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Local adaptation is widely seen when species adapt to spatially heterogeneous environments. Although many theoretical studies have investigated the dynamics of local adaptation using 2-population models, there remains a need to extend the theoretical framework to continuous space settings, reflecting the real habitats of species. In this study, we use a multidimensional continuous space model and mathematically analyze the establishment process of local adaptation, with a specific emphasis on the relative roles of mutation and migration. First, the role of new mutations is evaluated by deriving the establishment probability of a locally adapted mutation using a branching process and a diffusion approximation. Next, the contribution of immigrants from a neighboring region with similar environmental conditions is considered. Theoretical predictions of the local adaptation rate agreed with the results of Wright–Fisher simulations in both mutation-driven and migration-driven cases. Evolutionary dynamics depend on several factors, including the strength of migration and selection, population density, habitat size, and spatial dimensions. These results offer a theoretical framework for assessing whether mutation or migration predominantly drives convergent local adaptation in spatially continuous environments in the presence of patchy regions with similar environmental conditions. [ABSTRACT FROM AUTHOR]

Copyright of Acta Agronomica Sinica is the property of Crop Science Society of China and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Schizophrenia is one of the most debilitating mental disorders that afflict mankind. A putative susceptibility locus for schizophrenia, the -308 G/A (rs361525) polymorphism, is situated in the promoter region of the TNF-α gene and has attracted substantial interest. Moreover, multiple studies have linked the A-allele to elevated TNF-α expression. It was essential to ascertain whether the promoter region influenced the inhabitants of Western Indonesia due to its paradoxical results. The subjects were adults of the Malayan-Mongoloid race, aged 15 to 40, diagnosed with schizophrenia according to the International Classification of Diseases, 10th edition criteria. They were required to be helpful and amenable to participating in an interview. The presence of mental problems, obesity, and general medical conditions affecting brain anatomy were deemed excluding factors. The inclusion criteria for the controls comprised individuals of the Malayan- Mongoloid race, aged 15 to 40, with no familial history of mental disorders, as well as a shown willingness to cooperate and participate in interviews. Obesity, general medical conditions affecting brain morphology, and a psychiatric disorder history were the exclusion criteria for the control group. Chi-square test and Hardy-Weinberg Equilibrium were used to analyse the result, and we found that there were no differences between genotypes and alleles in schizophrenia and healthy controls. In North Sumatera, we identified no correlation. between the -308 G/A TNF-α polymorphism and schizophrenia. A single polymorphism cannot be deemed a substantial risk factor for the onset of a specific disease. [ABSTRACT FROM AUTHOR]

Traditional maize possesses low concentrations of provitamin-A and vitamin-E, leading to various health concerns. Mutant alleles of crtRB1 and vte4 that enhance β-carotene (provitamin-A) and α-tocopherol (vitamin-E), respectively, in maize kernels have been explored in several biofortification programs. For genetic improvement of these target nutrients, uniplex-PCR assays are routinely used in marker-assisted selection. However, due to back-to-back breeding seasons, the time required for genotyping individually for each target gene in large backcross populations becomes a constraint for advancing the generations. Additionally, multiple PCR assays for various genes increase the required costs and resources. Here, we aimed to develop a multiplex-PCR assay to simultaneously identify different allelic forms of crtRB1 and vte4 genes and validate them in a backcross-based segregating population. The PCR assay was carried out using newly developed primers for crtRB1 and a gene-specific primer for vte4. The uniplex-PCR assay was standardized for selected primer pairs in the BC1F1 population segregating for crtRB1 and vte4 genes. Subsequently, a multiplex-PCR assay for crtRB1 and vte4 genes was developed and employed for genotyping in the BC1F1 population. The assay differentiated among four possible genotypic classes, namely crtRB1+crtRB1/vte4+vte4, crtRB1crtRB1/vte4+vte4, crtRB1+crtRB1/vte4+vte4+, and crtRB1crtRB1/vte4+vte4+. This newly developed multiplex-PCR assay saved 41.7% of the cost and 35.6% of the time compared to two individual uniplex-PCR assays. The developed assay could accelerate maize nutritional quality breeding programs through rapid and cost-effective genotyping for the target genes. This is the first report of a multiplex-PCR assay specific to crtRB1 and vte4 genes for its use in genomics-assisted breeding in maize. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii infects approximately 30% of the population, and there is currently no approved vaccine. Identifying immunogenic peptides with high affinity to different HLA molecules is a promising vaccine strategy. This study used an in silico approach using artificial neural networks to identify T. gondii peptides restricted to HLA-A*02, HLA-A*24, and HLA-B*35 alleles. Proteomes from seven T. gondii strains and transcriptomic data of overexpressed genes from T. gondii-RH in human PBMC were also used. Parasite protein sequences were analyzed with R 'Epitope Prediction' library. Peptide candidates were evaluated in the artificial neural networks based on the probabilities of output neurons (p > 0.5). The IFN-γ responses in PBMC from T. gondii seronegative and seropositive individuals were evaluated by ELISpot. Peptides with higher IFN-γ induction were evaluated to identify cytotoxic response in CD8+ T cells (CD107a). In silico analysis identified 36 peptides from T. gondii proteins with predicted affinity to HLA-A*02, A*24, and B*35 alleles. Experiments with PBMCs revealed that a peptide restricted to HLA-A02 (P1: FLFAWITYV) induced a significant increase in IFN-γ-producing cells (p = 0.004). For HLA-A24, a peptide (P8: VFAFAFAFFLI) also induced a significant IFN-γ response (p = 0.004), while for the HLA-B*35 allele, the P6 peptide (YPIAPSFAM) induced a response that differed significantly from the control (p = 0.05). These peptides induced also a significant percentage of central memory CD8 + T cells expressing the degranulation marker CD107a (p < 0.05). Finally, we identified three T. gondii peptides that induced IFN-γ response, and a cytotoxic response measured by CD107a expression on CD45RAneg-CD8 cells. These peptides could be considered part of a multi-epitope vaccine against toxoplasmosis in humans. [ABSTRACT FROM AUTHOR]

Dietary Mn intake may have a beneficial effect in reducing cancer risk; however, its association with thyroid cancer (TC) risk remains inadequately understood. Additionally, Mn was associated with inflammation markers. Thus, we examined whether dietary Mn intake emerges a protective role against TC and whether this preventative effect has an interaction with IL1 receptor type 1 (IL1R1) rs3917225. The prospective study was designed at National Cancer Center in Korea between October 2007 and December 2020 including 17 754 participants. We identified TC cases by following participants until December 2020. Mn intake was collected using a semiquantitative food frequency questionnaire (SQFFQ). Genotyping was performed to determine IL1R1 rs3917225. The hazard ratios (HR) and 95 % confidence interval (CI) were calculated with a Cox proportional hazards model. We ascertained 108 incident TC cases throughout follow-up duration. Dietary Mn intake was found to be inversely associated with TC risk (HR (95 % CI)=0·64 (0·44, 0·95)). However, IL1R1 rs3917225 seemed to modify this association; the protective effect was limited to G-allele carriers (HR = 0·30 (0·11, 0·86), P interaction=0·028). A higher dietary Mn was suggested to be a protective factor against TC. Additionally, we drew a potential biological interaction between Mn intake and IL1R1 rs3917225 with a greater effect among individuals with a minor allele. This implies that when considering the cancer-preventive role of Mn, it is important to account for the influence of inflammatory gene participation. [ABSTRACT FROM AUTHOR]

