Allele Frequencies Research Articles

Ginkgo biloba for Tardive Dyskinesia and Plasma MnSOD Activity: Association with MnSOD Ala-9Val Variant: A Randomized, Double-blind Trial.

Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype. An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls. EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients. EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.

The CD244 rs3766379 variant showed no association with susceptibility to rheumatoid arthritis while soluble CD244 was associated with disease activity

Cluster of differentiation 244 (CD244), a member of the signaling lymphocytic activation molecule (SLAM) family, is one of the major cell surface receptors of the SLAM family with activating and inhibitory signaling potentials that is involved in the functional regulation of inflammatory reactions. It has recently been suggested that soluble CD244 levels are dysregulated in patients with rheumatoid arthritis (RA), but the evidence is not conclusive. Furthermore, the CD244 rs3766379 variant showed conflicting results regarding association with disease susceptibility. In this cross-sectional case-control study, serum CD244 concentration was determined in 123 RA patients and 60 controls using an enzyme-linked immunosorbent assay kit. The CD244 rs3766379 variant was also genotyped using real-time polymerase chain reaction principles. Results revealed that Log10-transformed serum concentrations (mean ± standard error) of soluble CD244 were significantly elevated in RA patients compared to controls (0.53 ± 0.04 vs. 0.29 ± 0.02 ng/mL; probability = 0.003), especially in patients with high disease activity (0.73 ± 0.12 vs. 0.29 ± 0.02 ng/mL; probability = 0.003), where CD244 showed reliable discrimination between patients and controls (area under the curve = 0.698; probability = 0.023). The rs3766379 allele and genotype frequencies showed no significant differences between patients and controls. Furthermore, this variant did not affect CD244 concentration. In conclusion, CD244 levels were up-regulated in the serum of patients with RA, particularly those with high disease activity. The CD244 rs3766379 variant was not associated with susceptibility to RA and had no effect on serum CD244 concentration.

Field-evolved resistance to neonicotinoids in the mosquito, Anopheles gambiae, is associated with mutations of nicotinic acetylcholine receptor subunits combined with cytochrome P450-mediated detoxification

New insecticides prequalified for malaria control interventions include modulators of nicotinic acetylcholine receptors that act selectively on different subunits leading to variable sensitivity among arthropods. This study aimed to investigate the molecular mechanisms underlying contrasting susceptibility to neonicotinoids observed in wild populations of two mosquito sibling species. Bioassays and a synergist test with piperonyl butoxide revealed that the sister taxa, Anopheles gambiae and An. coluzzii, from Yaounde, Cameroon, both have the potential to develop resistance to acetamiprid through cytochrome P450-mediated detoxification. However, contrary to An. coluzzii, An. gambiae populations are evolving cross-resistance to several active ingredients facilitated by mutations of nicotinic acetylcholine receptors (nAChRs). We sequenced coding regions on the β1 and α6 nAChR subunits where variants associated with resistance to neonicotinoids or to spinosyns have been found in agricultural pests and detected no mutation in An. coluzzii. By contrast, six nucleotide substitutions including an amino acid change in one of the loops that modulate ligand binding and affect sensitivity were present in the resistant species, An. gambiae. Allele frequency distributions were consistent with the spread of beneficial mutations that likely reduce the affinity of An. gambiae nAChRs for synthetic modulators. Our findings provide critical information for the application and resistance management of nAChR modulators in malaria prevention.

Differential distribution of NAT2 polymorphisms and NAT2 acetylator phenotypes among indigenous populations of the Brazilian Amazon.

