Journal of Genetics and Genomics最新文献

Although the spatial characteristics within the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) have been identified, the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear. Using spatial transcriptomics (ST) and single-cell RNA-sequencing (scRNA-seq) data from multi-regional LUAD biopsies, consisting of tumor core, tumor edge and normal area, we sought to delineate the spatial heterogeneity and driving factors of cell co-localization. Two cancer cell sub-clusters (Cancer_c1 and Cancer_c2), associated with LUAD initiation and metastasis respectively, exhibit distinct spatial distributions and immune cell colocalizations. In particular, Cancer_c1, enriched within the tumor core, could directly interact with B cells or indirectly recruit B cells through macrophages. Conversely, Cancer_c2 enriched within the tumor edge exhibits co-localization with CD8⁺ T cells. Collectively, our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD, providing insights for developing therapeutic strategies for cancer intervention.

Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries, supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli. Genetic variants that regulate gene expression, known as expression quantitative trait loci (eQTL), are primarily shaped by human migration history and evolutionary forces, likewise, regulation of gene expression in principle could have been influenced by these events. Therefore, a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped. Recent studies, however, suggest that eQTL is enriched in genes that are selectively constrained. Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations. In addition, such studies are primarily dominated by the major populations of European ancestry, leaving many marginalized populations underrepresented. These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity, which potentially hinders precision medicine. This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective, subsequently discuss their influence on phenomics, as well as challenges and opportunities in the applications to precision medicine.

Soybean (Glycine max) is a vital foundation of global food security, providing a primary source of high-quality protein and oil for human consumption and animal feed. The rising global population has significantly increased the demand for soybeans, emphasizing the urgency of developing high-yield, stress-tolerant, and nutritionally superior cultivars. The extensive collection of soybean germplasm resources-including wild relatives, landraces, and cultivars-represents a valuable reservoir of genetic diversity critical for breeding advancements. Recent breakthroughs in genomic technologies, particularly high-throughput sequencing and multi-omics approaches, have revolutionized the identification of key genes associated with essential agronomic traits within these resources. These innovations enable precise and strategic utilization of genetic diversity, empowering breeders to integrate traits that improve yield potential, resilience to biotic and abiotic stresses, and nutritional quality. This review highlights the critical role of genetic resources and omics-driven innovations in soybean breeding. It also offers insights into strategies for accelerating the development of elite soybean cultivars to meet the growing demands of global soybean production.

Sex-specific neurons play pivotal roles in regulating sexually dimorphic behaviors. In insects, the sex determination gene doublesex (dsx) establishes major sexual dimorphism of the nervous system, in which male-specific dsx^M promotes neuronal development, while female-specific dsx^F inhibits neuronal development by promoting neuronal apoptosis. In this study, we find that dsx regulates the number of dsx-expressing central neurons in Drosophila in cell-specific manners. Although dsx^M overall promotes an increase in the number of dsx neurons, it inhibits the emergence of specific pC1 neurons. dsx^F reduces the number of different pC1/pC2 subtypes, but promotes the formation of pC1d. We also find that dsx^M and dsx^F barely affect the number of some pC2 neurons. Changes in the number of pC1/pC2 neuron numbers alter their roles in regulating different behaviors, including courtship, aggression, and locomotion. Our results demonstrate the multifaceted functions of dsx in sexually dimorphic neuronal development and behaviors.

mTORC1/2 play central roles as signaling hubs of cell growth and metabolism and are therapeutic targets for several diseases. However, the human genetic evidence linking mutations of mTORC1/2 to obesity remains elusive. Using whole-exome sequencing of 1,944 cases with severe obesity and 2,161 healthy lean controls, we identify a rare RICTOR p.I116V variant enriched in 9 unrelated cases. In Rictor null mouse embryonic fibroblasts, overexpression of the RICTOR p.I116V mutant increases phosphorylation of AKT, a canonical mTORC2 substrate, compared to wild-type RICTOR, indicating a gain-of-function change. Consistent with the human obesity phenotype, the knock-in mice carrying homogenous Rictor p.I116V variants gain more body weight under a high-fat diet. Additionally, the stromal vascular fraction cells derived from inguinal white adipose tissue of knock-in mice display an enhanced capacity for adipocyte differentiation via AKT activity. These findings illustrate that the rare gain-of-function RICTOR p.I116V mutation activates AKT signaling, promotes adipogenesis, and contributes to obesity in humans.