This study used 10 pairs of microsatellites to analyze the genetic diversity of the Odontobutis obscurus population in Guangxi. Clear and stable amplified bands were obtained in samples from three Odontobutis obscurus populations in Qinzhou City (QZ), Hechi City (HC), and Liuzhou City (LZ), showing varying degrees of polymorphism. The effective alleles for 10 loci range from 0.926 6 to 4.2130, with an average of 2.162 1 and an expected heterozygosity of 0.106 8 to 0.843 1, with an average of 0.475 1, the observed heterozygosity is between 0.149 1 and 0.803 4, with an average of 0.486 8. The polymorphism information content is between 0.081 1 and 0.5984, with an average polymorphism infor- mation content of 0.311 0.The number of effective alleles in the three populations is HC>LZ>QZ, the observed heterozygosity value is HC>LZ> QZ, the expected heterozygosity value is HC>LZ>QZ, and the population polymorphism information content is HC>LZ>QZ.There is moderate genetic differentiation among the three different populations of HC, LZ, and QZ, with an average gene differentiation coefficient of 0.100 3, indi- cating that 10.03% of genetic differentiation comes from among the three different populations in the field, and 89.97% of genetic differentiation comes from within individuals of the Odontobutis obscurus. [ABSTRACT FROM AUTHOR]

Background: Scrapie is an infectious prion disease in sheep. Selective breeding for resistant genotypes of the prion protein gene (PRNP) is an effective way to prevent scrapie outbreaks. Genotyping all selection candidates in a population is expensive but existing pedigree records can help infer the probabilities of genotypes in relatives of genotyped animals. Results: We used linear models to predict allele content for the various PRNP alleles found in Icelandic sheep and compiled the available estimates of relative scrapie susceptibility (RSS) associated with PRNP genotypes from the literature. Using the predicted allele content and the genotypic RSS we calculated estimated breeding values (EBV) for RSS. We tested the predictions on simulated data under different scenarios that varied in the proportion of genotyped sheep, genotyping strategy, pedigree recording accuracy, genotyping error rates and assumed heritability of allele content. Prediction of allele content for rare alleles was less successful than for alleles with moderate frequencies. The accuracy of allele content and RSS EBV predictions was not affected by the assumed heritability, but the dispersion of prediction was affected. In a scenario where 40% of rams were genotyped and no errors in genotyping or recorded pedigree, the accuracy of RSS EBV for ungenotyped selection candidates was 0.49. If only 20% of rams were genotyped, or rams and ewes were genotyped randomly, or there were 10% pedigree errors, or there were 2% genotyping errors, the accuracy decreased by 0.07, 0.08, 0.03 and 0.04, respectively. With empirical data, the accuracy of RSS EBV for ungenotyped sheep was 0.46–0.65. Conclusions: A linear model for predicting allele content for the PRNP gene, combined with estimates of relative susceptibility associated with PRNP genotypes, can provide RSS EBV for scrapie resistance for ungenotyped selection candidates with accuracy up to 0.65. These RSS EBV can complement selection strategies based on PRNP genotypes, especially in populations where resistant genotypes are rare. [ABSTRACT FROM AUTHOR]

The rapid virulence variation of Magnaporthe oryzae (M. oryzae) to rice is a big challenge for rice blast control. Even though many studies have been done by scientists all over the world, the mechanism of virulence variation in M. oryzae remains elusive. AM16, an avirulent M. oryzae strain reported in our previous study, provides an excellent entry point to explore the mechanism of virulence variation in M. oryzae. In this study, we found that the Pmk1 and Mac1 had specific mutations in strain AM16. The AM16 strains overexpressing Pmk1 Guy11 or (and) Mac1 Guy11 allele from strain Guy11 displayed significantly increasing conidiation, functional appressorium formation, and restoring pathogenicity to rice. Moreover, we observed that the strains overexpressing Mac1 Guy11 had stronger conidia forming capacity than that of the strains overexpressing Pmk1 Guy11, while the appressorium formation rate of strains overexpressing Pmk1 Guy11 was similar to that of strains overexpressing Pmk1 Guy11- Mac1 Guy11, much higher than that of the strains overexpressing Mac1 Guy11. Taken together, our results reveal that the natural mutation of Pmk1 and Mac1 genes are important, but not the sole cause, for the loss of virulence in strain AM16. The functional difference between Pmk1 and Mac1 in the growth and development of M. oryzae was first discovered, providing new insight into the pathogenic mechanism of M. oryzae. [ABSTRACT FROM AUTHOR]

Simple Summary: Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and high relapse rate. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS) in order to identify genetic alteration driving relapse. Four main genetic pathways leading to relapse in adults were identified: IKZF1plus genetic profile, RAS mutations and TP53 alterations in Philadelphia chromosome (Ph)-negative B-ALL and acquisition of ABL1 mutations in Ph-positive patients. In addition, three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS). Four main genetic pathways leading to relapse in adults were identified: IKZF1plus genetic profile, RAS mutations and TP53 alterations in Ph-negative B-ALL and acquisition of ABL1 mutations in Ph-positive patients. The most frequently deleted gene at diagnosis was IKZF1 (52%), and 70% of these patients had IKZF1plus profile. Notably, 88% of patients with IKZF1plus at diagnosis retained this genetic profile at relapse. Conversely, the acquisition of RAS mutations or the expansion of subclones (normalized variant allele frequency < 25%) present from diagnosis were observed in 24% of Ph-negative patients at relapse. In addition, 24% of relapses in the Ph-negative cohort could potentially be driven by TP53 alterations. Of these cases, five presented from diagnosis, and four emerged at relapse, mostly as "double-hit" events involving both TP53 deletion and mutation. In Ph-positive B-ALL, the main genetic finding at relapse was the acquisition of ABL1 mutations (86%). Three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. These findings underscore the need for personalized therapeutic strategies to improve clinical outcomes in adult patients with B-ALL. [ABSTRACT FROM AUTHOR]

Background Case Presentation and Methods Results and Discussion Conclusion Among the alleles of the ABO system, cisAB and B(A) are the most intriguing due to their ability to encode a glycosyltransferase that can synthesize both A and B antigens. This dual activity leads to the formation of the AB phenotype, even in the presence of the O allele; resolution is achieved by molecular analyses.We describe herein a Brazilian family in which the mother (M42.1) of group AB and the father (M42.2) of group O have two children of group AB (M42.3 and M42.4). Serological characterization involved ABO and H phenotyping tests and serial dilution of ABO monoclonal antibodies. Characterization of ABO genotypes and alleles were performed by PCR‐RFLP and sequencing.In serological tests, red blood cells from M42.1, M42.3, and M42.4 showed an intermediate reactivity pattern between A1B and A2B. Molecular analyses revealed the presence of the ABO*O.01.01/O.01.01 genotype in M42.2 and the ABO*cisAB.05/O.01.01 genotype in M42.1, M42.3, and M42.4. The ABO*cisAB.05 allele encodes a glycosyltransferase able to synthesize A and B antigens in quantities sufficient to cause an agglutination reaction higher than that observed in A2B phenotypes.The combination of serological and molecular methods used in this study allowed us to determine the serological pattern, identify the ABO alleles, and explain the inheritance of the AB phenotype in this family. [ABSTRACT FROM AUTHOR]

ABSTRACT Understanding the complex genetic mechanisms controlling rice heading is crucial for rice breeding that aims to promote heading while minimizing adverse impacts on other agronomic traits. However, the allelic variations of major heading date genes in Korean rice cultivars and their effects on key agronomic traits remain unclear. Therefore, we catalogued the allele types of four major heading date genes (Hd1, OsPRR37, Ghd7 and DTH8) in 292 Korean commercial rice cultivars and investigated their individual and combined effects on major agronomic traits over 4 years under natural long‐day conditions. Our study showed that non‐functional hd1 allele have been extensively adopted in developing early maturing cultivars, whereas the alleles associated with early heading in OsPRR37, Ghd7 and DTH8 and their combinations have been rarely used in Korean rice breeding programmes. Alleles within the same functional group exhibited distinct effects on major agronomic traits, highlighting the need for more precise evaluations under isogenic backgrounds. Our study provides useful insights for breeding early maturing rice cultivars that maintain high yield by exploring under‐utilized alleles of heading date genes and their combinations. [ABSTRACT FROM AUTHOR]

