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Cell Genomics May 2024Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and...
Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and highly mutable gene families. Even in this context, we discovered unprecedented variation in the hyper-variable (HYP) effectors of plant-parasitic nematodes. HYP effectors are single-gene loci that potentially harbor thousands of alleles. Alleles vary in the organization, as well as the number, of motifs within a central hyper-variable domain (HVD). We dramatically expand the HYP repertoire of two plant-parasitic nematodes and define distinct species-specific "rules" underlying the apparently flawless genetic rearrangements. Finally, by analyzing the HYPs in 68 individual nematodes, we unexpectedly found that despite the huge number of alleles, most individuals are germline homozygous. These data support a mechanism of programmed genetic variation, termed HVD editing, where alterations are locus specific, strictly governed by rules, and theoretically produce thousands of variants without errors.
PubMed: 38815588
DOI: 10.1016/j.xgen.2024.100580 -
PLoS Genetics May 2024Exceptions to Mendelian inheritance often highlight novel chromosomal behaviors. The maize Pl1-Rhoades allele conferring plant pigmentation can display inheritance...
Exceptions to Mendelian inheritance often highlight novel chromosomal behaviors. The maize Pl1-Rhoades allele conferring plant pigmentation can display inheritance patterns deviating from Mendelian expectations in a behavior known as paramutation. However, the chromosome features mediating such exceptions remain unknown. Here we show that small RNA production reflecting RNA polymerase IV function within a distal downstream set of five tandem repeats is coincident with meiotically-heritable repression of the Pl1-Rhoades transcription unit. A related pl1 haplotype with three, but not one with two, repeat units also displays the trans-homolog silencing typifying paramutations. 4C interactions, CHD3a-dependent small RNA profiles, nuclease sensitivity, and polyadenylated RNA levels highlight a repeat subregion having regulatory potential. Our comparative and mutant analyses show that transcriptional repression of Pl1-Rhoades correlates with 24-nucleotide RNA production and cytosine methylation at this subregion indicating the action of a specific DNA-dependent RNA polymerase complex. These findings support a working model in which pl1 paramutation depends on trans-chromosomal RNA-directed DNA methylation operating at a discrete cis-linked and copy-number-dependent transcriptional regulatory element.
PubMed: 38814980
DOI: 10.1371/journal.pgen.1011296 -
PloS One 2024As we continue to convert green spaces into roadways and buildings, connectivity between populations and biodiversity will continue to decline. In threatened and...
As we continue to convert green spaces into roadways and buildings, connectivity between populations and biodiversity will continue to decline. In threatened and endangered species, this trend is particularly concerning because the cessation of immigration can cause increased inbreeding and loss of genetic diversity, leading to lower adaptability and higher extirpation probabilities in these populations. Unfortunately, monitoring changes in genetic diversity from management actions such as assisted migration and predicting the extent of introduced genetic variation that is needed to prevent extirpation is difficult and costly in situ. Therefore, we designed an agent-based model to link population-wide genetic variability and the influx of unique alleles via immigration to population stability and extirpation outcomes. These models showed that management of connectivity can be critical in restoring at-risk populations and reducing the effects of inbreeding depression. However, the rescued populations were more similar to the migrant source population (average FST range 0.05-0.10) compared to the historical recipient population (average FST range 0.23-0.37). This means that these management actions not only recovered the populations from the effects of inbreeding depression, but they did so in a way that changed the evolutionary trajectory that was predicted and expected for these populations prior to the population crash. This change was most extreme in populations with the smallest population sizes, which are representative of critically endangered species that could reasonably be considered candidates for restored connectivity or translocation strategies. Understanding how these at-risk populations change in response to varying management interventions has broad implications for the long-term adaptability of these populations and can improve future efforts for protecting locally adapted allele complexes when connectivity is restored.
Topics: Ecosystem; Endangered Species; Conservation of Natural Resources; Biological Evolution; Animals; Genetic Variation; Population Dynamics; Biodiversity
PubMed: 38814889
DOI: 10.1371/journal.pone.0304276 -
Blood Transfusion = Trasfusione Del... Apr 2024The Rh blood group system is highly complex, polymorphic, and immunogenic. The presence of RHD gene variants in RhD negative pregnant women is a challenge in fetal RHD...