We report, for the first time, the distribution of four no-function NAT2 single nucleotide polymorphisms and inferred NAT2 acetylator phenotypes in three indigenous groups (Munduruku, Paiter-Suruí, and Yanomami), living in reservation areas in the Brazilian Amazon. Two hundred and seventy-six participants from three indigenous groups (92 for each group) were included and genotyped for four NAT2 polymorphisms (rs1801279, rs1801280, rs1799930, and rs1799931) by the TaqMan system. Minor Allele Frequency (MAF) was determined and NAT2 acetylator phenotypes were inferred. NAT2 rs1801279G>A was absent in all cohorts; rs1799930G>A was absent in Yanomami and rare (MAF 0.016) in Munduruku and Paiter-Suruí; MAF of rs1801280T>C ranged five-fold (0.092-0.433), and MAF of rs1799931G>A varied between 0.179 and 0.283, among the three groups. The distribution of NAT2 phenotypes differed significantly across cohorts; the prevalence of the slow acetylator phenotype ranged from 16.3% in Yanomami to 33.3% in Munduruku to 48.9% in Paiter-Suruí. This three-fold range of variation is of major clinical relevance because the NAT2 slow phenotype is associated with higher risk of hepatotoxicity with antituberculosis chemotherapy and high incidence rates of tuberculosis and burden of latent infection among Munduruku, Paiter-Surui, and Yanomami peoples. According to the frequency of the NAT2 slow acetylator phenotype, the estimated number of individuals needed to be genotyped to prevent one additional event of hepatotoxicity range from 31 (Munduruku) to 39 (Paiter-Surui) and to 67 (Yanomami). The rs1801279 polymorphism was not found in any of the cohorts, while the MAF of the other polymorphisms showed significant variation between the cohorts. The difference in the prevalence of the NAT2 slow acetylator phenotype, which is linked to isoniazid-induced hepatotoxicity, was observed in the different study cohorts.

Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort

IntroductionOsimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib. MethodsFrom 09 to 2019 to 02-2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥ 0.10 %. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice. ResultsThe driver mutation was detected in 42/51 plasma samples (82 %) and in 50/51 tumor samples (98 %), concordance rate was 80 %. In 41/51 (80 %) patients ≥ 1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5 %), 39 in tumor (75 %), nineteen in both. RM concordance rate was 36.5 %. ConclusionCombined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.

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 characteri-stics. 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 investi-gate 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 as-sessments were performed. Serum TNF-alpha (TNF-α), TNF-α-converting enzyme (TACE), and angiotensin-con-verting enzyme 2 (ACE2) were measured using enzyme-linked immunosorbent assay. ACE (I/D) (rs4646994), ACE2 rs2285666, and TNF-α-308G/A single nucleotide poly-morphisms (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 in creased in 20 patients (40%) of the case group. Positive chest com-puted tomography finding of COVID-19 infection were demonstrated among 40% of patients using COVID-19 Re-porting and Data System categories (ground-glass op-acity 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.

Association between the ARMS2 rs10490924 risk genotype and dry-age related macular degeneration patients with and without reticular pseudodrusen in a Turkish population: findings from a study conducted at a tertiary clinic.

To evaluate the relationship between the presence of reticular pseudodrusen (RPD) and the risk allele of ARMS2 rs10490924 variation in dry-AMD patients by using multimodal imaging. Also, to compare patients with and without RPD and healthy volunteers according to the distribution of the risk allele. In this cross-sectional study, dry-AMD patients with (Group A,n = 50) and without (Group B,n = 50) RPD and healthy volunteers (Group C,n = 50) were enrolled. After detailed ophthalmologic examination, confocal scanning laser ophthalmoscope (Heidelberg, Germany) was used to acquire near infra-red (NIR) imaging for RPD and the diagnosis was confirmed by Spectral Domain-Optical coherence tomography (Heidelberg, Germany). In silent choroidal neovascularization suspicion, optical coherence tomography angiography (Optovue, Fremont, CA) was performed and those were excluded. For genetic assessment, peripheric blood sampling was performed. Using next-generation sequencing technique (NGS), ARMS2 rs10490924 single nucleotide polymorphism was investigated. Groups were compared according to the distribution of the risky allele. 150 eyes of 150 participants were included. In Group A, 42% (21) of patients were heterozygous for the T risk allele, 30% (15) were homozygous, and the risk allele was not detected in 28% (14). In Group B, 44% (22) of patients were heterozygous, 17% (8) were homozygous, and the risk allele was not detected in 39% (20). In Group C, 30% (15) of participants were heterozygous, 4% (2) were homozygous, and variation was not observed in 64% (32). Homozygous participants in Group A were significantly higher than other two groups (Group A-B: OR = 2.67, 95% CI: 0.895, 8.020; Group A-C: OR = 17.14, 95% CI: 3.449, 85.208) while in Group B, homozygous individuals were higher than Group C (respectively, p values 0.0039, 0.0002, 0.013). T risky allele frequencies were 51%, 38%, and 20% in Groups A, B, and C, respectively, which was significantly higher in Group A (p = 0.02). Genetic influence in AMD is inevitable while certain differences according to different ethnicities may apply. Association of genetic variations and imaging findings like RPD is lacking among literature for different populations. By the aspect of this study, the relationship between RPD and ARMS2 rs10490924 polymorphism in dry-AMD patients were highlighted among Turkish population by using multimodal imaging for the first time. What is Known? Pathophysiology of age-related macular degeneration is influenced from multiple factors including single nucleotide polymorphisms. The variations of ARMS2 are suspected well in the current literature. Reticular pseudodrusen is related to advanced stages of age related macular degeneration disease. What is New? The ARMS2 rs10490924 risk genotype is associated with the presence of reticular pseudodrusen in dryage related macular degeneration patients. Homozygous genotype of T risk allele is evaluated significantly higher in dry age related macular degeneration patientswith reticular pseudodrusen.

