Differences In Allele Frequencies Research Articles

Strength of Genetic Associations with Thyrotropin Values Differs Between Populations with Similarity to African and European Reference Populations.

Background: Epidemiological data suggest the population distribution of thyrotropin (TSH) values is shifted toward lower values in self-identified Black non-Hispanic individuals compared with self-identified White non-Hispanic individuals. It is unknown whether genetic differences between individuals with genetic similarities to African reference populations (GSA) and those with similarities to European reference populations (GSE) contribute to these observed differences. We aimed to compare genome-wide associations with TSH and putative causal TSH-associated variants between GSA and GSE groups. Methods: We performed genome-wide association studies (GWAS) in 9827 GSA individuals and 9827 GSE individuals with TSH values between 0.45 and 4.5 mU/L. We compared effect sizes and allele frequencies of previously reported putative causal TSH-associated variants and our power to detect associations with these variants between the two groups. We additionally focused on variants in PDE8B and PDE10A, loci that have been most strongly associated with TSH in previous GWAS in GSE populations. Results: Four loci attained genome-wide significance in the GSA group compared with seven in the GSE group. PDE8B was not significantly associated with TSH in the GSA group, despite its strong association in the GSE group. Eight putative causal variants had significantly different effect sizes between groups. There was ≥80% power in the GSA group to detect significant associations with variants in PDE8B, PDE10A, NFIA, and LOC105377480, with higher expected power than in the GSE group for variants in PDE8B, NFIA, and LOC105377480 and similar power for other variants in PDE8B and PDE10A. No additional putative causal variants in PDE8B and PDE10A had effect sizes that differed significantly between the groups; power to identify associations with additional putative causal variants in PDE8B and PDE10A was similar between the groups. Conclusions: Patterns of genetic associations with TSH differed between identically sized GSA and GSE groups. Failure to replicate the strongest associations previously reported in GSE individuals in our GSA population was not fully explained by differences in allele frequencies or power, assuming similar effect sizes. Larger GSA population GWAS are necessary to confirm our findings and further investigate the contribution of genetic factors to population differences in the distribution of TSH values.

Evaluation of plasma cell sorting methods in multiple myeloma patients: flow cytometry versus magnetic beads

BackgroundThe prognosis of a plasma cell neoplasm (PCN) varies depending on the presence of genetic abnormalities. However, detecting sensitive genetic mutations poses challenges due to the heterogeneous nature of the cell population in bone marrow aspiration. The established gold standard for cell sorting is fluorescence-activated cell sorting (FACS), which is associated with lengthy processing times, substantial cell quantities, and expensive equipment. Magnetic-activated cell sorting (MACS) can be performed without the need for FACS equipment and allows for rapid sorting of many cells, making it a practical alternative. Our objective is to conduct a comparative analysis of these two sorting techniques to assess whether MACS can viably replace FACS in clinical applications.MethodsPlasma cell purity, fluorescence in situ hybridization (FISH), and next-generation sequencing analyses were performed on FACS- and MACS-sorted bone marrow samples from 31 PCN patients.ResultsThe MACS-sorted samples yielded a higher percentage of plasma cells than FACS-sorted samples under microscopy (p = 0.0156) and flow cytometry (p = 0.0313). FISH performed by two methods in 10 samples showed the same results, and the proportion of abnormal cells was significantly higher in MACS than in FACS (p = 0.001). Wilcoxon matched-pairs signed rank test analysis showed that the median of differences of variant allele frequency (VAF) of two methods (VAF of MACS minus VAF of FACS) in the DNMT3A, TET2, and ASXL1 (DTA) group was − 0.006555 (p = 0.0020), while that in the non-DTA group was 0.002805 (p = 0.0019). Ten copy number variants (CNVs) were found in both FACS- and MACS-sorted samples, eight were identified only in MACS-sorted samples, and one was detected only in FACS-sorted samples.ConclusionOur study demonstrates that MACS is a viable alternative for plasma cell sorting in bone marrow samples of patients with PCN.

Association of MTHFR C677T and A1298C variants with preeclampsia risk and angiogenic imbalance in Tunisian women.

