Journal of Genetics and Genomics最新文献

Down syndrome (DS) is caused by an extra copy of chromosome 21 (Hsa21). Children with DS have an increased frequency of respiratory tract infections, impaired alveolar and vascular development, and pulmonary hypertension. How trisomy 21 causes lung diseases remains poorly understood. In this study, we use the Dp16 mouse model, which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16, to explore the gene dosage effects on DS-related lung diseases. The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes. Single-cell RNA sequencing (scRNA-seq) analysis highlights increased APP-related interactions among male Dp16 lung cells. Specifically, altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells. Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested. Moreover, scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells, which is validated by tissue immunofluorescence assessment. Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice. Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice, confirming the reproducibility of the results. Collectively, our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.

Flowering time is a critical agronomic trait with a profound effect on the productivity and adaptability of rapeseed (Brassica napus L.). Strategically advancing flowering time can reduce the risk of yield losses due to extreme climatic conditions and facilitate the cultivation of subsequent crops on the same land, thereby enhancing overall agricultural efficiency. In this review, we synthesize current information on flowering time regulation in rapeseed through an integrated analysis of its genetic, hormonal, and environmental dimensions, emphasizing their crosstalk and implications for yield. We consolidate multi-omics evidence from population genetics, functional genomics, and systems biology to create a haplotype-based framework that overcomes the trade-off between flowering time and yield, providing support for the precision breeding of early-maturing cultivars. The insights presented here could inform future research on flowering time regulation and guide strategies for increasing rapeseed productivity.

Carex capillifolia is an ecologically and economically important fodder grass widely distributed across the Northern Hemisphere, particularly in the Qinghai-Xizang Plateau. Research into its genetic diversity and genomic architecture has been limited. In this study, we present a high-quality genome assembly for C. capillifolia, spanning 386.65 Mb (contig N50 = 14.66 Mb) and comprising 29 chromosomes. Phylogenetic analysis reveals a close evolutionary relationship with C. littledalei, with divergence estimated at 2.19-6.1 million years ago. Comparative genomics analyses identify 26 shared chromosome fusion events specifically between these two species, highlighting a pattern of recent, lineage-specific karyotype reshuffling that contributes to the remarkable karyotypic diversity within Cyperaceae. Using population genomics, genome-environment association (GEA), and transcriptome analysis, we identify multiple climate-associated genetic variants and drought-tolerance genes. Notably, we identify an auxin response factor (ARF) gene and verify its role in enhancing drought tolerance through transgenic experiments. Furthermore, we pinpoint the Ruoergai (RRG) geo-group as possessing the highest adaptability to future climates, which harbors superior adaptive genetic variation and candidate genes that could be targeted in breeding closely related species.

Ubiquitination is a crucial post-translational modification regulating numerous biological processes in plant development and stress responses. This process involves the covalent attachment of ubiquitin molecules to different target proteins, primarily linked through lysine (K)48 or K63 residues of ubiquitin, which either marks them for degradation by the 26S proteasome or modifies their activity, localization, and stability. By modulating key regulatory proteins and signaling pathways, ubiquitination enables plants to adapt to challenging environments. K48-linked ubiquitination is the most prevalent form in plants, although some recent studies have also demonstrated the importance of K63-linked ubiquitination. This review focuses on the roles of K48- and K63-linked ubiquitination in plant development, including seed dormancy and germination, seed size, hypocotyl elongation, and flowering time, as well as in abiotic and biotic stresses. Furthermore, it highlights their potential functions in improving crop resilience through biotechnological strategies. Finally, we also discuss the future challenges in investigating plant regulatory networks mediated by protein ubiquitination.