European EHBP1L1 Genotyping Survey of Dyserythropoietic Anemia and Myopathy Syndrome in English Springer Spaniels

Dyserythropoietic anemia and myopathy syndrome (DAMS) with neonatal losses was recently characterized as an autosomal recessive disorder caused by an EHBP1L1 frameshift variant in English Springer Spaniels (ESSPs). The frequency and dissemination of the mutation remained unknown. The EHBP1L1 protein is essential for muscle function, and the Rab8/10-EHBP1L1-Bin1-dynamin axis participates in nuclear polarization during the enucleation of erythroblasts. Lack of EHBP1L1 function decreases enucleation, leading to increased numbers of nucleated erythrocytes, which are characteristic of DAMS. A genotyping survey for the EHBP1L1 variant was conducted based upon submitted samples of ESSPs from Europe. DNA was extracted, and a real-time PCR assay, with allele-specific TaqMan probes for EHBP1L1 wild-type and frameshift deletion, was applied. Between September 2022 and August 2024, 803 samples were received from 18 European countries. The EHBP1L1 mutant allele frequency was 9.7%, including 4 homozygous dogs and 148 heterozygotes. The mutant EHBP1L1 allele was found in 13 countries. A total of 6 homozygous and 73 heterozygous ESSPs reported on an open database could be tracked to an original common ancestor. Although the survey is biased, it indicates that the mutant EHBP1L1 variant is disseminated in the breed and across Europe. The genotyping of ESSPs is recommended to diagnose DAMS and guide breeders.

Rapid evolution of recombination landscapes during the divergence of cichlid ecotypes in Lake Masoko.

Variation of recombination rate along the genome is of crucial importance to rapid adaptation and organismal diversification. Many unknowns remain regarding how and why recombination landscapes evolve in nature. Here, we reconstruct recombination maps based on linkage disequilibrium and use subsampling and simulations to derive a new measure of recombination landscape evolution: the Population Recombination Divergence Index (PRDI). Using PRDI, we show that fine-scale recombination landscapes differ substantially between two cichlid fish ecotypes of Astatotilapia calliptera that diverged only ~2,500 generations ago. Perhaps surprisingly, recombination landscape differences are not driven by divergence in terms of allele frequency (FST) and nucleotide diversity (Δπ): although there is some association, we observe positive PRDI in regions where FST and Δπ are zero. We found a stronger association between evolution of recombination and 47 large haplotype blocks that are polymorphic in Lake Masoko, cover 21% of the genome, and appear to include multiple inversions. Among haplotype blocks, there is a strong and clear association between the degree of recombination divergence and differences between ecotypes in heterozygosity, consistent with recombination suppression in heterozygotes. Overall, our work provides a holistic view of changes in population recombination landscapes during early stages of speciation with gene flow.

Disease-Modifying Effect of HBS1L-MYB in HbE/β-Thalassemia Patients in Bangladeshi Population

Background: Thalassemias are a group of autosomal recessive disorders and the most common inherited disease worldwide. Fetal hemoglobin (HbF) is the main oxygen carrier protein in the human fetus. Elevated HbF level is known to ameliorate the severity of HbE/β and β-thalassemia. This study aimed to investigate whether two commonly known HbF-associated SNPs (rs28384513 and rs4895441) in the HBS1L-MYB region are associated with HbF level and disease severity in Bangladeshi HbE/β-thalassemia patients. Methods: Blood samples were collected from 160 participants (120 HbE/β-thalassemia patients and 40 healthy controls). Hematological analysis was performed using complete blood count (CBC) and capillary Hb electrophoresis. After genomic DNA extraction, real-time PCR-based high-resolution melting (HRM) for SNP detection, targeting the HBS1L-MYB intergenic region, was done. Results: Patients carrying rs28384513 and rs4895441 SNPs had significantly higher HbF (1.29 ± 1.63 and 1.49 ± 1.7 g/dL, respectively) compared to major allele ‘TT’ and ‘AA’ (0.87 ± 1.1 and 1.19 ± 1.65 g/dL, respectively) with a p-value of 0.01 and 0.03, respectively. It has been detected that HbF levels in SNP-carrying patients significantly correlated with the higher transfusion interval (60 days, r = 0.38, p &lt; 0.0001) and age of first transfusion (65 months, r = 0.26, p &lt; 0.0028) in these patients. Further, non-transfusion-dependent patients had the highest HbF level (2.03 ± 2.05 g/dL) compared to transfusion-dependent moderate (0.58 ± 0.78 g/dL) and severe (0.84 ± 1.27 g/dL) patients generating a significant p-value &lt; 0.0001 in One-Way ANOVA test. The minor allele frequencies of rs28384513 (G) and rs4895441 (G) were found to be 0.43 and 0.11 respectively. Conclusion: These findings suggest that SNPs of HBS1L-MYB may have a role in elevated HbF levels and ameliorating disease severity in terms of transfusion in HbE/β-thalassemia patients.