Study cases comprised 675 Tunisian pregnant women, of whom 350 PE presented with PE, and the remaining 325 normotensive women served as controls. Genotyping of C677T and A1298C variants was performed by real-time PCR. There was no statistically significant difference in the minor allele frequencies of C677T and A1298C between preeclampsia cases and controls after adjusting for key covariates. In addition, the prevalence of MTHFR C677T and A1298C minor allele homozygote genotypes was significantly higher in PE cases. The association of 1298C/C, but not 677T/T, with PE persisted after adjusting for the main covariates. Carrying the (minor) 677T allele was associated with marginally higher BMI, significantly higher sFlt-1 serum levels, and median sFlt-1/PlGF ratio and sFlt-1/PlGF ratio≥85. Setting the major allele homozygotes (C677/A1298) as a reference, haplotype analysis demonstrated a higher prevalence of C677/C1298 and T677/C1298 haplotypes (P=0.03) in PE cases compared to controls, which persisted for C677/C1298, but not T677/C1298 after controlling for key covariates. Our results support an association between MTHFR polymorphisms and increased risk of PE, and an imbalance of PE-associated sFLT-1/PlGF.

Occurrence and allele frequencies of genetic variants associated with Varroa drone brood resistance (DBR) in African Apis mellifera subspecies.

The ectoparasite Varroa destructor is a major contributor to the global decline of honeybee colonies (Apis mellifera), especially in the Northern Hemisphere. However, Varroa-resistant honeybee populations have been reported in various regions around the globe, including Europe and Africa. This resistance is primarily attributed to the trait known as Suppressed Mite Reproduction (SMR), which significantly reduces the reproductive success of Varroa mites within these colonies. Although this trait is still poorly understood, several efforts have been made to unravel the genetic basis of SMR. For example, a study in Belgium determined eight genetic variants in the honeybee genome that are associated with the infertility of mites in drone brood (Drone Brood Resistance or DBR). As these eight variants were found and validated in subpopulations of European subspecies only, there is limited knowledge about the occurrence of these markers in African honeybees. Hence, this study was designed to determine the allele frequencies of these eight genetic variants in African honeybee populations. More specifically, we used qPCR assays with dual-labeled probes to analyze bee samples collected from Benin, Ethiopia, and Uganda. Our results showed the presence of seven of the eight variants in African Apis mellifera subspecies, which may contribute to their innate resistance against the Varroa mite. Moreover, we found significant differences in allele frequencies among the three sampled African bee populations, suggesting the presence of genetic diversity within these populations, potentially altering their resistance to Varroa. This study revealed similar allele frequencies between African honeybees and bee samples from the European iberiensis-subspecies (A lineage), while Ethiopian bees showed distinct distributions, indicative of a unique lineage. Overall, the occurrence of most DBR-associated genetic variants in African honeybees opens research opportunities to elucidate the predictive properties and potential of these genetic variants in the African continent by examining genotype-phenotype associations.

Interleukin-17A and Interleukin-17F Gene Polymorphisms in Egyptian Patients with Chronic Hepatitis C and Hepatocellular Carcinoma.

Interleukin IL-17A and IL-17F are critical cytokines involved in inflammatory processes. Genetic variations in IL-17A and IL-17F might be linked to chronic hepatitis C (CHC) and an increased risk of hepatocellular carcinoma (HCC), a cancer associated with long-term inflammation. This study aims to examine the relationship between specific polymorphisms in IL-17A (rs2275913) and IL-17F (rs763780) and their association with HCV-related HCC in an Egyptian population. Authors conducted a case-control study involving 52 patients with chronic hepatitis C, 49 patients with HCV-related HCC, and 51 healthy controls. The study assessed the connection between the IL-17A rs2275913 and IL-17F rs763780 polymorphisms and chronic hepatitis C patients. Genotyping was performed using real-time PCR with TaqMan MGB-probe allelic discrimination. No significant differences in genotype and allele frequencies for IL-17A rs2275913 and IL-17F rs763780 were observed between CHC or HCC patients and control subjects. However, significant associations were found indicating an increased risk of HCC linked to CHC: the GG genotype of IL-17A rs2275913 in a recessive model (P = 0.0129); and CT and CT + CC genotypes as well as the C allele of IL-17F rs763780 (P = 0.0038, P = 0.0055 and P = 0.0277, respectively). The study identifies a significant association between IL-17F rs763780 polymorphisms and a higher risk of HCC in Egyptian patients with chronic hepatitis C. No significant correlation was found between the IL-17A rs2275913 polymorphism and either chronic hepatitis C or HCC.