For the first time, the allelic diversity of exon 2 of the DRB1 gene (class II of the major histocompatibility complex, MHC) was determined by NGS sequencing in natural populations of two species of hamsters of the genus Allocricetulus: Eversmann's hamster (A. eversmanni) and the Mongolian hamster (A. curtatus). These species are genetically close, but allopatric and demonstrate different habitat preferences. Eversmann's hamster inhabits the steppes and is often associated with anthropogenic landscapes, while the Mongolian hamster prefers semi-deserts and deserts, where anthropogenic pressure is almost absent. The analysis revealed a significant effect of positive selection on the diversity of alleles of the DRB1 gene in both species studied. However, Eversmann's hamster is characterized by a large average distance between alleles, but a smaller proportion of heterozygous individuals, while the Mongolian hamster is characterized by a large individual variety of alleles. Thus, despite the extensive range of Eversmann's hamster, we noted significantly less genetic diversity of adaptive genes, which may be due to increased anthropogenic exposure. [ABSTRACT FROM AUTHOR]

The adaptive immune system generates a diverse array of B-cell receptors through the processes of V(D)J recombination and somatic hypermutation. B-cell receptors that bind to an antigen will undergo clonal expansion, creating a Darwinian evolutionary dynamic within individuals. A key step in studying these dynamics is to identify sequences derived from the same ancestral V(D)J recombination event (i.e. a clonal family). There are a number of widely used methods for accomplishing this task but a major limitation of all of them is that they rely, at least in part, on the ability to map sequences to a germline reference set. This requirement is particularly problematic in non-model systems where we often know little about the germline allelic diversity in the study population. Recognizing that delimiting B-cell clonal families is analogous to delimiting species from single locus data, we propose a novel strategy of reconstructing the phylogenetic tree of all B-cell sequences in a sample and using a popular species delimitation method, multi-rate Poisson Tree Processes (mPTP), to delimit clonal families. Using extensive simulations, we show that not only does this phylogenetically explicit approach perform well for the purpose of delimiting clonal families when no reference allele set is available, it performs similarly to state-of-the-art techniques developed specifically for B-cell data even when we have a complete reference allele set. Additionally, our analysis of an empirical dataset shows that mPTP performs similarly to leading methods in the field. These findings demonstrate the utility of using off-the-shelf phylogenetic techniques for analyzing B-cell clonal dynamics in non-model systems, and suggests that phylogenetic inference techniques may be potentially combined with mapping based approaches for even more robust inferences, even in model systems. [ABSTRACT FROM AUTHOR]

NARROW LEAF1 (NAL1) is one of the key genes in regulating photosynthesis and plant architecture. As the antagonistic effects of NAL1 have concurrent impacts on photosynthesis and yield component traits, how we can effectively utilize the NAL1 gene to further increase rice yield is not clear. In this study, we used two different main functional NAL1 alleles, each of which has previously been proven to have specifically advantageous traits, and tested whether the combined NAL1 alleles have a higher yield than the homozygous alleles. Our results exhibited that the combined NAL1 alleles had better parent heterosis (BPH) for panicle number and the total filled grain number per plant, and had middle parent heterosis (MPH) for spikelet number per panicle without affecting thousand-grain weight when compared with the homozygous alleles. In consequence, the NAL1 hybrid plants displayed highly increased grain yield compared with both homozygous parents. The hybrid plants also had better plant architecture and higher canopy photosynthesis. Western blot and proteomics results showed the hybrid plants had a middle abundant NAL1 protein level, and the upregulated proteins were mainly involved in the nucleus and DNA binding process but the downregulated proteins were mainly involved in the oxidation-reduction process, single-organism metabolic process, and fatty acid biosynthetic process. Furthermore, the hybrid vigor effect of NAL1 was confirmed by substituting the mutual male parent 9311 with 9311-NIL in two super hybrid rice varieties (LYP9 and YLY1). This study demonstrates that we can achieve a higher level of grain production in hybrid rice by using the heterosis of NAL1. [ABSTRACT FROM AUTHOR]

The influence of the SNP rs174575 (C/G) within the fatty acid desaturase 2 gene on the levels of long-chain PUFA was determined through statistical meta-analysis. Six databases were searched to retrieve the relevant literature. Original data were analysed using Stata 17·0, encompassing summary statistics, tests for heterogeneity, assessment of publication bias, subgroup analysis and sensitivity analysis. A total of ten studies were identified and grouped into twelve trials. Our results showed that individuals who carried the minor G allele of rs174575 had significantly higher dihomo- γ -linolenic acid levels (P = 0·005) and lower arachidonic acid levels (P = 0·033) than individuals who were homozygous for the major allele. The subgroup analysis revealed that the G-allele carriers of rs174575 were significantly positively correlated with linoleic acid (P = 0·002) and dihomo- γ -linolenic acid (P < 0·001) and negatively correlated with arachidonic acid (P = 0·004) in the European populations group. This particular SNP showed a potential association with higher concentrations of dihomo- γ -linolenic acid (P = 0·050) and lower concentrations of arachidonic acid (P = 0·030) within the breast milk group. This meta-analysis has been registered in the PROSPERO database (ID: CRD42023470562). [ABSTRACT FROM AUTHOR]

Background selection, by which selection on deleterious alleles reduces diversity at linked neutral sites, influences patterns of total neutral diversity, πT, and genetic differentiation, FST, in structured populations. The theory of background selection may be split into two regimes: the background selection regime, where selection pressures are strong and mutation rates are sufficiently low such that deleterious alleles are at a deterministic mutation-selection balance, and the interference selection regime, where selection pressures are weak and mutation rates are sufficiently high that deleterious alleles accumulate and interfere with another, leading to selective interference. Previous work has quantified the effects of background selection on πT and FST only for deleterious alleles in the background selection regime. Furthermore, there is evidence to suggest that migration reduces the effects of background selection on FST, but this has not been fully explained. Here, we derive novel theory to predict the effects of migration on background selection experienced by a subpopulation and extend previous theory from the interference selection regime to make predictions in an island model. Using simulations, we show that this theory best predicts FST and πT. Moreover, we demonstrate that background selection may generate minimal increases in FST under sufficiently high migration rates, because migration reduces correlated effects on fitness over generations within subpopulations. However, we show that background selection may still cause substantial reductions in πT, particularly for metapopulations with a larger effective population size. Our work further extends the theory of background selection into structured populations, and suggests that background selection will minimally confound locus-to-locus FST scans. Author summary: Most mutations that affect fitness incur deleterious effects and are ultimately removed via natural selection. Consequently, nearby neutral variants may also experience the effects of selection; this is termed background selection. Background selection greatly influences patterns of genetic diversity both between and within populations among virtually all extant species, and is therefore of great interest to geneticists. Previous models of background selection have been primarily restricted to populations with completely random mating. However, it is well known that most natural populations exhibit some form of spatial structure. Here, we explore the effects of background selection in spatially structured populations, and we find that migration between subpopulations may attenuate the effects of background selection acting to increase genetic differentiation among populations. We derive novel theory to account for this effect by considering that individuals with deleterious alleles may migrate out of a local subpopulation prior to being removed by the population via selection. Our work demonstrates that, when migration rates are high, background selection does not substantially influence genetic differentiation among populations. Despite this, we find that background selection may greatly decrease genetic diversity within subpopulations and in the whole metapopulation. [ABSTRACT FROM AUTHOR]

Beckwith-Wiedemann syndrome (BWS) is caused by a gain of methylation (GOM) at the imprinting control region within the Igf2-H19 domain on the maternal allele (H19-ICR GOM). Mutations in the binding sites of several transcription factors are involved in H19-ICR GOM and BWS. However, the responsible sequence(s) for H19-ICR GOM with BWS-like overgrowth has not been identified in mice. Here, we report that a mutation in the SOX-OCT binding site (SOBS) causes partial H19-ICR GOM, which does not extend beyond CTCF binding site 3 (CTS3). Moreover, simultaneously mutating both SOBS and CTS3 causes complete GOM of the entire H19-ICR, leading to the misexpression of the imprinted genes, and frequent BWS-like overgrowth. In addition, CTS3 is critical for CTCF/cohesin-mediated chromatin conformation. These results indicate that SOBS and CTS3 are the sequences in which mutations cause H19-ICR GOM leading to BWS-like overgrowth and are essential for maintaining the unmethylated state of maternal H19-ICR. SOX-OCT binding site and CTCF binding site 3 in H19-ICR are the sequences in which mutations cause H19-ICR hypermethylation leading to Beckwith-Wiedemann syndrome-like overgrowth. [ABSTRACT FROM AUTHOR]