BACKGROUND
The Rh blood group system is highly complex, polymorphic, and immunogenic. The presence of RHD gene variants in RhD negative pregnant women is a challenge in fetal RHD genotyping as it may influence the antenatal management of anti-D prophylaxis. The aim of this study was to determine the efficiency of a non-invasive single-exon approach in the obstetric population of Western Sweden in a 31-month follow up. The frequency and type of maternal RHD variants were explored and the relation to the ethnicity was elucidated. Discrepant results between fetal RHD genotyping and serological blood group typing of newborns were investigated and clarified.
MATERIALS AND METHODS
RHD exon 4 was analysed with quantitative real-time PCR technique in a total of 6,948 blood samples from RhD negative women in early pregnancy. All cases with suspected maternal RHD gene and discrepant results observed in newborn samples, were further investigated using both serological and molecular technologies.
RESULTS
A total of 43 samples (0.6%) had inconclusive fetal genotyping result due the presence of a maternal RHD gene. These findings were in most cases (>66%) observed in pregnant women of non-European ancestry. Additionally, two novel RHD alleles were found. Seven discrepant results between fetal RHD genotype and serological RhD type of the newborns, were shown to be related to D antigen variants in newborns. Assay sensitivity was 99.95%, specificity 100%, and accuracy 99.97%.
DISCUSSION
The single-exon approach for fetal RHD screening early in pregnancy is an appropriate choice in the population of Western Sweden, with a very low frequency of inconclusive results caused by the presence of maternal RHD gene variants. Due to the high sensitivity, specificity, and accuracy of the test, serological typing of neonates born to RhD negative women has no longer been performed at our laboratory since June 2023.
PubMed: 38814881
DOI: 10.2450/BloodTransfus.741 -
Blood Transfusion = Trasfusione Del... May 2024
PubMed: 38814878
DOI: 10.2450/BloodTransfus.807 -
International Journal of General... 2024The role of aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases has been gradually studied. However, it is unclear whether polymorphism is associated with the...
BACKGROUND
The role of aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases has been gradually studied. However, it is unclear whether polymorphism is associated with the risk of early onset (onset age ≤55 years old in men and ≤65 years old in women) coronary artery stenosis (CAS). The association between single nucleotide polymorphism (SNP) rs671 and risk in patients with early onset CAS was investigated in this study.
METHODS
The study included 213 early onset CAS patients and 352 individuals without CAS were set as controls. The rs671 polymorphism was genotyped by polymerase chain reaction (PCR) - microarray. Differences in rs671 genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for gender, body mass index (BMI), smoking history, drinking history, and diabetes mellitus to assess the relationship between rs671 genotypes and early onset CAS risk.
RESULTS
The frequency of the rs671 G/G genotype was lower in the early onset CAS patients (43.7% vs 55.3%, =0.007) than that in the controls. The frequency of the rs671 A allele was higher (32.9% vs 25.0%) than that in the controls (=0.005). After adjusting for other confounding factors, multivariate logistic regression showed that rs671 A/A genotype (A/A vs G/G: odds ratio (OR) 2.508, 95% confidence interval (CI): 1.130-5.569, =0.024), overweight (BMI≥24.0 vs 18.5-23.9: OR 5.047, 95% CI: 3.275-7.777, <0.001), history of smoking (yes vs no: OR 2.813, 95% CI: 1.595-4.961, <0.001), and diabetes mellitus (yes vs no: OR 2.191, 95% CI: 1.397-3.437, =0.001) were the independent risk factors of early onset CAS.
CONCLUSION
In men ≤55 years old and women ≤65 years old, individuals with rs671 A/A genotype, overweight (BMI ≥24.0 kg/m), smoking history, and diabetes mellitus increased risk of developing CAS.
PubMed: 38813240
DOI: 10.2147/IJGM.S461004 -
Frontiers in Pharmacology 2024Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of...
BACKGROUND
Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of pain management studies. In this context, we aimed 1) to decipher the pharmacogenetic variant landscape among Mediterranean populations compared to worldwide populations in order to identify therapeutic biomarkers for personalized pain management and 2) to better understand the biological process of pain management through investigation of pharmacogenes pathways.