Evaluating Genomic Selection in beef cattle: Insights from computer simulations using real SNP data

Genomic Selection (GS) is a method that employs genomic data to estimate breeding values and rank candidates for selection. Despite its numerous advantages, its application in cattle breeding programs remains in the early stages in many livestock systems developed in tropical and subtropical environments, such as those in Paraguay. Computational simulations are powerful tools that enhance our understanding of GS applications in different scenarios and are invaluable as an initial step before implementing this technique in "real" genetic improvement programs. In this study, real data from single nucleotide polymorphisms (SNPs) of the Indicus and Taurus breeds were employed to simulate three crossing schemes: F1 crosses, grading up, and rotational crosses. Phenotypes were selected for traits related to shear force, growth, and tolerance. The predictive accuracy of three 50k SNP chips, differing in their SNP selection methodologies, was compared: random selection, selection based on minimum allele frequency differences between breeds, and selection based on minimum allele frequency differences between breeds with a threshold of 0.09 in Taurus. The findings indicate that rotational crossing demonstrates optimal predictive accuracy (0.38), while marker selection based on allele frequency differences between breeds (0.18 and 0.17, respectively) does not benefit predictions significantly.

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Chromosome X-wide common variant association study in autism spectrum disorder.

Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9×10-6 to 1.51×10-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p= 3.57×10-7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p= 9.47×10-6). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.

Pharmacogenomic profiling of the South Korean population: Insights and implications for personalized medicine.

Adverse drug reactions (ADRs) pose substantial public health issues, necessitating population-specific characterization due to variations in pharmacogenes. This study delineates the pharmacogenomic (PGx) landscape of the South Korean (SKR) population, focusing on 21 core pharmacogenes. Whole genome sequencing (WGS) was conducted on 396 individuals, including 99 healthy volunteers, 95 patients with chronic diseases, 81 with colon cancer, 81 with breast cancer, and 40 with gastric cancer, to identify genotype-specific drug dosing recommendations. Our detailed analysis, utilizing high-throughput genotyping (HTG) of CYP2D6 and comparative data from the 1,000 Genomes Project (1KG) and the US National Marrow Donor Program (NMDP), revealed significant pharmacogenetic diversity in core pharmacogenes such as CYP2B6, CYP2C19, CYP4F2, NUDT15, and CYP2D6. Notably, intermediate metabolizer frequencies for CYP2B6 in SKR (3.28%) were comparable to Europeans (5.77%) and East Asians (5.36%) but significantly differed from other global populations (p < 0.01). For CYP2C19, 48.74% of SKR individuals were classified as intermediate metabolizers, with the *35 allele (2.02%) being unique to SKR, the allele not observed in other East Asian populations. Additionally, the high-risk *3 allele in CYP4F2 was significantly more frequent in SKR (34.72%) than in other East Asian populations (p < 0.01). NUDT15 poor metabolizers were found in 0.76% of SKR, aligning closely with other East Asians (1.59%), while TPMT poor metabolizers were predominantly observed in Europeans and Africans, with one case in SKR. We identified significant allele frequency differences in CYP2D6 variants rs1065852 and rs1135840. Among the 72 drugs analyzed, 93.43% (n = 370) of patients required dosage adjustments for at least one drug, with an average of 4.5 drugs per patient. Moreover, 31.31% (n = 124) required adjustments for more than five drugs. These findings reveal the substantial pharmacogenetic diversity of the SKR population within the global population, emphasizing the urgency of integrating population-specific PGx data into clinical practice to ensure safe and effective drug therapies. This comprehensive PGx profiling in SKR not only advances personalized medicine but also holds the potential to significantly improve healthcare outcomes on a broader scale.

