Advanced genetics (Hoboken, N.J.)最新文献

Pseudogenes, as important products of genomic evolution, play unique regulatory roles in species adaptation. This review systematically summarizes the major types, functions, and regulatory mechanisms of metazoans pseudogenes, with a particular focus on their formation during primate evolution and the mechanisms underlying their retention in the human genome. Previous studies suggest that the loss of function in pseudogenes releases selective pressure, allowing them to evolve neutrally; furthermore, their latent functional or adaptive potential, such as reactivation, neofunctionalization, or evolutionary advantages conferred by gene silencing, further promotes their persistence. For instance, the integration of certain pseudogenes can introduce novel regulatory functions, while pseudogenization-induced gene inactivation may also provide selective benefits. Recent technological advances, including long-read sequencing, single-cell omics, and CRISPR-based functional interrogation, have greatly expanded our understanding of pseudogenes. We propose that pseudogene-mediated regulation plays a critical role in evolutionary processes and highlight their dynamic roles in both physiological and pathological contexts. We further discuss current research progress, limitations, and future directions, offering new perspectives for understanding genomic evolution and biomedical significance of pseudogenes.

Lung cancer is a major global malignancy with debated roles for cathepsin H (CTSH), a lysosomal protease, and underexplored regulation by metabolites. We analyzed lung cancer incidence and hyperglycemia-related mortality trends (1990-2021) using Joinpoint regression. Mendelian randomization (MR), meta-analysis, and two-step mediation examined CTSH and 233 metabolic traits. Single-cell RNA sequencing (scRNA-seq) and TCGA/HPA datasets validated CTSH expression. Lung cancer incidence decreased overall but rose in women, while fasting hyperglycemia-related mortality increased. CTSH elevated lung cancer and adenocarcinoma risks, with docosahexaenoic acid (22:6) and omega-3 fatty acids driving adenocarcinoma progression. A higher linoleic acid (18:2)/total fatty acid ratio reduced risk. scRNA-seq identified CTSH in myeloid cells, especially "mo-Mac," which promoted tumors. CTSH expression patterns were evaluated using TCGA and HPA data, revealing protein-level overexpression in tumors with some divergence from transcriptomic results. CTSH is linked to lung cancer, particularly adenocarcinoma, with modest effects mediated by metabolites like omega-3 fatty acids. Its prominent expression in macrophages suggests novel therapeutic targets. These findings, though consistent, require further validation due to modest effect sizes and dataset heterogeneity.

RNA modifications add a dynamic and versatile regulatory layer to gene expression, influencing RNA stability, splicing, translation, and cellular responses. Despite their importance, traditional detection methods-such as antibody-based enrichment, chemical labeling, or indirect sequencing approaches-often suffer from limited resolution, biases, and an inability to capture modifications in their native RNA context. Oxford Nanopore Technologies (ONT) direct RNA sequencing (DRS) overcomes many of these limitations by enabling amplification-free, single-molecule, and single-nucleotide detection of diverse RNA modifications directly from native RNA molecules. In this review, recent advances in applying ONT DRS to characterize modifications beyond the extensively studied N⁶-methyladenosine (m⁶A), including 2'-O-methylation (Nm), N¹-methyladenosine (m¹A), 5-methylcytosine (m⁵C), N⁴-acetylcytidine (ac⁴C), N⁷-methylguanosine (m⁷G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing are summarized. Computational frameworks and basecalling innovations are highlighted that improve modification calling, with particular emphasis on approaches that detect co-occurring modifications and reveal their potential regulatory cross-talk within individual transcripts. Finally, emerging applications across synthetic systems, non-model organisms, and disease contexts are discussed, and offer a forward-looking perspective on integrating nanopore-based epitranscriptomics with multi-omics platforms to achieve a deeper and more comprehensive understanding of RNA regulation.

Illuminating Life with Optogenetics

Beams of light orchestrate cellular control: light-gated ion channels shape ion flux; photoswitchable enzymes and receptors modulate signaling pathways; light-controlled protein interactions tune function; and light-regulated gene expression. In article 202500021, Xiao Duan, Mo Zhu, and Shiqiang Gao review two decades of optogenetics, from fundamental biology to early clinical translation. The cover image is based on the article Two Decades of Optogenetic Tools: A Retrospective and a Look Ahead by Xiao Duan et al., https://doi.org/10.1002/ggn2.202500021.

