Association of HLA-DQ4/5 genotype polymorphisms with celiac disease in a group of children in Southwest Iran: A case-control study.

Background and Aim: Celiac disease (CD) has proinflammatory and pathogenic immune responses to gluten in intestinal tissue, leading to structural changes in the mucosa of the small intestine. The association of human leukocyte antigen (HLA)-DQ2 and DQ8 genotypes with CD has been previously reported. This test has a negative predictive value close to 100%, so its main purpose is to rule out the detection of CD completely or almost completely. There is limited information regarding HLA-DQ4/5 in CD. This study was conducted to determine the HLA-DQ4/5 genotypes in a group of Southwestern Iranian children with CD. Methods: We conducted a case-control study in Southwest Iran involving 100 participants, employing a nonprobabilistic sampling method. Samples were taken from participants' oral buccal mucosa at Imam Sajjad Hospital of Yasuj, Iran. Then DNA was extracted from these samples and used to determine the frequency of HLA-DQ4/5 genotypes through Sequence-Specific Primer-Polymerase Chain Reaction assay. SPSS 20 was utilized for statistical analyses. Results: Fifty diagnosed patients with CD (high anti-tissue transglutaminase [tTG]-IgA level [upper limit of normal] with pathological findings of Marsh III) and 50 non-CD individuals (normal anti-tTG-IgA level and normal total IgA level) were enrolled in the study from August 5, 2022 to October 15, 2023. Findings showed that the DQ4a*4b allele has the highest frequency in the CD samples (78%, p < 0.01) followed by the DQ5a*5b allele (12%, p < 0.01). Additionally, there was a higher prevalence of DQ4/DQ5 in patients with CD compared to controls (odds ratio = 6.5, confidence interval = 0.84 to 69.46, p < 0.01). Furthermore, a significant association was found among HLA DQ4/5 genotype, age (>9.5) (p < 0.01), and gender (female) (p < 0.05). Conclusion: The observed significant differences among HLA-DQ4 and HLA-DQ5 in Iranian CD samples against controls and the high value of the relative risks showed the significant function of the studied alleles in the prevalence of CD in Iranian patients.

Phenomics in Livestock Research: Bottlenecks and Promises of Digital Phenotyping and Other Quantification Techniques on a Global Scale.

Bottlenecks in moving genomics to real-life applications also include phenomics. This is true not only for genomics medicine and public health genomics but also in ecology and livestock phenomics. This expert narrative review explores the intricate relationship between genetic makeup and observable phenotypic traits across various biological levels in the context of livestock research. We unpack and emphasize the significance of precise phenotypic data in selective breeding outcomes and examine the multifaceted applications of phenomics, ranging from improvement to assessing welfare, reproductive traits, and environmental adaptation in livestock. As phenotypic traits exhibit strong correlations, their measurement alongside specific biological outcomes provides insights into performance, overall health, and clinical endpoints like morbidity and disease. In addition, automated assessment of livestock holds potential for monitoring the dynamic phenotypic traits across various species, facilitating a deeper comprehension of how they adapt to their environment and attendant stressors. A key challenge in genetic improvement in livestock is predicting individuals with optimal fitness without direct measurement. Temporal predictions from unmanned aerial systems can surpass genomic predictions, offering in-depth data on livestock. In the near future, digital phenotyping and digital biomarkers may further unravel the genetic intricacies of stress tolerance, adaptation and welfare aspects of animals enabling the selection of climate-resilient and productive livestock. This expert review thus delves into challenges associated with phenotyping and discusses technological advancements shaping the future of biological research concerning livestock.

Tropical trees inherit low-frequency somatic mutations.

A new study by Schmitt et al. revealed that somatic mutations in tropical trees are passed on to their offspring. Furthermore, the study noted that the majority of inherited mutations were present at low allelic frequencies within the tree.

A comprehensive investigation of dietary micronutrients intakes and the risk of alcoholic liver disease.

BACKGROUND: The investigation of dietary micronutrients intakes and the risk of alcoholic liver disease (ALD) based on observational studies was limited. OBJECTIVES: Our study aimed to explore the associations of 30 dietary micronutrients intakes with the risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and the risk of ALD. METHODS: A case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1,386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-hour dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrients intakes with the risk of ALD. We conducted stratified analyses on the associations between dietary micronutrients intakes and the risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and the risk of ALD. RESULTS: Our findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with the risk of ALD (all false discovery rate-Ptrend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (Pinteraction= 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 (IGF-1) were the top three biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and the risk of ALD. CONCLUSIONS: Dietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with the risk of ALD.