Mapping the relative accuracy of cross-ancestry prediction

The overwhelming majority of participants in genome-wide association studies (GWAS) have European (EUR) ancestry, and polygenic scores (PGS) derived from EURs often perform poorly in non-EURs. Previous studies suggest that between-ancestry differences in allele frequencies and linkage disequilibrium are significant contributors to the poor portability of PGS in cross-ancestry prediction. We hypothesize that the portability of (local) PGS varies significantly over the genome. Therefore, we develop a method, MC-ANOVA, to estimate the loss of accuracy in cross-ancestry prediction attributable to allele frequency and linkage disequilibrium differences between ancestries. Using data from the UK Biobank we develop PGS relative accuracy (RA) maps quantifying the local portability of EUR-derived PGS in non-EUR ancestries. We report substantial variability in RA along the genome, suggesting that even in ancestries with low overall RA of EUR-derived effects (e.g., African), there are regions with high RA. We substantiate our findings using six complex traits, which show that EUR-derived effects from regions where MC-ANOVA predicts high RA also have high empirical RA in real PGS. We provide software implementing MC-ANOVA and RA maps for several non-EUR ancestries. These maps can be used to interpret similarities and differences in GWAS results between groups and to improve cross-ancestry prediction.

Suggestive evidence of male specific genetic association of IL8 -251T>A promoter polymorphism with primary angle closure glaucoma in a north Indian Punjabi population

BackgroundOverproduction of IL-8 in the retina and optic nerve may affect the survival of retinal ganglion cells (RGCs) and contribute to axonal damage in glaucoma. The -251T > A functional variant in the promoter region of the IL8 gene is known to affect its transcriptional activity, as demonstrated in in vitro assays.MethodsThe present study investigates the genetic association of this polymorphism with primary glaucoma in a North Indian Punjabi cohort. A total of 226 primary open angle glaucoma (POAG), 132 primary angle closure glaucoma (PACG) patients and 424 matched controls were recruited. Genotyping was performed using the restriction length polymorphism (RFLP) method.ResultsAssociation analysis was done by PLINK software and appropriate corrections were applied for potential confounding variables. No significant differences in allele or genotype frequency were observed in pooled cases when compared to controls. However, after segregating the data into POAG and PACG and based on sex, significant difference was observed in the allele frequency among PACG males and control male subjects (p = 0.014, OR = 0.52, 95% CI = 0.31–0.88). The heterozygous ‘AT’ genotype provided 0.46 times protection for PACG among males (p = 0.028, OR = 0.46, 95% CI = 0.23–0.92). Genetic model analysis revealed that the combination of ‘AT + AA’ genotypes conferred protection against the development of PACG among male subjects under a dominant model (p = 0.013, OR = 0.44, 95% CI = 0.23–0.84; pcorr=0.003, OR = 0.30, 95% CI = 0.14–0.67).ConclusionsThis study suggests a genetic association of the -251T > A variant with PACG in males in the targeted population and highlights the importance of sex- specific analysis in glaucoma. The biological mechanisms underlying these differences should be further explored to better understand the observed sex bias in PACG.

CYP19 and ESR2 polymorphisms as potential culprits in cryptorchidism.

Cryptorchidism impairs sperm development and increases the risk of infertility and testicular cancer. Estrogen signalling is critical for proper descent of the testicles, and hormonal imbalances play a role in cryptorchidism. CYP19, also known as aromatase, encodes an enzyme that converts testosterone, a male sex hormone, into estradiol, the main form of estrogen. While estrogen receptors can be activated by estrogen, CYP19 plays an important role in regulating local estrogen levels in tissues such as the testes, as it affects cellular processes controlled by estrogen receptors. We aimed to investigate the relationship between polymorphisms in the CYP19 (rs2414096) and ESR2 (rs4986938) and susceptibility to cryptorchidism. We genotyped CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms using PCR-RFLP in DNA isolated from blood samples of cryptorchid children (n=41) and healthy controls (n=42). The differences in genotype and allele frequencies between the cryptorchidism and control groups were calculated using the chi-square (χ2). In cryptorchidism patients, genotypes (p<0.05) and allele frequencies (p<0.05) of CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms showed significant differences compared to controls. CYP19 (rs2414096) and ESR2 (rs4986938), the AA genotype and A allele frequency may be risk factors for cryptorchidism, while the GG genotype and G allele may be protective against cryptorchidism. Our study provides compelling evidence for a significant association between polymorphisms in the CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms and cryptorchidism susceptibility. These findings extend previous research implicating genetic factors in testicular descent but go further by identifying specific polymorphisms associated with increased risk. While previous studies have suggested a role for estrogen imbalance in cryptorchidism, our results provide concrete genetic evidence supporting this hypothesis. The relatively small sample size necessitates replication in larger cohorts to further validate our findings. Additionally, functional studies are warranted to elucidate the precise mechanisms by which these genetic variants influence cryptorchidism risk. Despite these limitations, our results represent a significant step in unravelling the complex aetiology of this common birth defect. Our findings show that polymorphisms in CYP19 (rs2414096) and ESR2 (rs4986938), which play a role in estrogen production, are significantly associated with cryptorchidism susceptibility, highlighting the potential role of estrogen pathway variations in testicular descent.

