Common Genetic Background Research Articles

The Clinical Phenotype of Patients with Contact Polysensitization, a Retrospective Cohort.

Background: Polysensitization, defined as contact sensitization to three or more allergens, is an allergic phenotype with a common genetic background. Our study aims to characterize the clinical features of patients with polysensitization. Methods: We analyzed patch test results of 5,082 patients from a designated contact dermatitis clinic in Tel Aviv between 2012 and 2022 and compared the polysensitized group with nonsensitized and oligosensitized patients, hence patients reacting to 1 or 2 allergens. Results: About 8.5% of patients were polysensitized. In the nonsensitized group, there were significantly fewer female patients and more children (P < 0.05) than in the polysensitized group. Asthma prevalence was linearly associated with the number of positive reactions in patch test. Polysensitized patients were more commonly suffering from hand eczema and an occupational etiology (P < 0.05). Textile dye mix, lyral, fragrance mix II, formaldehyde, colophonium, and p-phenylendiamine were more common sensitizers among the polysensitized group, whereas nickel sulfate, 2-hydroxyethyl methacrylate, fragrance mix 1, p-tert-butylphenol formaldehyde resin, and sodium metabisulfite were more common among the oligosensitized group. Conclusions: The association between polysensitization, asthma prevalence, and sensitization to volatile allergens raises an intriguing clinical phenotype. Further mechanistic studies are needed in this regard.

Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages

Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Does HLA explain the high incidence of childhood-onset type 1 diabetes in the Canary Islands? The role of Asp57 DQB1 molecules

The Canary Islands inhabitants, a recently admixed population with significant North African genetic influence, has the highest incidence of childhood-onset type 1 diabetes (T1D) in Spain and one of the highest in Europe. HLA accounts for half of the genetic risk of T1D.AimsTo characterize the classical HLA-DRB1 and HLA-DQB1 alleles in children from Gran Canaria with and without T1D.MethodsWe analyzed classic HLA-DRB1 and HLA-DQB1 alleles in childhood-onset T1D patients (n = 309) and control children without T1D (n = 222) from the island of Gran Canaria. We also analyzed the presence or absence of aspartic acid at position 57 in the HLA-DQB1 gene and arginine at position 52 in the HLA-DQA1 gene. Genotyping of classical HLA-DQB1 and HLA-DRB1 alleles was performed at two-digit resolution using Luminex technology. The chi-square test (or Fisher's exact test) and odds ratio (OR) were computed to assess differences in allele and genotype frequencies between patients and controls. Logistic regression analysis was also used.ResultsMean age at diagnosis of T1D was 7.4 ± 3.6 years (46% female). Mean age of the controls was 7.6 ± 1.1 years (55% female). DRB1*03 (OR = 4.2; p = 2.13–13), DRB1*04 (OR = 6.6; p ≤ 2.00–16), DRB1* 07 (OR = 0.37; p = 9.73–06), DRB1*11 (OR = 0.17; p = 6.72–09), DRB1*12, DRB1*13 (OR = 0.38; p = 1.21–05), DRB1*14 (OR = 0.0; p = 0.0024), DRB1*15 (OR = 0.13; p = 7.78–07) and DRB1*16 (OR = 0.21; p = 0.003) exhibited significant differences in frequency between groups. Among the DQB1* alleles, DQB1*02 (OR: 2.3; p = 5.13–06), DQB1*03 (OR = 1.7; p = 1.89–03), DQB1*05 (OR = 0.64; p = 0.027) and DQB1*06 (OR = 0.19; p = 6.25–14) exhibited significant differences. A total of 58% of the studied HLA-DQB1 genes in our control population lacked aspartic acid at position 57.ConclusionsIn this population, the overall distributions of the HLA-DRB1 and HLA-DQB1 alleles are similar to those in other European populations. However, the frequency of the non-Asp-57 HLA-DQB1 molecules is greater than that in other populations with a lower incidence of T1D. Based on genetic, historical and epidemiological data, we propose that a common genetic background might help explain the elevated pediatric T1D incidence in the Canary Islands, North-Africa and middle eastern countries.