Genetic risk factors for Mesoamerican nephropathy

Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the OPCML gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 10 −8 ). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America.

The role of complement factor I rare genetic variants in age related macular degeneration in Finland.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The alternative pathway (AP) of complement has been linked to the pathogenesis of AMD. In particular, rare variants (RVs) in the complement factor I (CFI) gene encoding the Factor I (FI) protein confer increased AMD risk. The prevalence of CFI RVs are well characterised in European AMD, however little is known about other populations. The Finnish population underwent genetic restriction events which have skewed allele frequencies in unexpected ways. A series of novel or enriched CFI RVs were identified in individuals with dry AMD from the Finnish Biobank Cooperative (FINBB), but the relationship between these genotypes and contribution to disease was unclear. Understanding how RVs impact the ability of FI to regulate the complement system is important to inform mechanistic understanding for how different genotypes contribute to disease development. To explore this a series of in vitro assays were used to functionally characterise the protein products of 3 CFI RVs enriched in FINBB dry AMD, where no prior data were available. The G547R variant resulted in almost complete loss of both classical pathway and AP regulatory potential. The c.982 g>a variant encoding G328R FI perturbed an exon splice enhancer site which resulted in exon skipping and a premature stop codon in vitro and low levels of FI in vivo. Despite detailed analysis no defect in levels or function was demonstrated in T107A. Functional characterization of all Finnish CFI RVs in the cohort allowed us to demonstrate that in Finnish dry AMD, collectively the type 1 CFI RVs (associated with FI haploinsufficiency) were significantly enriched with odds ratio (ORs) of 72.6 (95% confidence interval; CI 16.92 to 382.1). Meanwhile, type 2 CFI RVs (associated with FI dysfunction) collectively conferred a significant OR of 4.97 (95% CI 1.522 to 15.74), and non-impaired or normal CFI RV collectively conferred an of OR 3.19 (95% CI 2.410 to 4.191) although this was driven primarily by G261D. Overall, this study for the first time determined the ORs and functional effect for all CFI RVs within a Geographic Atrophy (GA) cohort, enabling calculations of combined risk scores that underline the risk conferred by type 1 and 2 CFI RVs in GA/AMD.

Genomic and bioacoustic variation in a midwife toad hybrid zone: A role for reinforcement?

Hybrid zones, i.e., geographic areas where diverging lineages meet, hybridize and eventually mix their genomes, offer opportunities to understand the mechanisms behind reproductive isolation and speciation. Hybrid zones are particularly well suited to study reinforcement, i.e., the process by which selection against hybridization increases reproductive barriers, which, in anuran amphibians, is typically expressed by increased divergence in advertisement calls-the main cue to assortative mating-in parapatric ranges. Using mitochondrial barcoding (16S sequences), population genomics (thousands of SNPs) and bioacoustic analyses (four call parameters), we examine the hybrid zone between two incipient species of midwife toads (Alytes obstetricans and A. almogavarii) in southern France, with the purposes of locating their transition, measuring genetic introgression, and documenting potential signatures of reinforcement. We map range boundaries in the Eastern Pyrenees and the southwestern foothills of the Massif Central, namely along the Ariège valley and the Montagne Noire area. Similarly to another transition between these species in Spain, we found the hybrid zone to be narrow, involving geographically restricted gene flow (~20 km wide allele frequency clines) and barrier loci (i.e., loci resisting introgression), both suggestive of partial post-zygotic isolation (hybrid incompatibilities). The calls of the species overlap less inside than outside the hybrid zone, due to a reduction of their standing variation rather than a shift towards distinctive variants. While neutral causes cannot be excluded, this pattern follows the general expectations of reinforcement, yet without reproductive character displacement. Our study highlights the potential of amphibian hybrid zones to assess the genetic and behavioral drivers of reproductive isolation in statu nascendi and under various evolutionary contexts.

