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PubMed2026

Methods for single-pair Ascaridia galli genetic crosses.

Ascarid parasites infect a wide range of hosts, causing significant clinical and economic impacts. However, genetic tools for studying ascarid biology remain limited. We optimized genetic crosses using Ascaridia galli , a common ascarid of chickens. Sexually immature larval parasites were recovered from donors, transferred to gelatin capsules, and then given orally to recipients. We successfully established single-pair matings in 32% of crossing attempts. This method to control genetic crosses further establishes the avian model for ascarid research and will enable future studies to create a high-quality reference genome, inbreed anthelmintic resistant and sensitive lines, and investigate host-pathogen interactions.

Journal Article↗

PubMed2025

Genetic crosses reveal genomic loci responsible for virulence in Cryptosporidium parvum infection.

The relationship between parasite genotype and pathogenesis is largely unknown for Cryptosporidium, a leading cause of diarrheal disease in children. An array of parasites with similar genomes produces varied disease outcomes in different hosts. Here, we isolate and characterize Cryptosporidium parvum strains that show marked differences in virulence and persistence in mice. Taking advantage of the sexual life cycle of this eukaryotic pathogen, we use genetic crosses to discover the underlying chromosomal loci. Whole-genome sequencing and bulk segregant analysis of infection-selected progeny mapped three loci on chromosomes 2, 6, and 7 associated with the ability to colonize and persist in mice and the positions of drug resistance genes. The chromosome 6 locus encodes the hyper-polymorphic surface glycoprotein GP60. Reverse genetic studies in both parental strains demonstrate that GP60 controls parasite burden and virulence, but not persistence, and reveal the dominance of the less virulent allele, suggesting it restricts virulence.

Cryptosporidium parvum↗

PubMed2026

MIF Promoter Variant rs755622 (-173G/C) in Younger and Older Turkish Adults: An Exploratory Cross-Sectional Genetic and in Silico Analysis.

Age-associated immune-inflammatory remodeling may be influenced by regulatory variation in the macrophage migration inhibitory factor gene (MIF). We conducted an exploratory cross-sectional comparison to assess whether MIF rs755622 (-173G/C) genotype distributions differ between predefined younger and older age groups in a Turkish population and to characterize the observed pattern using genetic-model and in silico analyses. We evaluated 368 individuals: 245 older adults aged 65-102 years and 123 younger controls aged 20-46 years. None of the 26 main association tests remained statistically significant after global multiplicity correction (minimum FDR q = 0.062; minimum Bonferroni-adjusted p = 0.108). Before correction, GC frequency was higher in the older group and increased across the ordered age categories, and sex-adjusted analyses yielded concordant nominal estimates. However, these nominal patterns were sensitive to younger-control genotype reclassification and were not supported by an allele-level or additive association. Younger controls showed Hardy-Weinberg disequilibrium (p < 0.001), without sequencing confirmation, and deterministic and scenario-based Monte Carlo genotype-reclassification analyses indicated sensitivity of the nominal signal to uncertainty in control genotype classification. GTEx data provide C-allele-oriented expression context but do not validate function in this cohort. These preliminary findings warrant independent genotype verification, ancestry-matched replication, and direct functional investigation in future studies.

Humans↗

PubMed2025

Leveraging local ancestry and cross-ancestry genetic architecture to improve genetic prediction of complex traits in admixed populations.