An assemblage-level comparison of genetic diversity and population genetic structure between island and mainland ant populations.

Island biotas provide unparalleled opportunities to examine evolutionary processes. Founder effects and bottlenecks, for example, typically decrease genetic diversity in island populations, while selection for reduced dispersal can increase population structure. Given that support for these generalities mostly comes from single-species analyses, assemblage-level comparisons are needed to clarify how (i) colonization affects the gene pools of interacting insular organisms, and (ii) patterns of genetic differentiation vary within assemblages of organisms. Here, we use genome-wide sequence data from ultraconserved elements (UCEs) to compare genetic diversity and population structure of mainland and island populations of nine ant species in coastal southern California. As expected, island populations (from Santa Cruz Island) had lower expected heterozygosity and Watterson's theta compared to mainland populations (from the Lompoc Valley). Island populations, however, exhibited smaller genetic distances among samples, indicating less population subdivision. Within the focal assemblage, pairwise Fst values revealed pronounced interspecific variation in mainland-island differentiation, which increases with gyne body size. Our results reveal population differences across an assemblage of interacting species, and illuminate general patterns of insularization in ants. Compared to single-species studies, our analysis of nine conspecific population pairs from the same island-mainland system offers a powerful approach to studying fundamental evolutionary processes.

Genetic-environment associations explain genetic differentiation and variation between western and eastern North Pacific rhinoceros auklet (Cerorhinca monocerata) breeding colonies.

Animals are strongly connected to the environments they live in and may become adapted to local environments. Examining genetic-environment associations of key indicator species, like seabirds, provides greater insights into the forces that drive evolution in marine systems. Here we examined a RADseq dataset of 19,213 SNPs for 99 rhinoceros auklets (Cerorhinca monocerata) from five western Pacific and 10 eastern Pacific breeding colonies. We used partial redundancy analyses to identify candidate adaptive loci and to quantify the effects of environmental variation on population genetic structure. We identified 262 candidate adaptive loci, which accounted for 3.0% of the observed genetic variation among western Pacific and eastern Pacific breeding colonies. Genetic variation was more strongly associated with pH and maximum current velocity, than maximum sea surface temperature. Genetic-environment associations explain genetic differences between western and eastern Pacific populations; however, genetic variation within the western and eastern Pacific Ocean populations appears to follow a pattern of isolation-by-distance. This study represents a first to quantify the relationship between environmental and genetic variation for this widely distributed marine species and provides greater insights into the evolutionary forces that act on marine species.

Broadcasters, receivers, functional groups of metabolites, and the link to heart failure by revealing metabolomic network connectivity.

BACKGROUND AND OBJECTIVE: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline. METHODS: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites. RESULTS: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet. CONCLUSION: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.

The genomic landscape of the immune system in lung cancer: present insights and continuing investigations.

Lung cancer is one of the most prevalent malignancies worldwide, contributing to over a million cancer-related deaths annually. Despite extensive research investigating the genetic factors associated with lung cancer susceptibility and prognosis, few studies have explored genetic predispositions regarding the immune system. This review discusses the most recent genomic findings related to the susceptibility to or protection against lung cancer, patient survival, and therapeutic responses. The results demonstrated the effect of immunogenetic variations in immune system-related genes associated with innate and adaptive immune responses, cytokine, and chemokine secretions, and signaling pathways. These genetic diversities may affect the crosstalk between tumor and immune cells within the tumor microenvironment, influencing cancer progression, invasion, and prognosis. Given the considerable variability in the individual immunegenomics profiles, future studies should prioritize large-scale analyses to identify potential genetic variations associated with lung cancer using highthroughput technologies across different populations. This approach will provide further information for predicting response to targeted therapy and promotes the development of new measures for individualized cancer treatment.

Genomic variation induced by a low concentration of ethyl methanesulfonate (EMS) in quinoa 'Longli-4' variety.