Bivariate genome-wide association study of circulating fibrinogen and C-reactive protein levels

BackgroundFibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP. ObjectivesTo identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS. MethodsWe performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data. ResultsWe identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS. ConclusionBivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.

New Insights into the Exosome-Induced Migration of Uveal Melanoma Cells and the Pre-Metastatic Niche Formation in the Liver.

UM is an aggressive intraocular tumor characterized by high plasticity and a propensity to metastasize in the liver. However, the underlying mechanisms governing liver tropism remain poorly understood. Given the emerging significance of exosomes, we sought to investigate the contribution of UM-derived exosomes to specific steps of the metastatic process. Firstly, we isolated exosomes from UM cells sharing a common genetic background and different metastatic properties. A comparison of protein cargo reveals an overrepresentation of proteins related to cytoskeleton remodeling and actin filament-based movement in exosomes derived from the parental cells that may favor the detachment of cells from the primary site. Secondly, we assessed the role of macrophages in reprogramming the HHSCs by exosomes. The activation of HHSCs triggered a pro-inflammatory and pro-fibrotic environment through cytokine production, upregulation of extracellular matrix molecules, and the activation of signaling pathways. Finally, we found that activated HHSCs promote increased adhesion and migration of UM cells. Our findings shed light on the pivotal role of exosomes in pre-metastatic niche construction in the liver.

A MYB family transcription factor TdRCA1 from wild emmer wheat regulates anthocyanin biosynthesis in coleoptile.

As important secondary metabolites in plants, anthocyanins not only contribute to colored plants organs, but also provide protections against various biotic and abiotic stresses. In this study, a MYB transcription factor gene TdRCA1 from wild emmer wheat regulating anthocyanin biosynthesis in wheat coleoptile was identified on the short arm of chromosome 7A in common wheat genetic background. The TdRCA1 overexpression lines showed colored callus, coleoptile, auricle and stem nodes, as well as up regulation of six anthocyanin-related structural genes. The expression of TdRCA1 was activated by light in a temporal manner. While coleoptile color of 48 and 60h dark-grown seedlings changed from green to red after 24h light treatment, those grown in dark for 72 and 96h failed to develop red coleoptiles after light restoration. Interestingly, the over expression of TdRCA1 resulted in increased resistance to Fusarium crown rot, a chronic and severe fungal disease in many cereal growing regions in the world. Our results offer a better understanding of the molecular basis of coleoptile color in bread wheat.

Genetic diversity and population structure of Piper nigrum (black pepper) accessions based on next-generation SNP markers.

Despite the economic importance of Piper nigrum (black pepper), a highly valued crop worldwide, development and utilization of genomic resources have remained limited, with diversity assessments often relying on only a few samples or DNA markers. Here we employed restriction-site associated DNA sequencing to analyze 175 P. nigrum accessions from eight main black pepper growing regions in Sri Lanka. The sequencing effort resulted in 1,976 million raw reads, averaging 11.3 million reads per accession, revealing 150,356 high-quality single nucleotide polymorphisms (SNPs) distributed across 26 chromosomes. Population structure analysis revealed two subpopulations (K = 2): a dominant group consisting of 152 accessions sourced from both home gardens and large-scale cultivations, and a smaller group comprising 23 accessions exclusively from native collections in home gardens. This clustering was further supported by principal component analysis, with the first two principal components explaining 35.2 and 12.1% of the total variation. Genetic diversity analysis indicated substantial gene flow (Nm = 342.21) and a low fixation index (FST = 0.00073) between the two subpopulations, with no clear genetic differentiation among accessions from different agro-climatic regions. These findings demonstrate that most current black pepper genotypes grown in Sri Lanka share a common genetic background, emphasizing the necessity to broaden the genetic base to enhance resilience to biotic and abiotic stresses. This study represents the first attempt at analyzing black pepper genetic diversity using high-resolution SNP markers, laying the foundation for future genome-wide association studies for SNP-based gene discovery and breeding.

The Waxy Gene Has Pleiotropic Effects on Hot Water-Soluble and -Insoluble Amylose Contents in Rice (Oryza sativa) Grains.