The broader application of polygenic risk score (PRS) is hindered by the limited transferability of PRS developed in Europeans to non-European populations. While many statistical methods have been developed to improve the performance of PRS in non-European populations, most of them focused on discrete genetic ancestry clusters and did not consider admixed individuals. Admixed individuals pose a unique challenge for PRS calculation due to the complexity of local ancestry and cross-ancestry effect sizes. Here, we present a statistical method called SDPR_admix for calculating PRS in admixed individuals. SDPR_admix characterizes the joint distribution of the effect sizes of a genetic variant with two ancestries to be both zero, ancestry enriched, or shared with correlation. SDPR_admix outperformed other methods in simulations and improved the prediction of real traits in European-African admixed individuals in UK Biobank when trained on the Population Architecture using Genomics and Epidemiology (PAGE) dataset (N = 13,000). Deployment of SDPR_admix on All of Us (N = 52,000) further increased the prediction accuracy by approximately 5-fold on average compared with training on PAGE. This enhancement was achieved with manageable computational time and cost, demonstrating the feasibility of training PRS models on large-scale All of Us data. We provided several examples demonstrating that both ancestral-enriched and shared effects, as included in the SDPR_admix prediction model, are helpful for improving polygenic prediction in admixed populations. We also applied SDPR_admix to construct PRS for admixed Americans with mixture of European and Amerindigenous ancestries and showed that SDPR_admix overall outperformed other methods.

Humans↗

PubMed2025

Stress-induced altered expression of hippocampal nuclear and mitochondrial encoded genes in rats and cross-species genetic associations reveal molecular links to depression.

BACKGROUND: Mitochondria play a pivotal role in energy production, and their dysfunction not only hampers cells' ability to meet energy requirements but also contributes to the impairment of neural plasticity, a critical feature of depressive disorders. In this study, mitochondrial cross-omics analysis was carried out in the hippocampus of restraint rats to understand the role of mitochondria in depression pathophysiology. METHODS: The expression profiles of hippocampal mitochondrial and nuclear-encoded genes in mitochondrial fractions from restraint and handled control rats were obtained using high-throughput RNA sequencing. Weighted gene co-expression network analysis (WGCNA) was used to identify the gene co-expression and pathways associated with the restraint phenotype. Mutual Information Network algorithm tools Arance, CLR, and MRNET were additionally used to screen the functional modules and hub genes and their similarity with the WGCNA-based network analysis. Finally, cross-species homology followed by gene association analysis was conducted to obtain SNPs and haplotypes related to depression phenotype. RESULTS: A significant proportion of mitochondrial and nuclear-encoded genes showed differential regulation in the hippocampus of restraint rats. WGCNA and Mutual Information Network analysis yielded distinct functional modules significantly related to restraint phenotype. Further network analysis revealed distinct co-expression patterns associated with differentially expressed genes associated with these modules. Cross-species analysis showed 39 significantly associated SNPs with the depression phenotype, where the most significant SNP, rs10899570, was located within the TENM4 gene. Further, rs1573529 and rs10899570 were distributed into the linkage disequilibrium block where SNPs were highly correlated. Subsequent haplotype analysis showed that rs1573529 and rs10899570 were significantly associated with depressive behavior. CONCLUSIONS: The study demonstrates a significant impact of restraint stress on mitochondrial functions and genetic association, suggesting their critical role in depression pathophysiology.

Animals↗

PubMed2005

Linkage group selection: rapid gene discovery in malaria parasites.

The identification of parasite genes controlling phenotypes such as drug resistance, virulence, immunogenicity, and transmission is vital to malaria research. Classical genetic methods have achieved these goals only rarely and with difficulty. We describe here a novel genetic method, Linkage Group Selection (LGS), which achieves rapid de novo location of genes encoding selectable phenotypes of malaria parasites. A phenotype-specific selection pressure is applied to the uncloned progeny of a genetic cross between two malaria parasites that differ in the relevant phenotype. Selected and unselected progeny are analyzed using genome-wide quantitative genetic markers. Markers of the "sensitive" parent, which are reduced after selection, are sequenced and located in genomic databases. They are expected to be closely linked to gene(s) determining the phenotype under selection. We have validated LGS with the rodent malaria parasite Plasmodium chabaudi chabaudi using a phenotype, pyrimethamine resistance, whose controlling gene, that encoding dihydrofolate reductase (dhfr), is known. We show that molecular markers closely linked to dhfr, and only those linked to this gene, were reduced or removed by pyrimethamine treatment in accordance with the expectations of LGS.

Animals↗

PubMed2022

Genomic landscape of drug response reveals mediators of anthelmintic resistance.

Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Ivermectin↗

PubMed2025

OsIDD6, an INDETERMINATE DOMAIN containing transcription factor in rice, plays an essential role in reproductive development.