Ancestry-Related Differences in Allele and Genotype Frequencies of EGF A61G Polymorphism in the Cuban Population

Background: The polymorphism rs4444903 of the Epidermal Growth Factor gene (EGF A61G) causes differences in the EGF serum levels. It has become a biomarker for genetic susceptibility to cancer and a pharmacogenomic marker for therapies involving the EGF/EGF-receptor pathway. Objective: The present study aimed to characterize the allele and genotype frequencies of the rs4444903 in a Cuban sample and its relationship to a specific genetic ancestry. Methods: A cross-sectional study was carried out. Genomic data was collected from a dense genome-wide genotyping array analysis of 948 Cubans from all provinces. The allele and genotype frequencies of the rs4444903 were calculated. Analysis of ancestryrelated allelic/genotypic differences was performed. Results: The frequencies for both alleles were found to be very similar (0.52 for G vs. 0.48 for A allele), and genotype frequencies were 24.3%, 47.9%, and 27.8% for AA, AG, and GG, respectively. Greater differences were found between Cuban provinces, with frequencies for the G allele ranging from 0.38 in Artemisa to 0.69 in Guantánamo and for the GG genotype from 14.29% in Mayabeque to 50.88% in Guantánamo. An increased Africanancestry proportion was related to a higher probability of carrying G allele and GG genotype, with a significant (p=0.0038, q=0.024) African-ancestry-enrichment pattern. Conclusion: African ancestry seems to contribute to an increase in the EGF61*G allele in Cubans. Geographic patterns in admixture proportions for African and European ancestry are a determinant factor in the allelic and genotypic frequency differences between Cuban provinces. Such differences should be observed when designing association studies and implementing therapeutic approaches based on the EGF/EGF receptor pathway in Cuba.

Selection for altruistic defense in structured populations.

We model natural selection for or against an anti-parasite (or anti-predator) defense allele in a host (or prey) population that is structured into many demes. The defense behavior has a fitness cost for the actor compared to non defenders ("cheaters") in the same deme and locally reduces parasite growth rates. Hutzenthaler et al. (2022) have analytically derived a criterion for fixation or extinction of defenders in the limit of large populations, many demes, weak selection and slow migration. Here, we use both individual-based and diffusion-based simulation approaches to analyze related models. We find that the criterion still leads to accurate predictions for settings with finitely many demes and with various migration patterns. A key mechanism of providing a benefit of the defense trait is genetic drift due to randomness of reproduction and death events leading to between-deme differences in defense allele frequencies and host population sizes. We discuss an inclusive-fitness interpretation of this mechanism and present in-silico evidence that under these conditions a defense trait can be altruistic and still spread in a structured population.

