Journal of Genetics and Genomics最新文献

The occurrence of severe thalassemia, an inherited blood disorder that is either blood-transfusion-dependent or fatal, can be mitigated through carrier screening. Here, we aim to evaluate the effectiveness and outcomes of pre-conceptional and early pregnancy screening initiatives for severe thalassemia prevention in a diverse population of 28,043 women. Using next-generation sequencing (NGS), we identify 4,226 (15.07%) thalassemia carriers across 29 ethnic groups and categorize them into high- (0.75%), low- (25.86%), and unknown-risk (69.19%) groups based on their spouses' screening results. Post-screening follow-up reveals 59 fetuses with severe thalassemia exclusively in high-risk couples, underscoring the efficacy of risk classification. Among 25,053 live births over 6 months of age, two severe thalassemia infants were born to unknown-risk couples, which was attributed to incomplete screening and late NGS-based testing for a rare variant. Notably, 64 rare variants are identified in 287 individuals, highlighting the genetic heterogeneity of thalassemia. We also observe that migrant flow significantly impacts carrier rates, with 93.90% of migrants to Chenzhou originating from high-prevalence regions in southern China. Our study demonstrates that NGS-based screening during pre-conception and early pregnancy is effective for severe thalassemia prevention, emphasizing the need for continuous screening efforts in areas with high and underestimated prevalence.

While methodology for determining the mode of evolution in coding sequences has been well established, evaluation of adaptation events in emerging types of phenotype data needs further development. Here, we propose an analysis framework (expression variance decomposition, EVaDe) for comparative single-cell expression data based on phenotypic evolution theory. After decomposing the gene expression variance into separate components, we use two strategies to identify genes exhibiting large between-taxon expression divergence and small within-cell-type expression noise in certain cell types, attributing this pattern to putative adaptive evolution. In a dataset of primate prefrontal cortex, we find that such human-specific key genes enrich with neurodevelopment-related functions, while most other genes exhibit neutral evolution patterns. Specific neuron types are found to harbor more of these key genes than other cell types, thus likely to have experienced more extensive adaptation. Reassuringly, at the molecular sequence level, the key genes are significantly associated with the rapidly evolving conserved non-coding elements. An additional case analysis comparing the naked mole-rat (NMR) with the mouse suggests that innate-immunity-related genes and cell types have undergone putative expression adaptation in NMR. Overall, the EVaDe framework may effectively probe adaptive evolution mode in single-cell expression data.

Nitric oxide (NO) is a key vasodilator that regulates vascular pressure and blood flow. Tibetans have developed a "blunted" mechanism for regulating NO levels at high altitude, with GTP cyclohydrolase 1 (GCH1) identified as a key candidate gene. Here, we present comprehensive genetic and functional analyses of GCH1, which exhibits strong Darwinian positive selection in Tibetans. We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans. Based on this observation, we generate the heterozygous Gch1 knockout (Gch1^+/-) mouse model to simulate its downregulation in Tibetans. We find that under prolonged hypoxia, the Gch1^+/- mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type (WT) controls, providing better oxygen supplies to the cardiovascular and pulmonary systems. Markedly, hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1^+/- mice compared with the WT controls, likely due to the adaptive changes in molecular regulations related to metabolism, inflammation, circadian rhythm, extracellular matrix, and oxidative stress. This study sheds light on the role of GCH1 in regulating blood NO, contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.

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.