INDETERMINATE DOMAIN containing proteins (IDD) are plant-specific transcriptional factors with a diverse range of roles in plants. Among the 15 IDD genes in rice, a staple food crop for the world, only about half have been functionally characterized. To elucidate the function of the remaining members, we created loss-of-function mutants using the CRISPR genome editing technique. Although no mutant exhibited obvious growth phenotypes, the Osidd6 mutant was completely sterile. By genetic crossing, we showed that both the male and female gametophytes were defective in the mutant. Histochemical staining and thin sectioning revealed that microspore development was compromised, likely due to a delay in tapetum degeneration. We also showed that meiosis was impaired in the mutant, resulting in defective megaspore development. Through a series of experiments, including transcriptome analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), in situ hybridization, β-glucuronidase (GUS) staining with promoter-GUS transgenic plants, yeast one-hybrid method, a dual-visible reporter assay, and transcriptional activity assay, we demonstrated that OsIDD6 is expressed in all cell types in the male and female reproductive organs and that the OsIDD6 protein directly regulates genes potentially having a role in meiosis and tapetum development. Since reproductive development is directly related to crop yield, OsIDD6 could be an important target for genetic manipulation in rice breeding.

Oryza↗

PubMed2025

Advances in large-scale DNA engineering with the CRISPR system.

In recent years, DNA engineering technology has undergone significant advancements, with clustered regularly interspaced short palindromic repeats (CRISPR)-based target-specific DNA insertion emerging as one of the most rapidly expanding and widely studied approaches. Traditional DNA insertion technologies employing recombinases typically involve introducing foreign DNA into genes in vivo by either pre-engineering recognition sequences specific to the recombinase or through genetic crossing to incorporate the requisite recognition sequence into the target gene. However, CRISPR-based gene insertion technologies have advanced to streamline this engineering process by combining the CRISPR-Cas module with recombinase enzymes. This process enables accurate and efficient one-step insertion of foreign DNA into the target gene in vivo. Here we provide an overview of the latest developments in CRISPR-based gene insertion technologies and discusses their potential future applications.

CRISPR-Cas Systems↗

PubMed2026

Digital Kennison: A bioinformatics pipeline for rapid mapping of sequences to the Drosophila melanogaster Y chromosome.

The Drosophila melanogaster Y chromosome is currently known to contain 13 single-copy protein-coding genes, six of which are essential for male fertility, as well as several non-coding genes and abundant repetitive DNA. Localization of Y-linked sequences has traditionally relied on labor-intensive crosses using Kennison's translocation strains, which map Y-linked loci by generating flies deficient for each of the six Y-chromosome fertility regions (ks-1, ks-2, kl-1, kl-2, kl-3, and kl-5). Here we present Digital Kennison, a computational pipeline that recasts this classical mapping strategy as a sequence-based analysis. The pipeline queries eight genomic databases derived from Kennison's strains using BLAST and read coverage, assigning sequences to fertility regions or the centromeric region with a calibrated confidence score. We benchmarked the method on 60 Y-linked sequences spanning all seven regions, including single-copy protein-coding genes, Mst77Y family members, non-coding RNAs, and the centromere. Digital Kennison achieved 97% precision while resolving challenging cases, including boundary-spanning genes (PRY and Ppr-Y), fragmented Mst77Y copies, and FDY, which has a closely related autosomal paralog. Beyond validating known localizations, the pipeline localized the unmapped gene CG41561 to the kl-1region and reassigned the transcript CR40629-RC from the kl-2 region to kl-5. It also localized 7 of 16 recently transferred Y-linked sequences, including 4 with high confidence. Applied to 904 R6 scaffolds, Digital Kennison assigned 75% to fertility regions, including five currently annotated as autosomal-pericentromeric. Digital Kennison reduces sequence localization from weeks of genetic crosses to minutes of computation while preserving the power of classical translocation mapping.

Drosophila melanogaster↗

PubMed2025

Disruption of HaVipR1 confers Vip3Aa resistance in the moth crop pest Helicoverpa armigera.