Copyright of Biomédica: Revista del Instituto Nacional de Salud is the property of Instituto Nacional de Salud of Colombia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This study aims to leverage the advanced capabilities of quantum computing to construct an efficient framework for processing large-scale health data, uncover potential higher-order correlations in medicine, and enhance the accuracy of smart healthcare diagnosis and treatment. A data processing framework is developed using quantum annealing algorithms and quantum circuits. We call it the quantum medical data simulation computational model (Q-MDSC). A unique encoding method based on quantum bits is employed for health data features, such as encoding symptom information from electronic health records into different quantum bits and representing different alleles of genetic data through superposition states of quantum bits. The properties of quantum entanglement are utilized to relate different data types, and quantum parallelism is harnessed to process multiple data combinations simultaneously. Additionally, this quantum computing framework is compared with traditional data mining methods using the same datasets, which include the Cochrane Systematic Review Database (https://www.cochranelibrary.com), the BioASQ Dataset (https://participants-area.bioasq.org), the PubMed Central Dataset (https://www.ncbi.nlm.nih.gov/pmc), and the Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov). The datasets are divided into training and testing sets in a 7:3 ratio during the experiments. Tests are conducted on association mining tasks of varying data scales and complexities, ranging from simple symptom-disease associations to complex gene-symptom-disease higher-order associations. The results indicate that, when processing large-scale data, the quantum computing framework improves overall computational speed by approximately 45% compared to traditional algorithms. Regarding uncovering higher-order correlations, the quantum computing framework enhances accuracy by about 30% relative to traditional algorithms. For early disease prediction, the accuracy achieved with the new framework is approximately 25% higher than that of conventional methods. Furthermore, for personalized treatment plan matching, the matching accuracy of the quantum computing framework surpasses traditional approaches by about 35%. These findings demonstrate the significant potential of the quantum computing-based smart healthcare framework for processing large-scale health data in the context of higher-order correlation mining, paving new pathways for the development of smart healthcare. This study utilizes multiple public datasets to achieve breakthroughs in computational speed, higher-order correlation mining, early disease prediction, and personalized treatment plan matching, thus opening new avenues for advancing smart healthcare. [ABSTRACT FROM AUTHOR]

Introduction: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele mediates risk. APOE4 carriers experience reduced mobility and faster decline in muscle strength, suggesting skeletal muscle involvement. Mitochondria are critical for muscle function and although we have reported defects in muscle mitochondrial respiration during early cognitive decline, APOE4 -mediated effects on muscle mitochondria are unknown. Methods: Here, we sought to determine the impact of APOE4 on skeletal muscle bioenergetics using young, male and female APOE3 (control) and APOE4 targeted replacement mice (n = 8 per genotype/sex combination). We examined the proteome, mitochondrial respiration, fiber size, and fiber-type distribution in skeletal muscle. Results: We found that APOE4 alters mitochondrial pathway expression in young mouse muscle in a sex-dependent manner without affecting respiration and fiber size or composition relative to APOE3. In both sexes, the expression of mitochondrial pathways involved in electron transport, ATP synthesis, and heat production by uncoupling proteins and mitochondrial dysfunction significantly differed between APOE4 and APOE3 muscle. For pathways with predicted direction of activation, electron transport and oxidative phosphorylation were upregulated while mitochondrial dysfunction and sirtuin signaling were downregulated in female APOE4 vs. APOE3 muscle. In males, sulfur amino acid metabolism was upregulated in APOE4 vs. APOE3 muscle. Discussion: This work highlights early involvement of skeletal muscle in a mouse model of APOE4 -linked AD, which may contribute to AD pathogenesis or serve as a biomarker for brain health. [ABSTRACT FROM AUTHOR]

This study was conducted to examine the possibility of reducing PCR reaction volume of the PowerPlex Fusion system to produce full DNA genotyping of some forensic casework samples. Human DNA profiling was analyzed by half and quarter PCR reaction volume of the PowerPlex® Fusion system amplification kit to examine the reliability of the obtained STR profiles. Serial DNA dilutions (1 ng, 0.5 ng, 0.125 ng, 0.0625 ng) of a buccal swab were used with half PCR reaction volume to analyze STR loci via estimating their peak height and stutter ratio. The peak height ratio was above 60% in all heterozygous loci obtained and the best ratio of stutter was in the sample with a concentration of 0.0125, as it was less than 16% in all loci. Half and quarter PCR reaction volumes were evaluated by different casework samples (blood, hairs, and nails). The results showed that half reaction volumes gave 100% STR profiles of blood and nail samples and 60% of hair samples gave complete profiles. In 40% of hair samples, alleles were dropped out in the loci Penta E and Penta D. Quarter PCR reaction volumes gave 30% of blood and hair samples and 20% of nail samples produced a complete STR profile. It was possible to reduce the PCR reaction volume by more than half while still obtaining a complete STR profile suitable for human identification, despite some negative results that may have been due to DNA purity issues. Further studies are necessary to generalize this conclusion. [ABSTRACT FROM AUTHOR]

Objectives Since June 2022, there has been a rise in the number of ceftriaxone-resistant Neisseria gonorrhoeae cases detected in England (n  = 15), of which a third were XDR. We describe the demographic and clinical details of the recent cases and investigate the phenotypic and molecular characteristics of the isolates. For a comprehensive overview, we also reviewed 16 ceftriaxone-resistant cases previously identified in England since December 2015 and performed a global genomic comparison of all publicly available ceftriaxone-resistant N. gonorrhoeae strains with mosaic penA alleles. Methods All N. gonorrhoeae isolates resistant to ceftriaxone (MIC > 0.125 mg/L) were whole-genome sequenced and compared with 142 global sequences of ceftriaxone-resistant N. gonorrhoeae. Demographic, behavioural and clinical data were collected. Results All cases were heterosexual, and most infections were associated with travel from the Asia-Pacific region. However, some had not travelled outside England within the previous few months. There were no ceftriaxone genital treatment failures, but three of five pharyngeal infections and the only rectal infection failed treatment. The isolates represented 13 different MLST STs, and most had the mosaic penA -60.001 allele. The global genomes clustered into eight major phylogroups, with regional associations. All XDR isolates belonged to the same phylogroup, represented by MLST ST16406. Conclusions Most cases of ceftriaxone-resistant N. gonorrhoeae detected in England were associated with travel from the Asia-Pacific region. All genital infections were successfully treated with ceftriaxone, but there were extragenital treatment failures. Ceftriaxone resistance continues to be associated with the penA -60.001 allele within multiple genetic backgrounds and with widespread dissemination in the Asia-Pacific region. [ABSTRACT FROM AUTHOR]

Amylose content, the key determinant of rice eating and cooking quality, is regulated primarily by the Waxy (Wx) gene. We adjusted the amylose content and transparency of semi-glutinous japonica rice carrying the Wxmp allele by genome editing of upstream open reading frame 6 (uORF6) of Wx. [ABSTRACT FROM AUTHOR]