Quinoa (Chenopodium quinoa, 2n = 4x = 36), a super pseudocereal crop, has been introduced into China nearly 60 years. Many excellent varieties have been developed through massive selection; however, few are developed through mutagenesis breeding. In this study, the 'Longli-4' variety, locally cultivated in Gansu province, Northwest China, was selected for experimentation. The grains of 'Longli-4' were treated with ethyl methanesulfonate (EMS) at a concentration of 0.8% for 8 h. Nine plants from independent M2 families were randomly selected to investigate the mutagenesis effect of EMS on the quinoa genome. The results indicated that the single nucleotide polymorphisms (SNPs) induced by EMS were unevenly distributed across all 18 chromosomes, with an average mutation frequency of 91.2 SNPs/Mb, ranging from 4.5 to 203.5 SNPs/Mb. A significant positive correlation between the number of SNPs and chromosome length was identified through linear model analysis. Transitions from G/C to A/T were the most predominated in all variant categories, accounting for 34.4-67.2% of the mutations, and SNPs were significantly enriched in intergenic regions, representing 69.2-75.1% of the total mutations. This study provides empirical support for the application of low concentration EMS treatment in quinoa breeding.

Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models.

Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.

Genetic diversity and population structure of Uganda cassava germplasm.

Cassava (Manihot esculenta Crantz) holds significant economic importance globally. Evaluating a diverse range of germplasm based on molecular characteristics not only enhances its preservation but also supports its utilization in breeding programs. In this study, we assessed genetic diversity and population structure among 155 cassava genotypes from Uganda using 5247 single nucleotide polymorphism (SNP) markers. Genotyping by sequencing (GBS) was employed for SNP discovery and to evaluate genetic diversity and population structure using the ADMIXTURE software. The cassava accessions comprised two populations: 49 accessions from Ugandan lines and 106 accessions resulting from crosses between South American and Ugandan lines. The average call rate of 96% was utilized to assess marker polymorphism. Polymorphic information content values of the markers ranged from 0.1 to 0.5 with an average of 0.4 which was moderately high. The principal component analysis (PCA) showed that the first two components captured ~ 24.2% of the genetic variation. The average genetic diversity was 0.3. The analysis of molecular variance (AMOVA) indicated that 66.02% and 33.98% of the total genetic variation occurred within accessions and between sub-populations, respectively. Five sub-populations were identified based on ADMIXTURE structure analysis (K = 5). Neighbor-joining tree and hierarchical clustering tree revealed the presence of three different groups which were primarily based on the source of the genotypes. The results suggested that there was considerable genetic variation among the cassava genotypes which is useful in cassava improvement and conservation efforts.

Enhancing drought tolerance in Malva parviflora plants through metabolic and genetic modulation using Beauveria bassiana inoculation.

BACKGROUND: Enhancing crops' drought resilience is necessary to maintain productivity levels. Plants interact synergistically with microorganisms like Beauveria bassiana to improve drought tolerance. Therefore, the current study investigates the effects of biopriming with B. bassiana on drought tolerance in Malva parviflora plants grown under regular irrigation (90% water holding capacity (WHC)), mild (60% WHC), and severe drought stress (30% WHC). RESULTS: The results showed that drought stress reduced the growth and physiological attributes of M. parviflora. However, those bioprimed with B. bassiana showed higher drought tolerance and enhanced growth, physiological, and biochemical parameters: drought stress enriched malondialdehyde and H2O2 contents. Conversely, exposure to B. bassiana reduced stress markers and significantly increased proline and ascorbic acid content under severe drought stress; it enhanced gibberellic acid and reduced ethylene. Bioprimed M. parviflora, under drought conditions, improved antioxidant enzymatic activity and the plant's nutritional status. Besides, ten Inter-Simple Sequence Repeat primers detected a 25% genetic variation between treatments. Genomic DNA template stability (GTS) decreased slightly and was more noticeable in response to drought stress; however, for drought-stressed plants, biopriming with B. bassiana retained the GTS. CONCLUSION: Under drought conditions, biopriming with B. bassiana enhanced Malva's growth and nutritional value. This could attenuate photosynthetic alterations, up-regulate secondary metabolites, activate the antioxidant system, and maintain genome integrity.

[Comparative analysis of the taxonomic classification criteria for a number of groups of pathogenic DNA and RNA viruses based on genomic data].