Rice (Oryza sativa) is a cereal crop with a starchy endosperm. Starch is composed of amylose and amylopectin. Amylose content (AC) is the principal determinant of rice quality, but varieties with similar ACs can still vary substantially in their quality. In this study, we analyzed the total AC (TAC) and its constituent fractions, the hot water-soluble amylose content (SAC) and hot water-insoluble amylose content (IAC), in two sets of related chromosome segment substitution lines of rice with a common genetic background grown in two years. We searched for quantitative trait loci (QTLs) associated with SAC, IAC, and TAC and identified one common QTL (qSAC-6, qIAC-6, and qTAC-6) on chromosome 6. Map-based cloning revealed that the gene underlying the trait associated with this common QTL is Waxy (Wx). An analysis of the colors of soluble and insoluble starch-iodine complexes and their λmax values (wavelengths at the positions of their peak absorbance values) as well as gel permeation chromatography revealed that Wx is responsible for the biosynthesis of amylose, comprising a large proportion of the soluble fractions of the SAC. Wx is also involved in the biosynthesis of long chains of amylopectin, comprising the hot water-insoluble fractions of the IAC. These findings highlight the pleiotropic effects of Wx on the SAC and IAC. This pleiotropy indicates that these traits have a positive genetic correlation. Therefore, further studies of rice quality should use rice varieties with the same Wx genotype to eliminate the pleiotropic effects of this gene, allowing the independent relationship between the SAC or IAC and rice quality to be elucidated through a multiple correlation analysis. These findings are applicable to other valuable cereal crops as well.

Genetic variations of low-density lipoprotein cholesterol on metabolic disorders in obstructive sleep apnea

BackgroundThe study aimed to explore the relationship between low-density lipoprotein cholesterol (LDL-C) genetic variants and obstructive sleep apnea (OSA) and its complications, including cardiovascular diseases (CVD), insulin resistance (IR), and metabolic syndrome (MS).Method4329 individuals with suspected OSA who underwent a comprehensive assessment of anthropometric, biochemical, and polysomnography (PSG) data, along with 30 LDL-C single nucleotide polymorphisms (SNPs) were enrolled. The 10-year Framingham CVD risk score (FRS), IR and MS were evaluated for each subject. Linear regression and logistic regression were utilized to examine the correlations among these variables.ResultsAfter the Benjamini-Hochberg correction, linear regression results indicated positive correlations between variants rs3741297 and rs629301 with FRS (β = 0.031, PBH=0.002; β = 0.026, PBH=0.015). Logistic regression revealed that rs3741297 increased MS risk among total subjects [OR = 1.67 (95% CI:1.369–2.038), PBH=1.32 × 10− 5] and increased IR risk in females [OR = 3.475 (95% CI:1.653–7.307), PBH=0.03]. In males, rs2642438 decreased MS risk [OR = 0.81 (95% CI:0.703–0.933), PBH=0.045].ConclusionsThe rs3741297 variant correlated with susceptibility to CVD, IR, and MS in the OSA population. OSA, CVD, IR and MS share a potentially common genetic background, which may promote precision medicine.Cinical trial registrationThe study protocol was registered with the Chinese Clinical Trial Registry (ChiCTR1900025714).

Comparison of Thermal and Mechanical Pain Testing Modalities in Sprague Dawley and Fischer 344 Rats (Rattus norvegicus).

While rodents are used extensively for studying pain, there is a lack of reported direct comparisons of thermal and mechanical pain testing methods in rats of different genetic backgrounds. Understanding the range of interindividual variability of withdrawal thresholds and thermal latencies based on these testing methods and/or genetic background is important for appropriate experimental design. Testing was performed in two common rat genetic backgrounds: outbred Sprague-Dawley (SD) and inbred Fischer 344 (F344). Male and female, 10- to 14-wk-old F344 and SD rats were used to assess withdrawal thresholds in 3 different modalities: the Randall-Selitto test (RST), Hargreaves test (HT), and tail flick test (TFT). The RST was performed by using an operator-controlled handheld instrument to generate a noxious pressure stimulus to the left hind paw. The HT and the TFT used an electronically controlled light source to deliver a noxious thermal stimulus to the left hind paw or tail tip, respectively. Rats of each sex and genetic background underwent one type of test on day 0 and day 7. Withdrawal thresholds and thermal latencies were compared among tests. No significant differences were observed. Our findings can serve as a guide for researchers considering these nociceptive tests for their experiments.