Mapping an avirulence gene in the sunflower parasitic weed Orobanche cumana and characterization of host selection based on virulence alleles

BackgroundSunflower broomrape (Orobanche cumana Wallr.) is a holoparasitic plant that jeopardizes sunflower production in most areas of Europe and Asia. Recently, populations with increased virulence, classified as race GGV, have been identified in Southern Spain’s Guadalquivir Valley gene pool. These populations overcome resistance genes in hybrids resistant to the predominant race FGV. This study aimed to (i) determine the inheritance and map the avirulence trait segregating in a cross between O. cumana individuals from populations EK23 (FGV) and IN201 (GGV), and (ii) characterize the host effect on the IN201 parental population allelic diversity.ResultsA segregating population consisting of 144 F2:3 families was evaluated for virulence using a differential sunflower genotype (Hybrid 1, resistant to race FGV and susceptible to race GGV) and genotyped with SNP markers. The ratio of avirulent to virulent F2:3 families was not significantly different to 1:3 (χ2 = 0.93; P = 0.34), indicating monogenic control of the avirulence/virulence trait. The AvrG−GV locus was mapped on the upper end of O. cumana chromosome 2, 9.2 cM distal from the SNP markers OS04791 and OS02805. Secretome analysis in the AvrG−GV region revealed a cysteine-rich CAP superfamily- and a glucan 1,3-beta-glucosidase family 3-encoding genes as possible candidates for AvrG−GV. SNP allelic analysis on the IN201 population parasitizing a highly susceptible genotype or the differential genotype Hybrid 1 showed that (i) IN201 structure was shaped towards virulent alleles at SNP loci linked to AvrG−GV (ii) there were significant allelic frequency differences associated with the host genotype at AvrG−GV–linked loci.ConclusionsThis study mapped for the first time an avirulence gene in parasitic plants using a classical genetic approach, confirmed a gene-for-gene model in the O.cumana –sunflower system, and showed the implication of this single avirulence gene in determining the structure of broomrape populations subjected to selection pressure posed by a resistant genotype. The results will contribute to a better understanding of the interaction between crops and weedy parasitic plants, and to effectively manage evolution of virulence by sustainable control strategies based on host genetic resistance.

Frequencies of an IFNL4 Variant in an Admixed Population from Amazonia and Its Influence on Hepatitis C Infection.

The rs12979860 polymorphism, related to the IFNL4 gene, is suggested as a factor that impacts fibrosis progression in hepatitis C virus (HCV) infection and exhibits a wide distribution pattern across global populations. In this retrospective cross-sectional study, we aimed to investigate the frequency of this variant in an Amazonian population from Brazil, as well as its association with liver fibrosis development and its staging in HCV carriers. Our results show a significant association of the TT genotype in the sample of patients with HCV (OR = 2.291; 95% CI = 1.088-4.826; p = 0.033) and the greater frequency of the T allele (62.1%), which is similar to the those of African populational groups. Populational genetics analysis showed significant differences in allele frequencies on global levels. The frequency of the C allele in the study population (37.8%) was like that of the African population (39.7%), and differed from all other populations, which ranged from 62.5% to 92.9%. These findings suggest that rs12979860 plays a role in susceptibility to hepatitis C. Additionally, they allow us to propose that the response to hepatitis C infection in this group may resemble that of the African population.

Clinical, biochemical, and genetic study of TACE/TNF-α/ACE signaling pathway in pediatric COVID-19 infection.

Pediatric patients infected with coronavirus disease 2019 (COVID-19) have unique clinical characteristics. Tumor necrosis factor (TNF) is a proinflammatory cytokine that greatly contributes to tumor pathogenesis. To describe the presenting characteristics of COVID-19 infection among pediatric patients, and investigate the possible role of the TNF-α signaling pathway. This prospective case-control study included 50 Egyptian pediatric patients with COVID-19 and 50 healthy controls. Clinical, laboratory, and radiological assessments were performed. Serum TNF-alpha (TNF-α), TNF-α-converting enzyme (TACE), and angiotensin-converting enzyme 2 (ACE2) were measured using enzyme-linked immunosorbent assay. ACE (I/D) (rs4646994), ACE2 rs2285666, and TNF-α-308G/A single nucleotide polymorphisms (SNPs) were performed using conventional polymerase chain reaction techniques with or without restriction fragment length polymorphism. The median age was 1 year (interquartile range [IQR], 0.31-2.50 years) in the case group and 1.45 years (IQR, 1.00-3.00) in the control group. The main presenting symptoms were fever (92%), dry cough (74%), and dyspnea (72%). The lymphocytic count was normal in 14 patients (28%), decreased in 16 patients (32%), and increased in 20 patients (40%) of the case group. Positive chest computed tomography finding of COVID-19 infection were demonstrated among 40% of patients using COVID-19 Reporting and Data System categories (ground-glass opacity with or without consolidations in the lungs). There were significant increased serum TACE and TNF-α with decreased ACE2 levels among cases versus controls (P< 0.001). The GG genotype and G allele of the TNF-α-308G/A SNP were significantly higher in patients than in controls (P<0.05 for both), with insignificant differences in genotype and allelic frequencies in the ACE (I/D) (rs4646994) and ACE2 rs2285666 SNPs. The TNF signaling pathway was significantly activated in pediatric COVID-19 infection. Only the TNF-α-308G/A SNP was significantly associated with pediatric COVID-19 infection.