Association of RS1126478 (LTF) with molar-incisor and generalized periodontitis.

LTF SNP rs1126478 (T>C) could modulate Lactoferrin function and release and has been associated with periodontal disease in different locations before, but not in America. Thus, this study aimed to assess the association between this SNP and Grade C Periodontitis (Generalized (PerioC-G) and Molar Incisor Pattern (PerioC-MIP)) and seek a relationship between its presence and LTF gingival crevicular fluid (GCF) production. Oral cells from 361 Brazilians and 375 North Americans patients (Diseased and Health Controls (PH) from both locations) were collected. DNA was extracted, and a prefabricated probe system determined rs116478 genotyping. Immunoenzymatic analysis detected LTF levels in GCF. Higher allelic altered-C frequency was associated with PerioC. For PerioC-G, CT and CC genotypes presented a frequency of 44.7% and 34.1%, respectively, while 37.3% and 26.4% were found to PH group (OD=2.1 (p=0.004) for CT and OD=2.3 (p=0.003) for CC). PerioC-G was associated with a lower concentration (742.2±717.9 pg/ml) of LTF than PerioC-MIP (5851±5859.2 pg/ml), p<0.0001. Multiple logistic regression showed that CC genotype impacted LTF levels by acting as a predictor (β =2.457, p=0.02, OD=1.17) despite the site or diagnosis. There is an association of rs1126478 with Grade C periodontitis, mainly the PerioC-G. Lower LTF levels in GCF might be associated with the generalized disease pattern. This study assessed and compared the genetic background in two distinct locations, paving the way for new studies regarding personalized risk and treatment for different ethnicities. As this SNP is in a region related to the antimicrobial function of LTF, it could impact PerioC-MIP and PerioC-G response against periodontopathogens. This discovery opens the way for in vitro studies analyzing the functionality of this SNP, and, in the future, it can be used to treat PerioC, individualizing the phenotypes.

ASSOCIATION OF VITAMIN D RECEPTOR GENE POLYMORPHISM WITH EXTERNAL APICAL ROOT RESORPTION IN ORTHODONTICALLY TREATED PATIENTS

The vitamin D receptor influences host immune responses and aspects of bone development, growth, and homeostasis. The aim of this study was to investigate the association of the vitamin D receptor TaqI gene polymorphism with external apical root resorption during orthodontic treatment. Methods: Our sample consisted of 50 patients aged 12 to 40 years who received fixed total orthodontic treatment during 1999 and 2000. External apical root resorption (EAR) of maxillary incisors was assessed on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, analysis of the vitamin D receptor TaqI polymorphism was performed by polymerase chain reaction followed by restriction fragment length polymorphism. Univariate and multivariate analyses were performed to assess the association of clinical and genetic variables with external apical root resorption (P&lt;0.05). There was a correlation between the VDR and RRAE variables (r= 0.306 and p= 0.030). The genotype resulting from the Taq1 cleavage and the allele frequencies differed between the groups with and without RRAE. Individuals carrying the T allele had a higher probability of developing RRAE when compared with individuals carrying the tt genotype (OR= 7.5; 95% CI= 1.8–31.4; p= 0.0094). The TaqI polymorphism of the vitamin D receptor gene was associated with external apical root resorption in orthodontically treated patients.

A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular-kidney complications.

Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events. Using whole-exome sequencing data, we constructed a weighted polygenic risk score (wPRS) consisting of 135 common variants (minor allele frequency >0.01) of 34 MDG based on r2>0.2 for linkage disequilibrium in a discovery case-control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9-46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3-61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events. In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4-61.7] years; disease duration 4.0 [1.0-9.0] years) observed for a median (IQR) of 17.5 (14.4-21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular-kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the 'bottom-20%-wPRS plus baseline disease duration <5 years' group as referent, the 'top-20%-wPRS plus baseline disease duration 5 to <10 years' group had unadjusted and adjusted HR of 1.60 (95% CI 1.17, 2.19, p=0.003) and 1.62 (95% CI 1.16, 2.26, p=0.005), respectively, for cardiovascular-kidney events compared with 1.38 (95% CI 0.97, 1.98, p=0.075) and 1.06 (95% CI 0.72, 1.57, p=0.752) in the 'bottom-20%-wPRS plus baseline disease duration ≥10 years' group. Common variants of MDG increased risk for YOD and cardiovascular-kidney events.