Simple Summary: Large genomic rearrangements of the PALB2 gene, especially deletions and duplications, are associated with hereditary breast–ovarian cancer. This study investigates intronic breakpoints linked to rearrangements in PALB2 exon 11, which is crucial for understanding the mechanisms affecting patients with hereditary breast and ovarian syndrome. Through next-generation sequencing, one duplication and three deletions were identified, confirmed by Multiplex Ligation-Dependent Probe Amplification. Detailed characterization revealed a tandem duplication of 5134 base pairs mediated by AluY repeats and identical deletions in three unrelated patients promoted by AluSx elements, resulting in a truncated PALB2 protein. These findings highlight the instability of intronic regions flanking exon 11 and suggest directions for future research on the prevalence and functional implications of these genomic alterations. Background/Objective: Large genomic rearrangements of PALB2 gene, particularly deletions and duplications, have been linked to hereditary breast–ovarian cancer. Our research specifically focuses on delineating the intronic breakpoints associated with rearrangements of PALB2 exon 11, which is crucial for understanding the mechanisms underlying these genomic changes in patients with hereditary breast and ovarian syndrome. Methods: By using next-generation sequencing, we identified one duplication and three deletions of PALB2 exon 11, confirmed by Multiplex Ligation-Dependent Probe Amplification analysis. To assess the impact on transcription and potential splicing issues, reverse-transcription PCR was performed on patients' RNA. For the detailed characterization of intronic breakpoints, the primer walking approach and long-range PCR were implemented, followed by Sanger sequencing. Results: Our analysis revealed a tandem duplication of 5134 base pairs (bp) mediated by AluY repeats located in introns 10 and 11, respectively. Moreover, identical deletions were identified in three unrelated patients, encompassing an approximate 8050 bp region mediated by AluSx elements. Both genomic alterations resulted in a truncated PALB2 protein due to the introduction of a premature stop codon. Conclusions: This study underscores the remarkable instability of intronic regions flanking exon 11 of PALB2 and identifies a previously unreported hotspot involving Alu repeats with very high sequence homology in introns 10 and 11 of the gene. Our findings suggest avenues for further research, such as investigating the prevalence of similar genomic rearrangements in larger cohorts and exploring functional studies to understand how these alterations contribute to hereditary breast cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: T cell receptor-engineered T (TCR-T) cell therapy, which engineers the cells of the immune system to enhance their ability for targeting tumor cells, holds great promise, especially for solid tumors. One major challenge in this field is the identification of the right T Cell Receptor, which constitutes the core of developing these therapies. Our study introduces a new approach for the discovery and analysis of the entire repertoire of naturally-occurring antigen-specific TCRs utilizing state-of-the-art single-cell sequencing technology. This method could greatly improve the development of personalized cancer therapies and may lead to more effective treatments for a variety of tumors. Background: Adoptive cell therapy is the most promising approach for battling cancer, with T cell receptor-engineered T (TCR-T) cell therapy emerging as the most viable option for treating solid tumors. Current techniques for preparing TCR-T cell therapy provide a limited number of candidates TCRs, missing the comprehensive view of the repertoire, which may hinder the identification of the most effective TCRs. Methods: Dendritic cells were primed with immunogenic peptides of the antigen of interest to expand antigen-specific CD8 T lymphocytes from peripheral blood. Following that, the entire repertoire of naturally occurring antigen-specific TCRs was analyzed using single-cell RNA sequencing, alongside the assessment of the dominancy, transcriptome, and binding specificity of the obtained clonotypes, utilizing the TCRscape tool and ERGO-II neural network to identify the most effective candidate for TCR-T cell therapy development. Finally, TCR-T cells with the candidate TCR were obtained, followed by assessing their functionality and selectivity. Results: The developed protocol achieved a remarkable increase in the percentage of antigen-specific T cells by more than 200-fold, with more than 100 antigen-specific TCR clonotypes identified. The resulting TCR-T cells demonstrated high cytotoxicity and selectivity for the targeted antigen, indicating their potential to preferentially target tumor cells. Conclusions: This study offers a comprehensive approach for the discovery and analysis of not only few, but the entire repertoire of naturally occurring antigen-specific TCRs for TCR-T cell therapy development. Additionally, the proposed approach can be tailored to accommodate different types of antigens and MHC variants, making it a highly versatile tool for both research and clinical applications. [ABSTRACT FROM AUTHOR]

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas. [ABSTRACT FROM AUTHOR]

The Zhejiang Han population, a subgroup of the Southern Han ethnic group, resides in Zhejiang Province, situated on the southeast coast of China. In this study, we conducted HLA genotyping for 813 voluntary umbilical cord blood donors from the Zhejiang Han population, targeting 11 HLA loci, namely HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1, using the next-generation sequencing method. Our analysis of the alleles and haplotypes revealed a high degree of polymorphism within these loci. A total of 289 unique HLA alleles were identified, with the HLA-B locus exhibiting the most significant diversity, while HLA-DRB4 displayed the lowest variation. Due to the inherent limitations of the sequencing method, some unresolvable alleles in the specific loci, such as HLA-DRB1, HLA-DPA1, and HLA-DPB1, were assigned as G group designation. In our comprehensive analysis across all 11 HLA loci, a total of 1204 haplotypes were estimated. The distribution of these alleles was similar to those of the Chinese Southern Han population while highly different from the Caucasian population. These findings contribute to a deeper understanding of the genetic characteristics of HLA loci within the Chinese Southern Han population. [ABSTRACT FROM AUTHOR]

‘Chamdongjin’ is a rice cultivar with a distinctively large grain size and good palatability, similar to ‘Sindongjin,’ which is a mega-cultivar in Korea. ‘Younghojinmi’ is a rice cultivar known for having the highest taste value among premium quality cultivars. In this study, we conducted quantitative trait loci (QTL) analysis of quality-related traits using recombinant inbred lines (RILs) derived from a cross between ‘Chamdongjin’ and ‘Younghojinmi’ to elucidate their genetic interactions. We analyzed 20 traits, including protein content, amylose content, glossiness of cooked rice, 7 traits related to grain appearance, 6 traits related to pasting properties, and 4 traits related to texture. Quality-related QTL were primarily detected on chromosome 3. In particular, GS3, one of the candidate genes for QTL, significantly influenced quality by affecting 14 different traits, including appearance traits such as head rice and the texture of cooked rice. Furthermore, RILs with the gs3 allele, which exhibited the large grains of ‘Chamdongjin,’ showed a lower protein content and higher amylose content than RILs with the GS3 allele. These lines also had lower head rice percentages and higher percentages of whiteness, opacity, and broken rice, indicating an inferior appearance quality. In terms of pasting properties, RILs with the gs3 allele showed a lower pasting temperature, peak viscosity, and breakdown, but a higher setback than RILs with the GS3 allele. Although the gs3 allele did not affect the glossiness, hardness, or toughness of the cooked rice, it resulted in higher adhesiveness and stickiness. Allelic alteration of the preharvest sprouting gene qLTG3-1 was found to affect seven quality-related traits, including pasting properties. Genes related to heading date (Hd18), culm length (SD1), and tiller number (OsTB1) were also associated with quality-related QTL. Alterations in the alleles of these genes caused variations in quality-related traits. Our identification of the association between quality-related traits and key agronomic genes is expected to support the effective development of rice cultivars with improved quality. [ABSTRACT FROM AUTHOR]

Background and Aims: Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late‐onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late‐onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients. Methods: The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects. Results: We observe a relatively mild axonal sensory‐motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression. Interpretation: CM2T has been definitively defined as a late‐onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included. [ABSTRACT FROM AUTHOR]

Locally adapted traits can exhibit a wide range of genetic architectures, from pronounced divergence at a few loci to small frequency divergence at many loci. The type of architecture that evolves depends strongly on the migration rate, as weakly selected loci experience swamping and do not make lasting contributions to divergence. Simulations from previous studies showed that even when mutations are strongly selected and should resist migration swamping, the architecture of adaptation can collapse and become transient at high mutation rates. Here, we use an analytical two-population model to study how this transition in genetic architecture depends upon population size, strength of selection, and parameters describing the mutation process. To do this, we develop a mathematical theory based on the diffusion approximation to predict the threshold mutation rate above which the transition occurs. We find that this performs well across a wide range of parameter space, based on comparisons with individual-based simulations. The threshold mutation rate depends most strongly on the average effect size of mutations, weakly on the strength of selection, and marginally on the population size. Across a wide range of the parameter space, we observe that the transition to a transient architecture occurs when the trait-wide mutation rate is 10 − 3 – 10 − 2 ⁠ , suggesting that this phenomenon is potentially relevant to complex traits with a large mutational target. On the other hand, based on the apparent stability of genetic architecture in many classic examples of local adaptation, our theory suggests that per-trait mutation rates are often relatively low. [ABSTRACT FROM AUTHOR]