Stem cell lineage commitment is governed by intricate interactions between epigenetic mechanisms and 3D genome organization. Traditional linear epigenetics, including DNA methylation and histone modifications, cannot fully elucidate the complex spatiotemporal regulation of gene expression. Recent advances in spatial genomics technologies, such as high-throughput chromosome conformation capture (Hi-C), single-cell Hi-C, and Chromatin immunoprecipitation combined with Hi-C (Hi-ChIP), have provided unprecedented insights into genome architecture, revealing key structural units like chromatin compartments, topologically associating domains (TADs), and chromatin loops. These structures dynamically reorganize during differentiation, influencing transcriptional accessibility and lineage-specific gene activation. Additionally, liquid-liquid phase separation (LLPS)-mediated transcriptional condensates, such as transcription factories and super-enhancers, have emerged as essential regulators of gene expression patterns during cell fate transitions. The integration of multiomics data and artificial intelligence-driven predictive modeling further enhances the understanding of these regulatory networks. Despite ongoing technical challenges, including limitations in resolution, data complexity, and causal inference, recent advances continue to push the field forward. Engineered interventions such as CRISPR-based spatial genome editing and AI-powered computational platforms hold great promise for translating structural insights into targeted therapeutic strategies in regenerative medicine.

The genome is like a kaleidoscope through which researchers have obtained varied findings, including favored mutations, disease susceptibility sites, and drug-responsive sites. Whether these findings have inherent connections is a question deserving investigation. Favored mutations enable humans to adapt to changing environments and lifestyles; however, the adaptation may come with some costs. This is because a favored mutation can change the frequency of varied neutral nucleotides across a large genomic region, and a favored mutation may become disfavored as environments and lifestyles change further. These are the best-known classes of connections whose causes and consequences have been understood. However, many favored mutations remain unidentified. Using a deep learning network (DeepFavored) that integrates statistical tests and is trained on large datasets, favored mutations are recently identified in 17 human populations. The analyses of the results, in conjunction with genome-wide association study (GWAS) data, suggest that the connection between adaptive evolution, disease susceptibility, and drug responsiveness (referred to as a trade-off) is extensive and highly population-specific. The analyses, along with other emerging evidence, suggest that there are other types of connections. In this commentary, these issues are discussed from both retrospective and prospective views, including current challenges and future directions.

Tumor immunometabolism and epigenetic modifications are intricately linked in reshaping the tumor microenvironment, with their crosstalk offering novel insights into cancer biology. Nutrient deprivation and metabolic byproducts drive metabolic reprogramming in immune cells, where metabolites act as epigenetic modulators to regulate immune-related gene expression and influence immune cell activation, differentiation, and functional states. The cellular complexity, dynamic interactions, and spatiotemporal heterogeneity of the tumor microenvironment pose significant challenges to current studies. Emerging technologies such as single-cell sequencing, spatial omics, and artificial intelligence provide powerful tools to address these complexities. This perspective discusses the crosstalk between tumor immunometabolism and epigenetic modifications, while also exploring how the emerging technologies may advance mechanistic insights and therapeutic innovation in this field.

Bone morphogenetic proteins (BMPs) and the fibroblast growth factor receptor 1 (FGFR1) gene play essential roles in the development and maintenance of the skeletal system. Brachydactyly is a genetic condition characterized by shortened or missing bones in the hands and feet. Several types of brachydactyly have been identified, each associated with different genetic mutations. However, some cases do not fit into existing classifications, necessitating further genetic investigation. A 34-year-old female patient with an absent middle phalanx in the second digit of her left foot and her 13-year-old son, who presented with absent or malformed middle and distal phalanx in all ten toes, are evaluated. Whole Genome Sequencing (WGS) analysis identifies a missense variant (c.1073A >T; p.K358M) in the BMP8A gene and a novel missense variant (c.1787C >T, p.Ser596Phe) in the FGFR1 gene. Functional protein association network analysis demonstrates a strong association of BMP8A and FGFR1 with other brachydactyly disease-causing genes. Given that these mutations have not been previously linked to any recognized brachydactyly subtype, they likely define a distinct genetic condition. The findings suggest a novel form of brachydactyly, which naming is proposed as brachydactyly type AB.

Over the past two decades, optogenetics has evolved from a conceptual framework into a powerful and versatile technology for controlling cellular processes with light. Rooted in the discovery and characterization of natural photoreceptors, the field has advanced through the development of genetically encoded, light-sensitive proteins that enable precise spatiotemporal control of ion flux, intracellular signaling, gene expression, and protein interactions. This review traces key milestones in the emergence of optogenetics and highlights the development of major optogenetic tools. From the perspective of genetic tool innovation, the focus is on how these tools have been engineered and optimized for novel or enhanced functions, altered spectral properties, improved light sensitivity, subcellular targeting, and beyond. Their broadening applications are also explored across neuroscience, cardiovascular biology, hematology, plant sciences, and other emerging fields. In addition, current trends such as all-optical approaches, multiplexed control, and clinical translation, particularly in vision restoration are discussed. Finally, ongoing challenges are addressed and outline future directions in optogenetic tool development and in vivo applications, positioning optogenetics as a transformative platform for basic research and therapeutic advancement.