Editorial: High-Throughput Sequencing-Based Investigation of Chronic Disease Markers and Mechanisms - Volume II

Hua Li¹Guoshuai Cai²Wen-Lian Chen³Xiaodong Zhao¹Yuriy L Orlov^4*

• ¹Shanghai Jiao Tong University, Shanghai, China
• ²University of Florida, Gainesville, United States
• ³Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ⁴Sechenov University, Moscow, Russia

Second generation (short-read, massively parallel) sequencing and third generation (long-read, single-molecule) sequencing technologies have matured rapidly, irreversibly altering how we interrogate human health and disease. A series of Frontiers in genetics Research Topics highlight this area (Orlov and Baranova, 2020; Anashkina et al., 2023). Building on the inaugural 2022 collection (Orlov et al., 2022), this second volume of “High-throughput Sequencing-based Investigation of Chronic Disease Markers and Mechanisms” (https://www.frontiersin.org/research-topics/53085/high-throughput-sequencing-based-investigation-of-chronic-disease-markers-and-mechanisms-volume-ii/articles) again harnesses deep sequencing technologies, sophisticated analytics, and cross scale validation to illuminate biomarkers and mechanisms that underlie a spectrum of chronic conditions - from inflammatory bowel disease to neuromuscular degeneration and pandemic infection. Together, the nine articles accepted in this Research Topic exemplify three converging trends: (i) omics integration across genome, epigenome, transcriptome and proteome; (ii) fast sequencing applications that translate into clinically actionable diagnostics; and (iii) mechanistic dissection of how candidate markers shape or signal pathophysiology.Gastrointestinal and metabolic diseases: decoding tissue specific signaturesCrohn’s disease remains clinically heterogeneous and therapeutically stubborn. Yang et al. performed bulk RNA-seq of intact bowel walls and revealed two strikingly up regulated transcripts, PDE1A [OMIM 171890] and SEMA3D [OMIM 609907], associated with smooth muscle cell apoptosis and autonomic dysregulation, respectively, providing a plausible axis for the distinctive neuromuscular complications of this disease.Turning to metabolic syndromes, Yao et al. mined public expression datasets, intersected them with ER stress gene sets, and narrowed 49 differentially expressed genes down to three diagnostic markers - CLGN [OMIM 601858], ILF2 [OMIM 603181], IMPA1 [OMIM 602064] - that were subsequently validated in mouse models and patient sera. The study underscores how in silico LASSO feature selection, when wedded to wet lab confirmation, can yield serum accessible biomarkers for type 2 diabetes mellitus.Oncology: multi omics and precise mutation discoveryTwo cancer focused articles showcase complementary high throughput strategies. Wang et al. isolated a circulating bio active peptide (YG 22) generated when adjuvant chemotherapy was combined with the traditional Chinese Jianpi formula; multi layer omics (transcriptome, metabolome, chromatin accessibility, H3K4me3 ChIP seq, NF κB ChIP seq) revealed that YG 22 reprograms epigenetic states and lysosomal pathways to suppress colorectal cancer cell viability. This study demonstrates the added value of peptide therapeutics derived from phytochemical regimens.At the single gene end of the spectrum, Zhang et al. applied targeted next generation sequencing to four myeloproliferative neoplasm cases that were “triple negative” by canonical testing, unmasking novel driver lesions and arguing for routine targeted sequencing in ambiguous myeloid diagnoses.Neuromuscular and neurodevelopmental research: from modifiers to toxicantsBy pairing bulk and single nucleus RNA-seq in healthy vastus lateralis versus tibialis anterior, Nieves Rodriguez et al. identified >3,400 genes - including those related to calcium release and collagen-containing extracellular matrix transcripts - that may dictate differential vulnerability of muscles in Duchenne muscular dystrophy, supplying an invaluable reference for stratified gene therapy design.Li et al. then leveraged whole exome sequencing of 113 patients with intellectual disability to uncover a novel de novo SYNGAP1 [OMIM 603384] splice site variant (c.664 2A>G). Minigene assays confirmed exon 7 skipping, emphasizing that modest intronic changes that are detectable by high depth sequencing can produce profound neurodevelopmental phenotypes.Complementing human genetics, Lyu et al. used comparative transcriptomics in zebrafish embryos to show that extremely small iron oxide nanoparticles (ESIONPs) perturb neuro‐muscular development and trigger ferroptosis. Weighted gene co expression network analysis (WGCNA) pinpointed stage-specific hub genes (highly connected nodes in the network), such as neurodevelopmental regulators and oxidative-stress mediators, whose dysregulation, together with elevated apoptosis markers, signals potential health risks of nanoparticle biomedical imaging.Infection and immunity: from viral alternative polyadenylation to host GWAS lociThe interface between host gene regulation and pathogen assault is another recurring theme. Tan et al. profiled grass carp cells during early grass carp reovirus infection and uncovered extensive shifts in alternative polyadenylation (APA) despite stable DNA methylation patterns, particularly affecting cytoskeletal and microtubule genes - an underappreciated layer of post transcriptional control in fish viral pathogenesis.On the human front, Loktionov et al. genotyped 10 GWAS significant loci in nearly 800 Russians and confirmed that the SLC6A20-LZTFL1 rs17713054 risk allele magnifies severe COVID 19 particularly in obese, low activity, or low dietary fruit subgroups, with concordant effects on thrombodynamics. Network analyses further highlighted interactive SNP constellations linking coagulation and immune genes. Such population targeted validation of multi locus risk underlines the translational scope of sequencing even after the acute pandemic phase.Methodological cross talk and shared biological threadsThe field of gene expression regulation including chronic disease markers has been covered in a Frontiers in Genetics Research Topic (Anashkina et al., 2023) based on omics data integration. Sequencing technologies give background for gene expression regulation studies at genome scale (Anashkina et al., 2021; Orlov et al., 2023).Across the current collection, several common methodological themes emerge. First, multi omics integration - whether combining peptidomics with chromatin readouts, or pairing methylome and APA maps - magnifies biological signals and reveals underlying mechanisms. Second, targeted or panel based sequencing continues to sharpen genetic diagnosis where standard assays falter. Third, bioinformatics methods (WGCNA, LASSO, SNP SNP interaction models) distill high dimensional data into clinically tractable results.Biologically, six recurrent pathways unite otherwise disparate studies: ER stress, calcium homeostasis, apoptotic regulation, extracellular matrix remodeling, innate immune activation, and ferroptosis. This convergence reinforces the idea that chronic diseases, despite tissue specificity, share certain conserved response architectures that are captured by high throughput sequencing.OutlookTogether, the nine articles in this volume broaden the map of chronic-disease markers, bring sequencing into daily clinical applications, and deepen our grasp of how genetic and epigenetic patterns drive long-term illness. Looking forward to this topic development, we may anticipate:•Single cell and spatial omics will dissect cell type-restricted marker function within complex tissues such as muscle, gut, and tumor microenvironments.•Long read platforms will resolve structural and splice isoform diversity.•Prospective, multi center cohorts integrating more data (e.g., diet, exercise) with host genetics, as illustrated in the COVID 19 study, will refine gene environment risk algorithms.•In addition, from the current perspective, AI applications will get a more important role in complex disease studies (Koshechkin et al., 2022; Zhang et al., 2024).