Heterosis was the catalyst for the domestication of cultivated strawberry (⁠ F r a g a r i a × a n a n a s s a ⁠), an interspecific hybrid species that originated in the 1700s. The hybrid origin was discovered because the phenotypes of spontaneous hybrids transgressed those of their parent species. The transgressions included fruit yield increases and other genetic gains in the twentieth century that sparked the global expansion of strawberry production. The importance of heterosis to the agricultural success of the hybrid species, however, has remained a mystery. Here we show that heterosis has disappeared (become fixed) among improved hybrids within a population (the California population) that has been under long-term selection for increased fruit yield, weight, and firmness. We found that the highest yielding hybrids are among the most highly inbred (59–79%), which seems counterintuitive for a highly heterozygous, outbreeder carrying heavy genetic loads. Although faint remnants of heterosis were discovered, the between-parent allele frequency differences and dispersed favorable dominant alleles necessary for heterosis have decreased nearly genome-wide within the California population. Conversely, heterosis was prevalent and significant among wide hybrids, especially for fruit count, a significant driver of genetic gains for fruit yield. We attributed the disappearance (fixation) of heterosis within the California population to increased homozygosity of favorable dominant alleles and inbreeding associated with selection, random genetic drift, and selective sweeps. Despite historical inbreeding, the highest yielding hybrids reported to-date are estimated to be heterozygous for 20,370–44,280 of 97,000–108,000 genes in the octoploid genome, the equivalent of an entire diploid genome or more. [ABSTRACT FROM AUTHOR]

Summary: Rice tillering is an important agronomic trait that influences plant architecture and ultimately affects yield. This can be genetically improved by mining favourable variations in genes associated with tillering. Based on a previous study on dynamic tiller number, we cloned the gene Tiller number 1a (Tn1a), which encodes a membrane‐localised protein containing the C2 domain that negatively regulates tillering in rice. A 272 bp insertion/deletion at 387 bp upstream of the start codon in the Tn1a promoter confers a differential transcriptional response and results in a change in tiller number. Moreover, the TCP family transcription factors Tb2 and TCP21 repress the Tn1a promoter activity by binding to the TCP recognition site within the 272 bp indel. In addition, we identified that Tn1a may affect the intracellular K+ content by interacting with a cation‐chloride cotransporter (OsCCC1), thereby affecting the expression of downstream tillering‐related genes. The Tn1a+272 bp allele, associated with high tillering, might have been preferably preserved in rice varieties in potassium‐poor regions during domestication. The discovery of Tn1a is of great significance for further elucidating the genetic basis of tillering characteristics in rice and provides a new and favourable allele for promoting the geographic adaptation of rice to soil potassium. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate a combined effect of dietary folic acid intake, multiple genetic polymorphisms in folate metabolism, and other environmental factors on red blood cell (RBC) folate concentration in pregnancy-preparing population. Methods: 519 pregnancy-preparing subjects (260 couples) were investigated. Dietary intake was measured by 3-day dietary recalls. 13 Single Nucleotide polymorphisms (SNPs) reported in association with one-carbon metabolism including the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were genotyped. RBC folate concentration was measured using chemiluminescence assay. Hierarchical regression was applied for covariate selection. Factors showed significance(p < 0.0125) on RBC folate level was included for prediction model construction and R2 estimation. Validation cohort analysis was performed as post-hoc analysis if applicable. Results: The median RBC folate was 212.8 ng/ml. Only 10% took folic acid supplementation within three months. Based on hierarchical selection, folic acid supplementation, genetic polymorphism (especially TT genotype of MTHFR C677T), serum folate level were determinants of the variance of RBC folate concentrations, with adjusted R2 of 0.178–0.242. MTHFR A1298C polymorphism, sex difference with other socio-demographic and lifestyle factors (age, BMI, alcohol drinking, smoking, education, occupation) explained little to change in RBC folate level. Validation in another sub-cohort(n = 8105) had adjusted R2 of 0.273. Conclusion: In pregnancy-preparing subjects, folic acid supplementation, serum folate level and TT allele of MTHFR C677T polymorphism were determinants of the total variance of RBC folate level, which explained 19.8% variance in our subjects and 27.3% in the validation cohort. Food folate intake, sex and other environmental factors explained little to RBC folate level. [ABSTRACT FROM AUTHOR]

Background and objectives. It can be argued that there is a genetic component that has a determining or promoting role in this direction. In the present pilot study, we aimed to identify an element of the HLA profile that is involved in the development of addiction. Methods. The 60 study participants were divided into two groups - the control group - 40 people without cannabis use and the case group - 20 people with cannabis addiction. Results. We identified both an allele and a haplotype with a potential protective role and a haplotype with a risk factor role in the development of cannabis addiction. Conclusions. The results of the present study indicate several potential alleles that may act as a protective or risk factor for the development of cannabis addiction. The determination of these genes may have an important role in identifying possible mechanisms of developing addiction. [ABSTRACT FROM AUTHOR]

Aim: Multiple sclerosis is believed to be an autoimmune disease that is influenced by T helper (Th) cell differentiation. GATA3 plays an important role in reducing the development and severity of MS by shifting the differentiation of Th cells to Th2 and regulatory T cells while inhibiting the differentiation of Th1 and Th17 cells. Considering the functional role of rs1058240 SNP in the 3'-UTR of GATA3 mRNA, the association of target SNP with the risk of RRMS was examined. Methods: Genomic DNA was extracted from whole blood samples of 200 RRMS patients and 226 healthy individuals as a control group. Different genotypes of rs1058240 SNP were determined using the RFLP-PCR technique. Statistical analysis was performed using SPSS software and χ2 and logistic regression tests. The stability of GATA3 mRNA secondary structures and the binding patterns of GATA3-miRNAs with different alleles were evaluated using RNAfold and RNAhybrid programs, respectively. Results: The results indicated that the GATA3 rs1058240 G allele (p value = 0.010, OR = 1.45, CI = 1.09-1.93) and GG genotype (adjusted p value = 0.017, OR = 2.27, 95%CI = 1.16-4.44) increased the risk of RRMS, particularly in women (adjusted p value = 0.006, OR = 2.99, 95%CI = 1.37-6.52). Bioinformatics analysis revealed that although the allelic variation of this polymorphism had only a slight effect on mRNA stability (-177 to −177.20), the G allele significantly increased miRNA binding strength and miRNA-mRNA thermodynamic stability for hsa-miR-337-5p, hsa-miR-4445-3p, hsa-miR-4485-3p, hsa-miR-95-3p (ΔMFE > 0) compared to the A allele. Conclusion: The G allele and GG genotype of rs1058240 in GATA3 mRNA 3'-UTR were found to be risk factors for increasing the susceptibility to RRMS. [ABSTRACT FROM AUTHOR]

Objective: Obesity is a serious health problem that progressively affects individuals' lives with comorbidities, such as heart disease, stroke, and diabetes mellitus. Since its prevalence has increased, particularly in children less than five years old, its genetic and environmental causes should be determined for prevention and control of the disease. The aim of this study was to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant. Methods: A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass index (BMI) calculations were performed on available family members. Whole exome sequencing (WES) was performed on a 7-month-old obese infant. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies <1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation. Results: Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (+4.25 standard deviation score weight-for-height) was evident in index case; his father and grandmother were also obese (BMIs 38.1 kg/m2 and 31.3 kg/m2, respectively). WES analysis revealed deleterious variants in SH2B1, PDE11A, ADCY3, and CAPN10 genes previously associated with obesity. All variants were evaluated as novel candidates for obesity, except PDE11A, and family segregation confirmed paternal inheritance. Conclusion: This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be followed up periodically due to increased risk for later childhood obesity. [ABSTRACT FROM AUTHOR]