Sequential introgression of a carotenoid processing gene underlies sexual ornament diversity in a genus of manakins.

In a hybrid zone between two tropical lekking birds, yellow male plumage of one species has introgressed asymmetrically replacing white plumage of another via sexual selection. Here, we present a detailed analysis of the plumage trait to uncover its physical and genetic bases and trace its evolutionary history. We determine that the carotenoid lutein underlies the yellow phenotype and describe microstructural feather features likely to enhance color appearance. These same features reduce predicted water shedding capacity of feathers, a potential liability in the tropics. Through genome-scale DNA sequencing of hybrids and each species in the genus, we identify BCO2 as the major gene responsible for the color polymorphism. The BCO2 gene tree and genome-wide allele frequency patterns suggest that carotenoid-pigmented collars initially arose in a third species and reached the hybrid zone through historical gene flow. Complex interplay between sexual selection and hybridization has thus shaped phenotypes of these species, where conspicuous sexual traits are key to male reproductive success.

The correlation of shift work and CLOCK, BMAL1, and PER1 gene polymorphisms with hypertension in healthcare workers: A cross-sectional study

This study aimed to investigate the polymorphisms of circadian clock genes and the association of shift work and gene polymorphisms with hypertension in healthcare workers. This study recruited 222 healthcare workers, of whom 76 had primary hypertension (Hyp group) and 146 served as controls (Control group). General information and working hours were collected through questionnaires. Next, the identification of specific single nucleotide polymorphism (SNP) loci related to the Circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like 1 (BMAL1), and PER1 genes was conducted by literature and PDGene database search. Venous blood samples were then collected for DNA extraction, and polymerase chain reaction-restriction fragment length polymorphism techniques were used to analyze the genotyping and allele frequency of the SNP sites. Finally, multivariate logistic regression was employed to analyze the association between various risk factors and hypertension in healthcare workers. Compared to the control group, the Hyp group had significantly higher proportions of alcohol consumption and family history of hypertension, while the average sleep duration and average exercise time were significantly lower. Shift work analysis showed that the Hyp group had a significantly lower average number of evening shifts per month while a much higher average number of night shifts per month compared to the control group. The GG genotype at the CLOCK rs1801260 locus was associated with a lower risk of hypertension (OR = 0.446), and the TT genotype of the BMAL1 rs11022775 locus also showed a similar protective effect (OR = 0.426). However, the genotype distribution of the PER1 rs2735611 locus was not significantly associated with the risk of hypertension. Multivariate regression analysis revealed that a family history of hypertension and insufficient sleep were significantly associated with the risk of hypertension, and the average number of night shifts per month was positively correlated with the risk of hypertension. Specific polymorphisms in the CLOCK and BMAL1 genes may have a protective effect against hypertension in healthcare workers, while polymorphisms in the PER1 gene are not significantly associated with the risk of hypertension. Additionally, a family history of hypertension, insufficient sleep, and shift work patterns may be significant risk factors for hypertension.

Asymptotics of the allele frequency spectrum and the number of alleles

Asymptotics of the allele frequency spectrum and the number of alleles

Two fitness inference schemes compared using allele frequencies from 1068 391 sequences sampled in the UK during the COVID-19 pandemic

Throughout the course of the SARS-CoV-2 pandemic, genetic variation has contributed to the spread and persistence of the virus. For example, various mutations have allowed SARS-CoV-2 to escape antibody neutralization or to bind more strongly to the receptors that it uses to enter human cells. Here, we compared two methods that estimate the fitness effects of viral mutations using the abundant sequence data gathered over the course of the pandemic. Both approaches are grounded in population genetics theory but with different assumptions. One approach, tQLE, features an epistatic fitness landscape and assumes that alleles are nearly in linkage equilibrium. Another approach, MPL, assumes a simple, additive fitness landscape, but allows for any level of correlation between alleles. We characterized differences in the distributions of fitness values inferred by each approach and in the ranks of fitness values that they assign to sequences across time. We find that in a large fraction of weeks the two methods are in good agreement as to their top-ranked sequences, i.e. as to which sequences observed that week are most fit. We also find that agreement between the ranking of sequences varies with genetic unimodality in the population in a given week.