Life Identification Number (LIN) codes for the genomic taxonomy of Corynebacterium diphtheriae strainsDelgado-Blas, Jose F.; Rethoret-Pasty, Martin; Brisse, Sylvain
doi: 10.1186/s13073-025-01579-6pmid: 41353550
BackgroundCorynebacterium diphtheriae, the causative agent of diphtheria, remains a public health concern, especially in regions with low vaccination coverage. While advances in genomic typing, such as core-genome Multi-Locus Sequence Typing (cgMLST), have improved our ability for strain identification, a standardized and stable genomic taxonomy is still lacking. This study aimed to establish a consistent taxonomic classification and nomenclature for C. diphtheriae strains using cgMLST-based Life Identification Number (LIN) codes.MethodsComparing 1,665 genomes from C. diphtheriae and closely related species C. belfantii and C. rouxii, we observed population-level genetic discontinuities in cgMLST profiles dissimilarities, and established hierarchical taxonomic levels based on optimal allelic difference thresholds. Ten-level LIN codes were defined, encompassing broad population structure subdivisions and fine-scale epidemiological levels. The LIN code system was implemented into the BIGSdb-Pasteur platform, and nicknames derived from the 7-loci MLST sequence types were given to sublineages and clonal groups.ResultscgMLST genetic thresholds were first defined at species and lineage levels (minimum of 1,240 and 1,035 allelic differences, respectively). Sublineages (SL), clonal groups (ClG), and genetic clusters (GC) were next defined with progressively finer allelic mismatch thresholds (500, 55, and 25 differences, respectively). A broad population diversity of C. diphtheriae was uncovered, with the distinction of > 400 SLs and > 1,000 GCs. For epidemiological purposes, five shallow-level thresholds (8, 4, 2,1, and 0 allelic mismatches) were defined, completing the 10-level LIN code taxonomy. We illustrate LIN codes applicability to investigate the genetic diversity and transmission chains of relevant clusters, such as SL8 (the 1990s ex-USSR outbreak) or SL384 (involved in outbreaks in Yemen and Europe).ConclusionsThe cgMLST-based LIN code system provides a stable genomic taxonomy for strains of C. diphtheriae, C. rouxii and C. belfantii. By defining ten hierarchical levels of resolution, this system effectively captures its phylogenetic diversity, facilitating population biology research and epidemiological surveillance. The public availability of this system in the BIGSdb-Pasteur platform provides a standardized framework for diphtheria genomic epidemiology with potential to harmonize global surveillance of diphtheria resurgence.
Collateral metabolic vulnerabilities unveiled by loss of isozyme diversity in breast cancerDing, Rui; Yu, Tian-Jian; Jiang, Yi-Zhou; Xiao, Yi; Shao, Zhi-Ming
doi: 10.1186/s13073-025-01573-ypmid: 41382155
BackgroundLoss of isozyme diversity (LID) refers to the selective dependency on a single isozyme following the functional collapse of its redundant counterparts, uncovering a metabolic vulnerability. This metabolic liability establishes LID as a novel framework for precision targeting strategy in cancer therapy.MethodsWe integrated a large-scale breast cancer multi-omics cohort to systematically delineate isozyme expression patterns and identify therapeutically promising LID targets across intrinsic molecular subtypes. Genomic and epigenetic data were employed to decipher the underlying causes of LID. Subsequent experiments were conducted to validate the collateral metabolic vulnerabilities arising from identified LID targets and investigate the associated mechanisms.ResultsOur analysis delineated the isozyme utilization patterns for metabolic reactions in breast cancer, which revealed widespread and significant LID phenomena. We further decoded the enrichment characteristics of these LID reactions and identified a set of potential clinically relevant LID targets across different subtypes. Further investigation revealed that copy number loss and epigenetic silencing predominantly drive these LIDs, as exemplified by luminal subtype-specific N-myristoyltransferase 2 (NMT2) deficiency caused by hypermethylation. Mechanistic studies demonstrated that NMT2 deficiency confers synthetic lethality with NMT1 inhibition, potentially through impaired myristoylation of the oncogenic effector FMR1 autosomal homolog 2 (FXR2). These findings underscored the potential of NMT inhibitors as viable therapeutic strategies for NMT2-deficient tumors.ConclusionsIn conclusion, this study constructed a comprehensive LID landscape across all breast cancer subtypes, advancing precision oncology through innovative metabolic targeting approaches.