Kernel hardness (KH) is a significant factor that influences wheat quality. In order to gain a better understanding of KH profiles and the effects of its associated genes in Chinese wheat cultivars growing under normal and latest stage drought stress conditions, 206 wheat cultivars were examined. The kernel hardness index (KHI) was measured by utilizing a single kernel hardness tester, and allelic variations of the puroindoline genes regulating KH were detected using KASP markers. The hardness test indicated that 121 (58.7%) were classified as hard wheat, 39 (18.9%) as soft wheat, and 46 (22.3%) as mixed wheat. Genotypic analysis revealed that 10 cultivars (4.9%) carried the superior Pina-D1b allele, 143 cultivars (69.4%) possessed the Pinb-D1b allele, representing the main allele for hard wheat, and 45 cultivars (21.8%) contained the Pinb-B2b allele. An analysis of the cumulative effect across five gene loci indicated that among the tested materials, none contained all five excellent gene loci simultaneously. However, materials with combinations of two, three, or four excellent gene loci exhibited significantly higher KHI values compared to those with zero or only one excellent locus. This finding suggests that the accumulation of excellent gene loci can enhance KH. Among various allelic combinations, Pina-D1 + M0159 displayed remarkably higher KH values than the others. Conversely, Pinb-D1 + M0380 exhibited significantly lower KH values. Drought stress during the late growth stage of wheat could enhance KH. [ABSTRACT FROM AUTHOR]

Background/Objectives: Neuroligins (NLGNs) are postsynaptic adhesion molecules critical for neuronal development that are highly associated with autism spectrum disorder (ASD). Here, we provide an overview of the literature on NLGN rare variants. In addition, we introduce a new approach to analyze human variation within NLGN genes to identify sensitive regions that have an increased frequency of ASD-associated variants to better understand NLGN function. Methods: To identify critical protein subdomains within the NLGN gene family, we developed an algorithm that assesses tolerance to missense mutations in human genetic variation by comparing clinical variants from ClinVar to reference variants from gnomAD. This approach provides tolerance values to subdomains within the protein. Results: Our algorithm identified several critical regions that were conserved across multiple NLGN isoforms. Importantly, this approach also identified a previously reported cluster of pathogenic variants in NLGN4X (also conserved in NLGN1 and NLGN3) as well as a region around the highly characterized NLGN3 R451C ASD-associated mutation. Additionally, we highlighted other, as of yet, uncharacterized regions enriched with mutations. Conclusions: The systematic analysis of NLGN ASD-associated variants compared to variants identified in the unaffected population (gnomAD) reveals conserved domains in NLGN isoforms that are tolerant to variation or are enriched in clinically relevant variants. Examination of databases also allows for predictions of the presumed tolerance to loss of an allele. The use of the algorithm we developed effectively allowed the evaluation of subdomains of NLGNs and can be used to examine other ASD-associated genes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Stargardt disease (STGD1) is an autosomal recessive disorder caused by pathogenic variants in ABCA4 that affects the retina and is characterised by progressive central vision loss. The onset of disease manifestations varies from childhood to early adulthood. Methods: Whole exome (WES), whole gene, and whole genome sequencing (WGS) were performed for a patient with STGD1. Results: WES revealed a heterozygous pathogenic missense variant in ABCA4, but no second pathogenic variant was found. ABCA4 whole-gene sequencing, subsequent WGS, and segregation analysis identified a complex deep-intronic allele (NM_000350.2(ABCA4):c.[1555-5882C>A;1555-5784C>G]) in trans to the missense variant. Minigene assays combined with nanopore sequencing were performed to characterise this deep-intronic complex allele in more detail. Surprisingly, the reference minigene revealed the existence of two pseudoexons in intron 11 of the ABCA4 gene that are included in low-abundance (<1%) transcripts. Both pseudoexons could be confirmed in cDNA derived from wildtype retinal organoids. Despite mild splicing predictions, the variant minigene revealed that the complex deep-intronic allele substantially increased the abundance of transcripts that included the pseudoexon overlapping with the variants. Two antisense oligonucleotides (AONs) were designed to rescue the aberrant splicing events. Both AONs increased the proportion of correctly spliced transcripts, and one of them rescued correct splicing to reference levels. Conclusions: Minigene assays combined with nanopore sequencing proved instrumental in identifying low-abundance transcripts including pseudoexons from wildtype ABCA4 intron 11, one of which was substantially increased by the complex allele. [ABSTRACT FROM AUTHOR]

Sexual reproduction with alternative generations in a life cycle is an important feature in eukaryotic evolution. Partial selfing can regulate the efficacy of purging deleterious alleles in the gametophyte phase and the masking effect in heterozygotes in the sporophyte phase. Here, we develop a new theory to analyze how selfing shapes fixation of a mutant allele that is expressed in the gametophyte or the sporophyte phase only or in two phases. In an infinitely large population, we analyze a critical selfing rate beyond which the mutant allele tends to be fixed under equilibrium between irreversible mutation and selection effects. The critical selfing rate varies with genes expressed in alternative phases. In a finite population with partial self-fertilization, we apply Wright's method to calculate the fixation probability of the mutant allele under flux equilibrium among irreversible mutation, selection, and drift effects and compare it with the fixation probability derived from diffusion model under equilibrium between selection and drift effects. Selfing facilitates fixation of the deleterious allele expressed in the gametophyte phase only but impedes fixation of the deleterious allele expressed in the sporophyte phase only. Selfing facilitates or impedes fixation of the deleterious allele expressed in two phases, depending upon how phase variation in selection occurs in a life cycle. The overall results help to understand the adaptive strategy that sexual reproductive plant species evolve through the joint effects of partial selfing and alternative generations in a life cycle. [ABSTRACT FROM AUTHOR]

The degree of immunological compatibility between donors and recipients greatly impacts allograft survival. In the United States kidney allocation system, HLA antigen‐level matching has been shown to cause ethnic disparities and thus, has been de‐emphasised. However, priority points are still awarded for antigen‐level zero‐ABDR matching, zero‐DR matching and one‐DR matching. Recently, the degree of HLA molecular (eplet) mismatch has emerged as a more accurate measure of immunological risk, and eplet mismatch load has gained attention as a possible biomarker to improve HLA compatibility. However, little is known about the frequency of eplets in population groups, which is a necessary step to ensure that candidates from any ethnical background can have similar chances at a well‐matched organ. Eplet frequencies were estimated using HLA alleles in the Common, Intermediate and Well‐Documented (CIWD) 3.0.0 catalogue for six population groups: African‐American (AFA), Asian‐Pacific Islander (API), European/European descent (EURO), Middle East/North Coast of Africa (MENA), Hispanic/Latino (HIS) and Native‐American (NAM). We determined that 98.6% (484 out of 491) of HLA eplets are expressed by the common HLA alleles in all population groups. Of the seven eplets that were expressed by less common HLA alleles, six were Class I eplets and one was expressed by HLA‐DQB1 alleles and most were expressed by HLA alleles that were more commonly observed in European/European descent populations. Our observations indicate that HLA eplets will not cause any significant disparity if applied to HLA molecular compatibility, regardless of the ethnic origin of both recipients and donors. [ABSTRACT FROM AUTHOR]

35 allele sequences were confirmed and extended: 12 HLA‐A, 9 HLA‐B, 6 HLA‐C, 2 HLA‐DQB1, and 6 HLA‐DRB1. [ABSTRACT FROM AUTHOR]

HLA‐B*40:298:02 differs from HLA‐B*40:01:01 by eight nucleotide positions residing in exon 1 to intron 6. [ABSTRACT FROM AUTHOR]

HLA‐compatibility remains an important triage test for deceased donor kidney allocation. Low–intermediate resolution donor HLA‐typing is typically available at allocation, but its accuracy in assigning pre‐transplant donor‐specific anti‐HLA antibody (DSA) and HLA mismatches compared to 2‐field high‐resolution typing is poorly characterised. Consecutive deceased donor/recipient pairs from a single centre between 2016 and 2020 were included. Majority of donor typing at HLA‐ABDRB1 loci were performed at low–intermediate resolution, with 2‐field high‐resolution NGS typing across extended loci performed by NGS‐technique post‐transplantation. We compared the two typing methods for (1) accuracy of pre‐transplant DSA assignment; (2) misassignment of HLA‐antigen/allele mismatches and performance of each model for acute rejection and (3) proportion of recipients who developed de novo DSA (dnDSA) when matched at antigen but mismatched at allele level. Of 179 deceased donor/recipient pairs, 157 donors had low–intermediate resolution typing and 22 with high‐resolution ONT typing. Sixty‐two recipients (35%) had potential pre‐transplant DSAs, with incorrect assignment of allele‐specific Class I and II actual DSAs in 31% and 53% of cases, respectively. NGS typing identified 59 (33%) additional HLA‐DRB1 allele mismatches. ONT typing accurately assigned pre‐transplant DSAs and allele mismatches in all cases. Seven (4%) recipients with antigen/allele level discordance developed dnDSAs, majority HLA‐DQ antibodies. Two‐field high‐resolution donor HLA typing may provide a more accurate transplant immunological risk assessment and identify those at risk of developing dnDSA to matched HLA antigen. [ABSTRACT FROM AUTHOR]

