense rare variants. Multi-omics evidence suggests that both SEPHS2 and CLVS2 may play roles in neurodegenerative diseases. For common variants, we validated 8 known loci related to cognitive decline, 3 of which originated from the only existing SCD genetic study conducted under a migraine background. Overall, our WGS-based study fills the gap in SCD research by providing vital genetic evidence from an East Asian population and offers insights into the pathogenic mechanisms of SCD.

Dysfunctional mitochondria are implicated in various diseases, but comprehensive characterization of mitochondrial DNA (mtDNA) in the Chinese population remains limited. Here, we conducted a systematic analysis of mtDNA from 7331 samples, comprising 4129 Chinese samples from the NyuWa cohort and 3202 samples from the 1000 Genomes Project (1KGP). We identified 7216 high-quality mtDNA variants, which classified 7266 samples into 22 macro-haplogroups, and detected 1466 nuclear mitochondrial DNA segments (NUMTs). Among these, 88 mtDNA variants and 642 NUMTs were specific to NyuWa. Genome-wide association analyses revealed significant correlations between 12 mtDNA variants and 199 nuclear DNA (nDNA) variants. Our findings demonstrated that all individuals in both NyuWa and 1KGP harbored common NUMTs, while one-fifth possessed ultra-rare NUMTs that tended to insert into nuclear gene regions. Notably, rare NUMTs in the NyuWa cohort showed significant enrichment of nuclear breakpoints in long interspersed nuclear elements (LINEs) compared to 1KGP. Overall, this study provides the first comprehensive profile of NUMTs in the Chinese population and establishes the most extensive resource of Chinese mtDNA variants and NUMTs to date based on high-depth whole-genome sequencing, providing valuable reference resources for genetic research on mtDNA-related diseases.

Although xenotransplantation has been revolutionized by the development of genome-edited pigs, it is still unknown whether these pigs and their offspring remain genomically stable. Here, we showed that GGTA1-knockout (GTKO) pigs accumulated an average of 1205 genome-wide genetic mutations, and their filial 1 (F1) offspring contained an average of 18 de novo mutations compared with wild-type controls and their parents. The majority of mutations were in regions annotated as intergenic without altering protein functions, and none were located at predicted off-target sites. RNA sequencing analysis and phenotypic observations indicated that the accumulated mutations may have only a limited influence on GTKO pigs, and most of the mutations in the GTKO pigs could be attributed to the electrotransfection of plasmids into cells. This is the first report demonstrating that genetic mutations in genome-edited pigs are inherited stably by the next generation, providing a reference for the safe application and a standard approach to breed genome-edited pigs for xenotransplantation.