Forensic STR Loci and Schizophrenia: An Exploration of Implications for Forensic Applications and Genetic Privacy.

Short tandem repeat (STR) loci are widely used in forensic genetics for identification and kinship analysis. Traditionally, these loci were selected to avoid medical associations, but recent studies suggest that loci such as TH01 and D16S539 may be linked to psychiatric conditions like schizophrenia. This study explores these potential associations and considers the privacy implications related to disease susceptibility. We analyzed 19 STR loci, including CODIS core loci and additional loci like Penta D and Penta E. Statistical analyses were conducted on a dataset of schizophrenia patients and matched control individuals to assess the relationship between STR polymorphisms and schizophrenia risk. No significant associations were found between the 19 analyzed loci and schizophrenia in this dataset. While initial analyses revealed minor allele frequency differences at the D3S1358, D13S317, and TPOX loci between the schizophrenia and control groups, these differences did not retain statistical significance following Bonferroni correction (corrected p < 0.0026 for all loci). Although no significant associations were found between STR loci and schizophrenia, this study highlights the importance of considering the potential for forensic DNA data to reveal health-related information. As forensic DNA databases continue to expand, there is a growing need to reassess ethical and legal guidelines to ensure the protection of individual privacy. Future research should continue exploring these genetic associations with larger, more diverse samples to further understand their implications.

Stochastic Epigenetic Modification and Evolution of Sex Determination in Vertebrates

In this report, we propose a novel mathematical model of the origin and evolution of sex determination in vertebrates that is based on the stochastic epigenetic modification (SEM) mechanism. We have previously shown that SEM, with rates consistent with experimental observation, can both increase the rate of gene fixation and decrease pseudogenization, thus dramatically improving the efficacy of evolution. Here, we present a conjectural model of the origin and evolution of sex determination wherein the SEM mechanism alone is sufficient to parsimoniously trigger and guide the evolution of heteromorphic sex chromosomes from the initial homomorphic chromosome configuration, without presupposing any allele frequency differences. Under this theoretical model, the SEM mechanism (i) predated vertebrate sex determination origins and evolution, (ii) has been conveniently and parsimoniously co-opted by the vertebrate sex determination systems during the evolutionary transitioning to the extant vertebrate sex determination, likely acting "on top" of these systems, and (iii) continues existing, alongside all known vertebrate sex determination systems, as a universal pan-vertebrate sex determination modulation mechanism.

Allele frequency impacts the cross-ancestry portability of gene expression prediction in lymphoblastoid cell lines

Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of prediction accuracy across ancestries. In this study, we used gene expression levels in lymphoblastoid cell lines to understand how much each genetic factor contributes to lowered portability of gene expression prediction from European to African ancestries. We found that cis-genetic effects on gene expression are highly similar between European and African individuals. However, we found that allele frequency differences of causal variants have a striking impact on prediction portability. For example, portability is reduced by more than 32% when the causal cis-variant is common (minor allele frequency, MAF >5%) in European samples (training population) but is rarer (MAF <5%) in African samples (prediction population). While large allele frequency differences can decrease portability through increasing LD differences, we also determined that causal allele frequency can significantly impact portability when the impact from LD is substantially controlled. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability resulting from differences in causal allele frequency. We conclude that causal cis-eQTL effects are highly similar in European and African individuals, and allele frequency differences have a large impact on the accuracy of gene expression prediction.