The dynamics of virulence evolution in vector‐borne plant pathogens can be complex. Here, we use individual‐based, quantitative‐genetic simulations to investigate how virulence evolution depends on genetic trade‐offs and population structure. Although quite generic, the model is inspired by the ecology of the plant‐pathogenic bacterium Xylella fastidiosa, and we use it to gain insights into possible modes of virulence evolution in that group. In particular, we aim to sharpen our intuition about how virulence may evolve over short time scales via antagonistically pleiotropic alleles affecting pathogen performance within hosts and vectors. We find that even when pathogens find themselves much more often in hosts than vectors, selection in the vector environment can cause correlational and potentially non‐adaptive changes in virulence in the host. The extent of such correlational virulence evolution depends on many system parameters, including the pathogen transmission rate, the proportion of the pathogen population occurring in hosts, the strengths of selection in host and vector environments, and the functional relationship between pathogen load and virulence. But there is a statistical interaction between the strength of selection in vectors and the proportion of the pathogen population in hosts, such that if within‐vector selection is strong enough, over the short term, it can dominate virulence evolution, even when the host environment predominates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Popcorn is the most popular specialty maize and it makes a significant contribution to the Indian and global economies. Despite perfect exploration of heterosis in field corn, progress in popcorn breeding remains constrained due to its narrow genetic base, leading to a significant dependence on imports. In this study, 15 landrace‐ and population‐derived inbreds from temperate and tropical germplasm were crossed with five testers, which are the parents of superior popcorn hybrids, in a line × tester mating design. RESULTS: Significant variation was observed in popping quality and agronomic traits among crosses evaluated across three locations representing diverse maize‐based agro‐climatic zones in India. Additive genetic variance governed the traits related to popping quality, whereas dominance variance was responsible for the agronomic traits. In addition to significant heterosis specific to certain traits, we identified promising crosses that exhibited superior performance in both popping quality and grain yield (GY). The genotype + genotype × environment (GGE) biplot methodology identified PMI‐PC‐104 and PMI‐PC‐101 as the best discriminating testers for popping quality traits and Dpcl‐15‐90 for GY. Lines PMI‐PC‐205, PMI‐PC‐207, and PMI‐PC‐209 were the best general combiners for popping quality traits and GY. The heterotic groups identified based on GGE‐biplots and the magnitude, direction and stability of combining ability effects would serve in the development of competitive popcorn hybrids for a sustainable popcorn market. CONCLUSION: Using the additive nature of popping quality traits and the dominant nature of GY, recurrent intrapopulation selection can be employed to derive desirable popping quality inbreds with high GY for genetic enhancement. Desirable popping quality alleles from novel germplasm can thus be combined with high‐yielding domestic elite inbreds to establish a sustainable popcorn breeding program. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to establish a droplet digital polymerase chain reaction (ddPCR) assay for South-East Asian (SEA) deletion based on a fully integrated digital PCR system DropXpert S6. Methods: A total of 151 whole blood samples, 10 chorionic villus samples, and 17 amniotic fluid samples were collected, including 106 SEA heterozygotes, 43 normal individuals, 10 Hb Bart's hydrops details, and 19 SEA deletions combined with other genotypes.Genotypes of these samples were determined by the Gap-PCR method. We perform a series of optimizations of the ddPCR system to ensure the performance of the entire ddPCR reaction, such as droplet stability, fluorescence clustering, sensitivity, and accuracy. Results: Our assay exhibited 99.4% (177/178) accuracy compared with the Gap-PCR method, and the minimum detection limit of DNA was 0.1 ng/μL.Both targets have reliable linearity, R2 = 0.9999 for the α-thalassemia SEA deletion allele and R2 = 1 for the wild-type allele. The coefficient of variation for α-thalassemia SEA deletion allele detection at 2 and 10 ng/μL concentrations was 5.42% and 1.91%, respectively. In contrast, the coefficient of variation for wild-type allele detection was 4.06% and 1.83%, demonstrating its high quantitative accuracy. In addition, the DropXpert S6 PCR system showed some advantages over other ddPCR instruments, such as reducing testing costs, simplifying and automating the workflow. Conclusions: The DropXpert S6 PCR system provided a highly accurate diagnosis for α-thalassemia SEA deletion and can be used to detect α-thalassemia as an alternative method. [ABSTRACT FROM AUTHOR]

Panama has a large number of wild animal species, which could host a highly diverse amount of genetic variants of Toxoplasma gondii (T. gondii). In this context, we highlight the importance of understanding the population structure of T. gondii in Panamanian wildlife and the genetic variants that can be rapidly transferred to domestic environments. This study analyzed the infection frequency and allelic composition of T. gondii in different tissue samples from wild animals. The infection frequency was measured by the PCR technique using the B1 gene as a molecular marker. The results showed a high frequency (65.6%) of infection in tissue samples collected from 221 wild animals. Stratified analyses for bird and mammal samples showed positivity rates of 67.2% and 70.12%, respectively, with no statistically significant differences. Infection frequency was also measured in five types of organs (brain, liver, heart, lung, and skeletal muscle), which showed homogeneous frequencies. The genetic diversity of the T. gondii population contained in the tissues of wild animals was analyzed by the Multilocus Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique, using five genes called SAG1, SAG2, SAG3, GRA6, and Apico. This analysis revealed the presence of alleles of these genes corresponding to T. gondii lineages I, II, and III. Allele III was only identified with the Apico gene in a single reptile individual analyzed. Our findings indicated diverse allelic distribution at the analyzed loci, suggesting that the tissues were probably infected by non-archetypal individuals of T. gondii. [ABSTRACT FROM AUTHOR]

Objective: Upper gastrointestinal bleeding (UGIB) has been identified as a potential adverse drug reaction associated with the use of low-dose aspirin (LDA). This study aimed to investigate the relationship between variants in the TBXA2R gene, which is involved in platelet aggregation, and the risk of UGIB in patients with cardiovascular diseases treated with LDA. Methods: A case-control study was conducted at a Brazilian hospital complex. Three groups were defined: (1) case group (n = 50): patients with cardiovascular disease who used LDA and were diagnosed with UGIB of non-variceal etiology, (2) LDA control group (n = 50): patients with cardiovascular disease who used LDA without developing UGIB, and (3) healthy control group (n = 189). Data were collected through face-to-face interviews, and blood samples were collected for the analysis of Helicobacter pylori infection and genotyping of 3 genetic variants [rs2238631 (C > T), rs4807491 (A > G), and rs1131882 (A > G)]. Results: The case group had a significantly higher frequency of carriers of the rs4807491.G allele compared to the control group of LDA users (P -value =.004). No significant difference was observed in the proportion of carriers of the rs2238631.T and 1131882.G variants between the studied groups. Carriers of rs2238631.T (OR: 4.515, 95% CI: 1.37-14.89) and rs4807491.G allele (OR: 3.232, 95% CI: 1.12-9.37) exhibited a higher risk of UGIB. Conclusion: These findings suggest that the presence of the rs2238631 and rs4807491 variant alleles is associates with a 3- to 4-fold increased risk of UGIB in patients with cardiovascular diseases treated with LDA. Future studies with larger sample sizes should confirm these results and to better identify individuals who may benefit from chronic LDA use. [ABSTRACT FROM AUTHOR]