Delineation and monitoring of the T cell repertoire of adoptive cell transfer product during the treatment of advanced melanomaKerr, Cameron; Soleimani, Shirin; Mulder, David T.; Nabbi, Arash; Gray, Diana; Pedersen, Stephanie; Sotov, Valentin; Sudhaman, Sumedha; Nguyen, Linh; Hirano, Naoto; Ohashi, Pamela S.; Butler, Marcus O.; Pugh, Trevor J.
doi: 10.1186/s13073-025-01583-wpmid: 41402893
BackgroundAdoptive cell transfer (ACT) of tumour-infiltrating lymphocytes (TIL) is an investigational treatment for solid tumours, with preliminary results showing objective clinical responses in some metastatic melanoma patients. The ability to sequence and track the T cell repertoire throughout ACT of TILs provides a method to identify T cell repertoire features associated with patients’ benefit from ACT. Identification of response biomarkers for patients receiving ACT of TILs has been limited. Conflicting evidence is observed in biomarkers such as the number of TILs in the infusion product, with some studies suggesting a relationship with response and others not. Meanwhile, certain potential biomarkers, such as the diversity of the post-infusion peripheral repertoire, have not yet been studied.MethodsIn this study, we sought to determine 1) the efficacy of using CapTCR-seq to track TILs in serial blood draws over the course of ACT immunotherapy 2) whether peripheral T cell repertoire statistics are associated with ACT response. In this study, 9 patients with cutaneous (n = 7) or mucosal (n = 2) melanoma received TIL ACT after chemotherapeutic depletion. Hybrid-capture CapTCR-seq was conducted on pre-/post-transfer peripheral blood mononuclear cells (PBMC) and cell-free DNA.ResultsComparison between PBMC DNA, PBMC RNA, and circulating free DNA (cfDNA) repertoires demonstrated an increased presence of shared T cell clonotypes post-infusion when compared with baseline samples. Higher abundance of TIL clonotypes in the PBMC baseline and post-infusion DNA T cell repertoires and the presence of shared DNA T cell clonotypes between timepoints was seen in responders when compared with non-responders according to RECIST criteria.ConclusionsThese results demonstrate effective tracking methodologies and suggest a predictive role for baseline repertoire statistics in response to the ACT of TILs.
Universal noninvasive prenatal diagnosis for monogenic disorders using cell-free plasma DNAZhang, Lanlan; Hua, Renyi; Wu, Yiming; Han, Xu; Wu, Yi; Fei, Hongjun; Zhao, Xinrong; Chang, Chunxin; Gao, Li; Chen, Yiyao; Xu, Hui; Li, Niu; Yang, Jingmin; Wang, Yanlin; Wang, Jian; Li, Shuyuan
doi: 10.1186/s13073-025-01588-5pmid: 41345873
BackgroundNoninvasive prenatal screening for aneuploidies and microdeletion/microduplication syndromes (MMS) has gained widespread clinical application. However, the development of noninvasive prenatal diagnosis for monogenic disorders (NIPT-M) has progressed slower. Existing NIPT-M approaches often require specialized designs, are limited to a narrow range of genes, or are expensive and impractical for clinical implementation.MethodsWe present HaploNIPD, a universal haplotype-based approach for NIPT-M, utilizing a targeted capture panel that includes 120,000 selected single-nucleotide polymorphisms. Maternal cell-free DNA (cfDNA) and genomic DNA (gDNA) from family members were targeted captured and massively parallel sequenced. Parental haplotypes were phased, and fetal genome-wide haplotypes and copy number profiles were determined. The clinical efficacy of HaploNIPD was assessed in 70 families with monogenic disorders and 152 samples with known fetal karyotypes.ResultsFetal haplotypes were accurately determined in 69 of 70 families (98.57%), with perfect concordance to invasive prenatal diagnosis results. One case was classified as “no call” due to a recombination event within the target region. Compared to fetal haplotypes derived from chorionic villus or amniotic fluid, the deduced fetal haplotypes in maternal plasma by HaploNIPD had an average genome-wide accuracy of 99.74% and 98.23% for paternal and maternal inheritance, respectively. All common aneuploidies (trisomies 13, 18 and 21, monosomy X, XXX, XXY, and XYY) and MMS were accurately identified.ConclusionsOur findings demonstrate the potential of HaploNIPD as a robust and versatile platform for NIPT-M capable of noninvasive genome-wide fetal haplotyping and simultaneous detection of aneuploidies and MMS, offering a scalable solution for comprehensive prenatal genetic diagnosis.