Cardiovascular diseases remain the leading cause of mortality worldwide. Mitochondrion, a key cellular organelle, harbors its own mitochondrial DNA (mtDNA) fundamental to cellular energy production through oxidative phosphorylation (OXPHOS). Beyond its canonical bioenergetic function, mtDNA integrity, copy number, and genetic variation play critical roles in maintaining cardiovascular function. This review provides a comprehensive overview of the multifaceted contributions of mtDNA to cardiovascular health and disease. We summarize the structural features and core biological functions of mtDNA, as well as the regulatory mechanisms governing its replication, biogenesis, and turnover. Particular emphasis is focused on mtDNA abnormalities, including point mutations, large-scale deletions, copy number alterations, and epigenetic modifications, and how these disturbances drive key pathogenic processes such as oxidative stress, chronic inflammation, apoptosis, and cellular senescence within the cardiovascular system. Furthermore, we highlight accumulating evidence linking mtDNA dysregulation to major cardiovascular disorders, including heart failure, atherosclerosis, and hypertension. Finally, we discuss the emerging diagnostic potential of circulating cell-free mtDNA and related mtDNA-derived metrics as non-invasive biomarkers, and outline therapeutic strategies aimed at preserving mtDNA integrity, modulating mtDNA content, or applying gene-based interventions to mitigate cardiovascular pathology.

Glutamine synthetase (GS) plays a crucial role in nitrogen (N) assimilation. Identifying elite alleles of GS genes can facilitate the breeding of wheat (Triticum aestivum) varieties with improved N use efficiency (NUE). Here, meta-quantitative trait loci (QTL) analysis based on five bi-parental linkage mapping populations reveals that TaGS1.1-6A co-localizes with a meta-QTL for N use- and yield-related traits. The promoter region of TaGS1.1-6A contains a variation caused by a miniature inverted-repeat transposable element (MITE) insertion. The MITE insertion induces DNA hypermethylation in the adjacent regions, thereby repressing TaGS1.1-6A transcription. The haplotype TaGS1.1-6A^HapII without the MITE insertion has been subjected to selection during wheat breeding, and is associated with increased photosynthetic N use efficiency, N utilization efficiency, spike grain number, and grain yield per plant when a BC₃F₄ population is grown under varying N supply levels. Conversely, CRISPR/Cas9-mediated mutation of TaGS1.1 shows reduction in these traits. Furthermore, we develop a breeding strategy to enhance wheat grain yield under different N supply conditions by pyramiding TaGS1.1-6A^HapII and the leaf senescence-delaying haplotype of TaNAM-A1. These findings suggest that TaGS1.1-6A contributes to N use- and yield-related traits, and TaGS1.1-6A^HapII holds significant value for breeding wheat with improved NUE and yield.

CTCF is a highly conserved zinc finger protein that plays critical roles in transcriptional regulation and three-dimensional (3D) genome organization. An alternative splice isoform of CTCF (CTCF-s), lacking the N-terminal domain and 2.5 zinc fingers, competes with CTCF for genomic occupancy and reduces CTCF-mediated chromatin interactions. However, the functional differences between CTCF and CTCF-s remain unclear. In this study, by using an auxin-inducible degron (AID2) system with doxycycline-inducible transgene expression, we systematically investigate the roles of CTCF and CTCF-s in human embryonic stem cells (hESCs). Acute degradation of endogenous CTCF and CTCF-s, followed by isoform-specific rescue, reveals that CTCF is essential for cell morphology and proliferation, whereas CTCF-s exerts much weaker effects. Genome-wide ChIP-seq and Hi-C analysis uncover distinct binding landscapes for CTCF and CTCF-s, as well as their differential contributions to chromatin conformation. Notably, our data indicate that CTCF-s, like CTCF, could either act as a boundary insulator or bind to gene promoters to modulate expression of a fraction of genes. Overall, our study reveals that CTCF is dominant in regulating chromatin boundary stability and gene regulation, while CTCF-s contributes to a lesser degree.

Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2^P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2^P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.

Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4-REC114 subcomplex on the chromosome axes. Additionally, Mei4^{Arg356*/Arg356*} mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4^+/Arg356* mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.