The basis for criteria of the taxonomic classification of DNA and RNA viruses based on data of the genomic sequencing are viewed in this review. The genomic sequences of viruses, which have genome represented by double-stranded DNA (orthopoxviruses as example), positive-sense single-stranded RNA (alphaviruses and flaviviruses as example), non-segmented negative-sense single-stranded RNA (filoviruses as example), segmented negative-sense single-stranded RNA (arenaviruses and phleboviruses as example) are analyzed. The levels of genetic variability that determine the assignment of compared viruses to taxa of various orders are established for each group of viruses.

Defects in Glabrous 3 (GL3) functionality underlie the absence of trichomes in Brassica napus.

Previously, expression of the Arabidopsis thaliana GLABRA3 (GL3) induced trichome formation in Brassica napus. GL3 orthologues were examined from glabrous (B. oleracea), semi-glabrous (B. napus), moderately hirsute (B. rapa), and very hirsute (B. villosa) Brassica species. Ectopic expression of BnGL3, BrGL3 alleles, or BvGL3 induced trichome formation in glabrous B. napus with the effect on trichome number commensurate with density in the original accessions. Chimeric GL3 proteins in which the B. napus amino terminal region, which interacts with MYB proteins, or the middle region, which interacts with the WD40 protein TTG1, was exchanged with corresponding regions from A. thaliana were as stimulatory to trichome production as AtGL3. Exchange of the carboxy-terminal region containing a bHLH domain and an ACT domain did not alter the trichome stimulatory activity, although modeling of the ACT domain identified differences that could affect GL3 dimerization. B. napus A- and C-genomes orthologues differed in their abilities to form homo- and heterodimers. Modeling of the amino-terminal region revealed a conserved domain that may represent the MYB factor binding pocket. This region interacted with the MYB factors GL1, CPC, and TRY, as well as with JAZ8, which is involved in jasmonic acid-mediated regulation of MYC-like transcription factors. Protein interaction studies indicated that GL1 interaction with GL3 from B. napus and A. thaliana may underlie the difference in their respective abilities to induce trichome formation.

Transporter-mediated drug-drug interactions: regulatory guidelines, in vitro and in vivo methodologies and translation, special populations, and the blood-brain barrier.

This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.

Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.

Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.

Modulation in the ratio of abscisic acid to gibberellin level determines genetic variation of seed dormancy in barley (Hordeum vulgare L.).

Abscisic acid (ABA) and gibberellin (GA) are major regulators of seed dormancy, an adaptive trait closely associated with preharvest sprouting. This study examined transcriptional regulation of ABA and GA metabolism genes and modulation of ABA and GA levels in seeds of barley genotypes exhibiting a range of dormancy phenotype. We observed a very strong negative correlation between genetic variation in seed germination and embryonic ABA level (r = 0.85), which is regulated by transcriptional modulation of HvNCED1 and/or HvCYP707A genes. A strong positive correlation was evident between variation in seed germination and GA level (r = 0.64), mediated via transcriptional regulation of GA biosynthesis genes, HvGA20ox2 and/or HvGA3oxs, and GA catabolism genes, HvGA2ox3 and/or HvGA3ox6. Modulation of the ABA and GA levels in the genotypes led to the prevalence of ABA to GA level ratio that exhibited a very strong negative correlation (r = 0.84) with seed germination, highlighting the importance of a shift in ABA/GA ratio in determining genetic variation of dormancy in barley seeds. Our results overall show that transcriptional regulation of specific ABA and GA metabolism genes underlies genetic variation in ABA/GA ratio and seed dormancy, reflecting the potential use of these genes as molecular tools for enhancing preharvest sprouting resistance in barley.

Methods for multiancestry genome-wide association study meta-analysis.

Genome-wide association studies (GWAS) have significantly enhanced our understanding of the genetic basis of complex diseases. Despite the technological advancements, gaps in our understanding remain, partly due to small effect sizes and inadequate coverage of genetic variation. Multiancestry GWAS meta-analysis (MAGMA) addresses these challenges by integrating genetic data from diverse populations, thereby increasing power to detect loci and improving fine-mapping resolution to identify causal variants across different ancestry groups. This review provides an overview of the protocols, statistical methods, and software of MAGMA, as well as highlighting some challenges associated with this approach.