Founder events influence recessive diseases in highly endogamous populations. Several Indian populations have experienced significant founder events due to strict endogamy. However, the clinical implications of it remain underexplored. Therefore, we perform whole-exome sequencing of 281 individuals from four South Indian populations, characterized by high IBD scores. Our study reveals a high inbreeding rate of 59% across the populations. We identify ∼29.2% of the variants that are exclusively present in a single population and uncovered 1284 unreported exonic variants, underscoring the underrepresentation of Indian populations in global databases. Among these, 23 are predicted to be deleterious, all present in heterozygous state may be pathogenic when homozygous, an expected phenomenon in endogamous populations. Approximately 16%-33% of the identified pathogenic variants showed significantly higher occurrence rates compared to the South Asian populations from 1000 Genomes dataset. Pharmacogenomic analysis revealed distinct allele frequencies of variants in CYP450 and non-CYP450 genes, highlighting heterogeneous drug responses and associated risks. We report a high prevalence of ankylosing spondylitis in Reddy population, linked to HLA-B*27:04 allele and strong founder effect. Our findings highlight the need for extensive genomic research in understudied Indian populations for better understanding of disease risk and evolving strategies for precision and preventive medicine.

The impact of mother-infant microbiota on neurodevelopment is an area of interest, but longitudinal studies are scarce. Using a cohort of 520 families from the Jiangsu birth cohort in China, we reveal that the maternal gut microbiota during early pregnancy play a substantial role, accounting for 3.34% of the variance in offspring neurodevelopmental scores. This contribution is notably higher than the 1.24% attributed to the infants' own microbiota at 1 year of age, underscoring the significant influence of maternal gut health on early child development. Remarkably, an elevation in maternal Bifidobacterium pseudocatenulatum is linked to decreased cognitive scores, whereas an enrichment of Bifidobacterium longum at 1 year of age is associated with higher cognitive scores. Furthermore, we find that maternal B. pseudocatenulatum is linked to heterolactic fermentation metabolic pathway, while infant B. longum is associated with the Bifidobacterium shunt pathway. In summary, our analysis implies that maternal and infant gut microbiota play a distinct role in neurodevelopment, suggesting potential strategies for improving neurodevelopmental outcomes during early pregnancy or infant development by targeting gut microbiota composition.

All plant organs are derived from stem cell-containing meristems. In maize, the shoot apical meristem (SAM) is responsible for generating all above-ground structures, including the male and female inflorescence meristems (IMs), which give rise to tassel and ear, respectively. Forward and reverse genetic studies on maize meristem mutants have driven forward our fundamental understanding of meristem maintenance and differentiation mechanisms. However, the high genetic redundancy of the maize genome has impeded progress in functional genomics. This review provides a comprehensive summary of the recent advancements in understanding maize meristem development, with a focus on the integration of single-cell and spatial technologies. We discuss the mechanisms governing stem cell maintenance and differentiation in SAM and IM, emphasizing the roles of gene regulatory networks, hormonal pathways, and cellular omics insights into stress responses and adaptation. Future directions include cross-species comparisons, multi-omics integration, and the application of these technologies to precision breeding and stress adaptation research, with the ultimate goal of translating our understanding of meristem into the development of higher yield varieties.

CRISPR-Cas technology has revolutionized our ability to understand and engineer organisms, evolving from a singular Cas9 model to a diverse CRISPR toolbox. A critical bottleneck in developing new Cas proteins is identifying protospacer adjacent motif (PAM) sequences. Due to the limitations of experimental methods, bioinformatics approaches have become essential. However, existing PAM prediction programs are limited by the small number of spacers in CRISPR-Cas systems, resulting in low accuracy. To address this, we develop PAMPHLET, a pipeline that uses homology searches to identify additional spacers, significantly increasing the number of spacers up to 18-fold. PAMPHLET is validated on 20 CRISPR-Cas systems and successfully predicts PAM sequences for 18 protospacers. These predictions are further validated using the DocMF platform, which characterizes protein-DNA recognition patterns via next-generation sequencing. The high consistency between PAMPHLET predictions and DocMF results for Cas proteins demonstrates the potential of PAMPHLET to enhance PAM sequence prediction accuracy, expedite the discovery process, and accelerate the development of CRISPR tools.