Whole-genome resequencing reveals genomic variation and dynamics in Ethiopian indigenous goats

Ethiopia has about 52 million indigenous goats with marked phenotypic variability, which is the outcome of natural and artificial selection. Here, we obtained whole-genome sequence data of three Ethiopian indigenous goat populations (Arab, Fellata, and Oromo) from northwestern Ethiopia and analyzed their genome-wide genetic diversity, population structure, and signatures of selection. We included genotype data from four other Ethiopian goat populations (Abergelle, Keffa, Gumuz, and Woyto-Guji) and goats from Asia; Europe; and eastern, southern, western, and northern Africa to investigate the genetic predisposition of the three Ethiopian populations and performed comparative genomic analysis. Genetic diversity analysis showed that Fellata goats exhibited the lowest heterozygosity values (Ho = 0.288 ± 0.005 and He = 0.334 ± 0.0001). The highest values were observed in Arab goats (Ho = 0.310 ± 0.010 and He = 0.347 ± 4.35e−05). A higher inbreeding coefficient (FROH = 0.137 ± 0.016) was recorded for Fellata goats than the 0.105 ± 0.030 recorded for Arab and the 0.112 ± 0.034 recorded for Oromo goats. This indicates that the Fellata goat population should be prioritized in future conservation activities. The three goat populations showed the majority (∼63%) of runs of homozygosity in the shorter (100–150 Kb) length category, illustrating ancient inbreeding and/or small founder effects. Population relationship and structure analysis separated the Ethiopian indigenous goats into two distinct genetic clusters lacking phylogeographic structure. Arab, Fellata, Oromo, Abergelle, and Keffa represented one genetic cluster. Gumuz and Woyto-Guji formed a separate cluster and shared a common genetic background with the Kenyan Boran goat. Genome-wide selection signature analysis identified nine strongest regions spanning 163 genes influencing adaptation to arid and semi-arid environments (HOXC12, HOXC13, HOXC4, HOXC6, and HOXC9, MAPK8IP2), immune response (IL18, TYK2, ICAM3, ADGRG1, and ADGRG3), and production and reproduction (RARG and DNMT1). Our results provide insights into a thorough understanding of genetic architecture underlying selection signatures in Ethiopian indigenous goats in a semi-arid tropical environment and deliver valuable information for goat genetic improvement, conservation strategy, genome-wide association study, and marker-assisted breeding.

Genetic underpinnings of fasting and oral glucose-stimulated based insulin sensitivity indices.

Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. We computed 21 IS indices, classified as fasting, OGTT0,120 and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in two cohorts. We used data from a family cohort (n=313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n=5,343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 was associated only with fasting indices, and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT0,120 indices. Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.

Wolbachia strains wMel and wAlbB differentially affect Aedes aegypti traits related to fecundity.

Two Wolbachia strains, wMel and wAlbB, have been transinfected into Aedes aegypti mosquitoes for population replacement with the aim of reducing dengue transmission. Epidemiological data from various endemic sites suggest a pronounced decrease in dengue transmission after implementing this strategy. In this study, we investigated the impact of the Wolbachia strains wMel and wAlbB on Ae. aegypti fitness in a common genetic background. We found that Ae. aegypti females infected with the wMel strain exhibited several significant differences compared with those infected with the wAlbB strain. Specifically, wMel-infected females laid significantly fewer eggs, ingested a lower amount of blood, had a reduced egg production rate, and exhibited a decreased Wolbachia density at a later age compared with mosquitoes infected with the wAlbB strain. Conversely, the wAlbB strain showed only mild negative effects when compared with Wolbachia-uninfected specimens. These differential effects on Ae. aegypti fitness following infection with either wMel or wAlbB may have important implications for the success of population replacement strategies in invading native Ae. aegypti populations in endemic settings. Further research is needed to better understand the underlying mechanisms responsible for these differences in fitness effects and their potential impact on the long-term efficacy of Wolbachia-based dengue control programs.IMPORTANCEThe transmission of arboviruses such as dengue, Zika, and chikungunya is on the rise globally. Among the most promising strategies to reduce arbovirus burden is the release of one out of two strains of Wolbachia-infected Aedes aegypti: wMel and wAlbB. One critical aspect of whether this approach will succeed involves the fitness cost of either Wolbachia strains on mosquito life history traits. For instance, we found that wMel-infected Ae. aegypti females laid significantly fewer eggs, ingested a lower amount of blood, had a reduced egg production rate, and exhibited a decreased Wolbachia density at a later age compared with mosquitoes infected with the wAlbB strain. Conversely, the wAlbB strain showed only mild negative effects when compared with Wolbachia-uninfected specimens. These differential effects on mosquito fitness following infection with either wMel or wAlbB may have important implications for the success of population replacement strategies in invading native Ae. aegypti populations.