The global reliance on Bacillus thuringiensis (Bt) proteins for controlling lepidopteran pests in cotton, corn, and soybean crops underscores the critical need to understand resistance mechanisms. Vip3Aa, one of the most widely deployed and currently effective Bt proteins in genetically modified crops, plays a pivotal role in pest management. This study investigates the molecular basis of Vip3Aa resistance in Australian Helicoverpa armigera through genetic crosses, and integrated genomic and transcriptomic analyses. We identified a previously uncharacterized gene, LOC110373801 (designated HaVipR1), as potentially important in Vip3Aa resistance in two field-derived resistant lines. Functional validation using CRISPR/Cas9 knockout in susceptible lines confirmed the gene's role in conferring high-level resistance to Vip3Aa. Despite extensive laboratory selection of Vip3Aa-resistant colonies in Lepidoptera, the biochemical mechanisms underlying resistance have remained elusive. Our research identifies HaVipR1 as a potential contributor to resistance, adding to our understanding of how insects may develop resistance to this important Bt protein. The identification of HaVipR1 contributes to our understanding of potential resistance mechanisms and may inform future resistance management strategies. Future work should explore the biochemical pathways influenced by HaVipR1 and assess its interactions with other resistance mechanisms. The approach utilized here underscores the value of field-derived resistant lines for understanding resistance in agricultural pests and highlights the need for targeted approaches to manage resistance sustainably.

Animals↗

PubMed2025

How to Study Gene Expression and Gain of Function of Hoxb1 in Mouse Heart Development.

Anterior Hox genes are required for genetic identity and anterior posterior patterning of the second heart field (SHF), which contributes to the formation of the embryonic heart in vertebrates. Defective contribution of SHF cells to the arterial or venous pole of the heart is often associated with severe congenital heart defects. The mouse Cre-lox system allows the activation of expression of any gene of interest in restricted tissues. We developed a gain of function approach that relies on the use of a CAG transgene to ectopically activate Hoxb1 expression in SHF cardiac progenitor cells through specific Cre activation. Therefore, we generated a floxed transgenic mouse line, CAG-Hoxb1-eGFP, which upon recombination by Cre recombinase conditionally induces robust Hoxb1 and eGFP expression. When induced within the anterior SHF lineage, we detected heart defects in mouse embryos such as right ventricular hypoplasia. Here, we describe the strategy for generating and genetically crossing this transgenic mouse line. We also provide detailed protocols for whole-mount embryo and paraffin section in situ RNAscope hybridization and X-gal staining allowing investigation of SHF contribution during heart development.

Animals↗

PubMed2026

Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

Animals↗

PubMed2025

Substantial non-homologous recombination and structural variation results from Brassica AABC and CCAB hybrid meiosis.

Meiotic crossovers contribute to genetic diversity and play a crucial role in homologous chromosome segregation. Non-homologous crossovers in Brassica, involving the exchange of genetic material between genomes, can be valuable for transferring novel traits or characteristics between Brassica species. However, there are a limited number of studies that specifically investigate crossover frequencies in populations of interspecific hybrids. We investigated the distribution and frequency of homologous crossover events, as well as non-homologous recombination and structural variation, in hybrids between B. juncea (AABB) × B. napus (AACC) (resulting in AABC hybrids; 5 genotypes) and B. napus (AACC) × B. carinata (BBCC) (resulting in CCAB hybrids; 4 genotypes). The analysis was performed on individuals derived from microspore culture of both unreduced and reduced gametes produced by the AABC and CCAB hybrids. All AABC and almost all CCAB unreduced gamete-derived individuals and most AABC and CCAB reduced gamete-derived individuals showed copy number variation indicative of non-homologous (A-C) recombination. Additionally, a higher frequency of homologous crossovers, also in centromeric and pericentromic regions, was observed in the diploid genomes of the AABC and CCAB hybrids. Overall, these hybrid types show high frequencies of A-C introgressions, which may be useful in B. juncea or B. carinata introgression breeding, and this increased recombination frequency may help break up existing linkage disequilibrium blocks in the Brassica A and C genomes.