NeoGuider: neoepitope prediction using advanced feature engineeringZhao, Xiaofei; Wei, Lei; Xie, Zhen; Zhang, Xuegong
doi: 10.1186/s13073-025-01592-9pmid: 41437280
The design of neoepitope-based cancer immunotherapy requires predicting the immunogenicity of each patient-specific neoepitope candidate. We designed NeoGuider, a machine-learning model to address nonlinearity and class imbalance in such prediction. Central to NeoGuider is a supervised feature-transformation approach, which estimates odds using our custom kernel density estimation followed by centered isotonic regression. We implemented NeoGuider as a bioinformatics pipeline, which detects neoepitope candidates from sequencing data and prioritizes such candidates by predicted immunogenicity. Benchmarking on 7 cohorts, 113 patients, and 635 immunogenic candidates showed that NeoGuider outperformed existing methods in neoepitope prediction. NeoGuider is open-source at https://github.com/XuegongLab/neoguider.
Transcriptome-wide association study revealed novel causal genes of renal-biopsy proven diabetic nephropathyMa, Zijian; Hou, Qing; Yang, Ruixiang; Shi, Jinsong; Kan, Shuyan; Zheng, Chunxia; Zhu, Xiaodong; Liu, Zhihong; Jiang, Song
doi: 10.1186/s13073-025-01590-xpmid: 41382137
BackgroundWhile genome-wide association studies (GWAS) have shown that genetic variants are linked to diabetic nephropathy (DN), the precise gene responsible for influencing risk remains largely unidentified, and the issue of missing heritability persists. This study seeks to identify new pathogenic genes using transcriptome-wide association study (TWAS) analysis in a cohort with renal biopsy-proven DN.MethodsA TWAS was conducted to investigate potential DN risk genes whose expression mediates the genotype effect on the phenotype. Gene expression levels were entered into our existing DN GWAS cohort including 2,279 renal biopsy-proven DN and 3,762 type 2 diabetes more than 10 years without any microvascular complications by using GEMMA software. The TWAS P-values were calculated using logistic regression models. Public data from ENCODE and GEO were obtained to annotate the function of genes and variants. Pathway enrichment analysis was performed with co-expressed genes. The role of GYS1 in DN was determined using Gys1-antisense oligonucleotide (ASO) in db/db mice.ResultsThe expression levels of 4,703 cis-heritable genes were analyzed from our renal biopsy-proven DN GWAS dataset. The TWAS results identified 17 genes (9 glomerular-only, 5 tubulointerstitial-only, and 3 shared) that were statistically significantly associated with DN susceptibility in both glomerular and tubulointerstitial regions. Notably, GYS1 and FOXJ2 emerged as novel findings. Furthermore, a gene prioritization strategy was developed, involving gene differential expression validation, clinical and pathological indicator correlation, and functional variant exploration. This approach identified GYS1 as the top causal gene. Risk variants (rs116573491 and rs111518556) of GYS1 were both discovered to increase GYS1 expression in vitro. GYS1 was found to be enriched in glomerular mesangial cells and was elevated in DN compared to healthy controls. Additionally, the level of GYS1 in glomeruli was inversely correlated with estimated GFR (eGFR) and positively correlated with 24-h proteinuria in DN patients. Gys1-ASO therapy halted the progression and development of DKD in db/db mice by reducing Gys1 expression.ConclusionsThis biopsy-based TWAS identifies 17 DN susceptibility genes and prioritized GYS1 as a probable driver of DN, links genetic risk to mesangial dysfunction, and demonstrates that Gys1 suppression mitigates disease progression, supporting GYS1 as a therapeutic target.