Prevalence of diabetes and insulin resistance in patients with diagnosis of schizophrenia or other psicotic disorders

IntroductionContrary to classical belief, people affected by this disease are at greater risk of developing organic pathologies.This risk has a very complex origin: a greater exposure to risk factors and specific socioeconomic conditions, a high prevalence of risk behaviors, the use of antipsychotics, and a potential common genetic background. (Reynolds et al.Int. J.Neuropsychopharmacol.2021; 24 854–855, Suvisaari J et al. Curr Diab Rep. 2016 16). Multiple studies demonstrate that Schizophrenia confers a high endogenous risk of Diabetes. Before patients diagnosed with Schizophrenia start taking antipsychotics (Andreassen OA et al. Am J Psychiatry. 2017;174 616-617), they have an approximately 3 times higher risk of developing Diabetes compared to the general population. The risk increases 3.6 times after the initiation of antipsychotic treatment compared to drug naive patients(Annamalai A et al World J Diabetes. 2017 390-396)ObjectivesTo study the association between Schizophrenia or other Psychotic Disorders and Diabetes Mellitus in a sample of patients diagnosed with Schizophrenia or other Psychotic Disorders.MethodsThis is a Descriptive and Cross-sectional Observational Study. Clinical Histories were reviewed and a personal or telephone interview was established to expand data related to the objectives of the study. The patients were recruited among the patients seen in the specific Severe Mental Disorder consultation who had a diagnosis of schizophrenia or other Psychotic Disorders, according to DSM 5-TR criteria.ResultsFrom a sample of 93 patients, 24 had Diabetes. The Prevalence of Diabetes in patients with Schizophrenia or other Psychotic Disorders was 25.8%. Of the patients without a diagnosis of Diabetes, 15 of them had values of Glycosylated Hemoglobin (HbA1c) for Prediabetes. Using the Chi-Square Test, statistically significant differences were found between the variable Main Psychiatric Medication and Diabetes. Patients treated with Clozapine, Aripiprazole and Olanzapine had a Prevalence of Diabetes of 40.9%, 33.3% and 28.5%, respectively.ConclusionsPrevalence of Diabetes in our sample was 3.4 times higher than the 7.51% of the general population in Spain. This presumes a significant importance and impact on the health of these patients. The diabetic patients in our sample were diagnosed with Diabetes years after the diagnosis of the mental illness, which seems to indicate that the causes have to do with lifestyle, dietary habits, weight, and exposure to chronic antipsychotics. Premature death in schizophrenia has several explanations, being of special importance the development of cardiovascular disorders and Diabetes This can be due to many reasons, but it is worth highlighting the metabolic side effects of some antipsychotics and lifestyle. In this sense, it is essential to carefully monitor this group of patients.Disclosure of InterestNone Declared

Genetics of autoimmune-associated interstitial lung diseases: A focus on rheumatoid arthritis

Recent advances in deciphering the genetic architecture of RA-ILD support the hypothesis of RA-ILD as a complex disease with a heterogeneous phenotype encompassing at least the usual interstitial pneumonia (UIP) and non-UIP high-resolution CT patterns. The results of genetic studies support the hypothesis of a common genetic background between idiopathic pulmonary fibrosis (IPF) and RA-ILD, and more specifically RA-UIP, a subset of the disease associated with a poor prognosis. Overall, these findings suggest the existence of shared pathogenic pathways between IPF and RA-ILD providing new opportunities for future intervention in RA-ILD, particularly with drugs that have been shown to be active in IPF.