Meiosis↗

PubMed2022

A Multitrait Locus Regulates Sarbecovirus Pathogenesis.

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.

Animals↗

PubMed2026

Genetic evidence and cross-species functional characterization implicate CNN2 in age-related macular degeneration susceptibility.

Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the aging population globally. Although genome-wide association studies (GWAS) have identified many AMD susceptibility loci, the genes and mechanisms underlying many of these associations remain unresolved. Here, we integrated expression quantitative trait locus (eQTL) data with AMD GWAS to prioritize nine putative genes. Through in vivo screening in zebrafish, we demonstrated that the downregulation of cnn2 and sarm1 expression led to ocular structural abnormalities and visual functional impairment. Subsequent mouse model studies confirmed that Cnn2 deficiency affected photoreceptor structure and function, impaired contrast sensitivity, and caused abnormalities in cone cell immunostaining. Given that CNN2 is predominantly expressed in endothelial cells, we propose that endothelial dysfunction may cascade to impair photoreceptor function. Collectively, through in silico prioritization and cross-species functional characterization, we identify CNN2 as a candidate susceptibility gene in AMD pathogenesis, providing vital underlying mechanistic insights.

Animals↗

PubMed2026

A Landscape of Drosophila melanogaster Disease Models: From Genetic Platforms to Cross-Disease Mechanisms and Translational Research.

Modeling human diseases using the fruit fly (Drosophila melanogaster) has established itself as a cornerstone of functional genomics and preclinical medicine. Despite its anatomical simplicity, the Drosophila genome shares remarkable functional conservation with human disease-related genes, enabling the study of complex physiological traits through accessible tissue models. Furthermore, beyond individual disease models, we propose a framework demonstrating how these diseases converge at common molecular centers, such as the breakdown of protein homeostasis, mitochondrial dysfunction, chronic inflammation, and organ-to-organ communication. Finally, we discuss strategies for integrating the Drosophila platform into drug development pipelines and establishing standards to enhance inter-laboratory reproducibility. Overall, this review highlights the enduring value of fruit flies as a model system, particularly when combined with AI-omics approaches to transform complex biological datasets into actionable therapeutic strategies.

Drosophila↗

PubMed2025

Blood Pressure Genetics in Han Taiwanese With Cross-Trait Analysis in East Asians: Insights Into Comorbidities, All-Cause Mortality, and Cardiovascular Mortality.

BACKGROUND: Hypertension is a major health burden in East Asia. However, the genetic architecture and clinical implications of blood pressure (BP) traits remain underexplored beyond European-focused studies. This large-scale study aimed to investigate hypertension, systolic BP, and diastolic BP, to uncover genetic links to comorbidities and mortality in Han Taiwanese individuals. METHODS: This large-scale study used China Medical University Hospital biobank data and conducted genome-wide association studies on 25 523 hypertension cases and 47 522 controls, plus 66 236 individuals for systolic BP and 66 152 for diastolic BP. Cross-trait genetic correlations were assessed across 5 East Asian biobanks. Mendelian randomization and polygenic risk scores were applied to assess causality and predict clinical outcomes. RESULTS: We identified 8 loci and 36 genes for hypertension, 7 loci and 17 genes for systolic BP, and 9 loci and 26 genes for diastolic BP. ATP2B1 and FGF5 were common to all BP traits, implicating calcium signaling and vascular remodeling pathways. Cross-trait analyses showed shared genetic liability between BP traits and cardiovascular and metabolic comorbidities. Phenome-wide association studies confirmed strong associations with circulatory diseases. Mendelian randomization analyses demonstrated that elevated BP causally increases the risk of unstable angina pectoris. Polygenic risk scores predicted significantly higher risks and earlier onset of unstable angina pectoris, all-cause mortality, and cardiovascular mortality among individuals in the top polygenic risk score quintiles. CONCLUSIONS: Our findings highlight the genetic basis of BP and comorbidities in East Asians, suggesting that BP genetic risk may inform future approaches to early risk assessment and prevention.

Aged↗