Idiopathic generalized epilepsy in a family with SCN4A-related myotonia.

Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed. All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

Application of JAK inhibitors in paradoxical reaction through immune-related dermatoses.

Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.

Generation of Human Isogenic Induced Pluripotent Stem Cell Lines with CRISPR Prime Editing.

We developed an efficient CRISPR prime editing protocol and generated isogenic-induced pluripotent stem cell (iPSC) lines carrying heterozygous or homozygous alleles for putatively causal single nucleotide variants at six type 2 diabetes loci (ABCC8, MTNR1B, TCF7L2, HNF4A, CAMK1D, and GCK). Our two-step sequence-based approach to first identify transfected cell pools with the highest fraction of edited cells significantly reduced the downstream efforts to isolate single clones of edited cells. We found that prime editing can make targeted genetic changes in iPSC and optimization of system components and guide RNA designs that were critical to achieve acceptable efficiency. Systems utilizing PEmax, epegRNA modifications, and MLH1dn provided significant benefit, producing editing efficiencies of 36-73%. Editing success and pegRNA design optimization required for each variant differed depending on the sequence at the target site. With attention to design, prime editing is a promising approach to generate isogenic iPSC lines, enabling the study of specific genetic changes in a common genetic background.

MAGE: metafounders-assisted genomic estimation of breeding value, a novel additive-dominance single-step model in crossbreeding systems.

Utilizing both purebred and crossbred data in animal genetics is widely recognized as an optimal strategy for enhancing the predictive accuracy of breeding values. Practically, the different genetic background among several purebred populations and their crossbred offspring populations limits the application of traditional prediction methods. Several studies endeavor to predict the crossbred performance via the partial relationship, which divides the data into distinct sub-populations based on the common genetic background, such as one single purebred population and its corresponding crossbred descendant. However, this strategy makes prediction inaccurate due to ignoring half of the parental information of crossbreed animals. Furthermore, dominance effects, although playing a significant role in crossbreeding systems, cannot be modeled under such a prediction model. To overcome this weakness, we developed a novel multi-breed single-step model using metafounders to assess ancestral relationships across diverse breeds under a unified framework. We proposed to use multi-breed dominance combined relationship matrices to model additive and dominance effects simultaneously. Our method provides a straightforward way to evaluate the heterosis of crossbreeds and the breeding values of purebred parents efficiently and accurately. We performed simulation and real data analyses to verify the potential of our proposed method. Our proposed model improved prediction accuracy under all scenarios considered compared to commonly used methods. The software for implementing our method is available at https://github.com/CAU-TeamLiuJF/MAGE.

Friend turned foe: selfish behavior of a spontaneously arising mitochondrial deletion in an experimentally evolved Caenorhabditis elegans population.

Selfish mitochondrial DNA (mtDNA) mutations are variants that can proliferate within cells and enjoy a replication or transmission bias without fitness benefits for the host. mtDNA deletions in Caenorhabditis elegans can reach high heteroplasmic frequencies despite significantly reducing fitness, illustrating how new mtDNA variants can give rise to genetic conflict between different levels of selection and between the nuclear and mitochondrial genomes. During a mutation accumulation experiment in C. elegans, a 1,034-bp deletion originated spontaneously and reached an 81.7% frequency within an experimental evolution line. This heteroplasmic mtDNA deletion, designated as meuDf1, eliminated portions of 2 protein-coding genes (coxIII and nd4) and tRNA-thr in entirety. mtDNA copy number in meuDf1 heteroplasmic individuals was 35% higher than in individuals with wild-type mitochondria. After backcrossing into a common genetic background, the meuDf1 mitotype was associated with reduction in several fitness traits and independent competition experiments found a 40% reduction in composite fitness. Experiments that relaxed individual selection by single individual bottlenecks demonstrated that the deletion-bearing mtDNA possessed a strong transmission bias, thereby qualifying it as a novel selfish mitotype.