MATERIALS AND METHODS
We collected genes and variants implicated in pain response using the Prisma guidelines from literature and PharmGK database. Next, we extracted these genes from genotyping data of 829 individuals. Then, we determined the variant distribution among the studied populations using multivariate (MDS) and admixture analysis with R and STRUCTURE software. We conducted a Chi2 test to compare the interethnic frequencies of the identified variants. We used SNPinfo web server, miRdSNP database to identify miRNA-binding sites. In addition, we investigated the functions of the identified genes and variants using pathway enrichment analysis and annotation tools. Finally, we performed docking analysis to assess the impact of variations on drug interactions.
RESULTS
We identified 63 variants implicated in pain management. MDS analysis revealed that Mediterranean populations are genetically similar to Mexican populations and divergent from other populations. STRUCTURE analysis showed that Mediterranean populations are mainly composed of European ancestry. We highlighted differences in the minor allele frequencies of three variants (rs633, rs4680, and rs165728) located in the gene. Moreover, variant annotation revealed ten variants with potential miRNA-binding sites. Finally, protein structure and docking analysis revealed that two missense variants (rs4680 and rs6267) induced a decrease in COMT protein activity and affinity for dopamine.
CONCLUSION
Our findings revealed that Mediterranean populations diverge from other ethnic groups. Furthermore, we emphasize the importance of pain-related pathways and miRNAs to better implement these markers as predictors of analgesic responses in the Mediterranean region.
PubMed: 38813106
DOI: 10.3389/fphar.2024.1380613 -
Central-European Journal of Immunology 2024Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death...
INTRODUCTION
Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death among people infected with HIV. Tuberculosis incidence in Latvia has decreased by 25% during the last 30 years, but the mortality level of TB remains significant. The HLA class II genes are responsible for antigen presentation and regulation of immune responses, which plays an important role in individual susceptibility to infection disease. Whether or not differential HLA polymorphism contributes to TB with HIV infection and TB without HIV infection in Latvian patients is unknown.
MATERIAL AND METHODS
For the detection of HLA class II DQA1, DQB1, and DRB1 alleles a total of 616 subjects were enrolled, including 80 primary active TB (PATB) patients, 168 HIV-1/TB patients, 168 HIV-1 patients and 200 HC individuals.
RESULTS
For immunodeficiency caused by TB, HIV-1 or HIV-1/TB coinfection, alleles DRB1*12:01, 14:01, 16:01, DQA1*01:02, 01:03, 02:01, 06:01, DQB1*03:03, 06:01 are identified as protective, but DRB1*07:01, 11:01, 15:01, DQA1*02:01, 03:01, DQB1*03:01, 05:01 are identified as risk alleles.
CONCLUSIONS
The results of our experimental pilot studies demonstrated that HLA class II genes may contribute to the genetic risk of TB and HIV-1/TB co-infection, possibly by reducing the presentation of protective Mycobacterium tuberculosis antigens to T-helpers. It is necessary to conduct repetitive, multicentre, and large sample studies in order to draw more scientific conclusions and to confirm the relationship between TB, HIV and HIV-1/TB co-infection susceptibility and gene polymorphisms.
PubMed: 38812605
DOI: 10.5114/ceji.2024.138738 -
Frontiers in Veterinary Science 2024Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)."...
BACKGROUND
Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)." Several studies reported that the shadow of prion protein (Sho), encoded by the shadow of prion protein gene (), is involved in prion disease development by accelerating the conformational conversion of PrP to PrP. Until now, genetic polymorphisms of the gene and the protein structure of Sho related to fragility to prion disease have not been investigated in pheasants, which are a species of poultry.
METHODS
Here, we identified the gene sequence by polymerase chain reaction (PCR) and compared the gene and Sho protein sequences among various prion disease-susceptible and -resistant species to identify the distinctive genetic features of pheasant Sho using Clustal Omega. In addition, we investigated genetic polymorphisms of the gene in pheasants and analyzed genotype, allele, and haplotype frequencies, as well as linkage disequilibrium among the genetic polymorphisms. Furthermore, we used programs, namely Mutpred2, MUpro and AMYCO, to investigate the effect of non-synonymous single nucleotide polymorphisms (SNPs). Finally, the predicted secondary and tertiary structures of Sho proteins from various species were analyzed by Alphafold2.
RESULTS
In the present study, we reported pheasant gene sequences for the first time and identified a total of 14 novel SNPs, including 7 non-synonymous and 4 synonymous SNPs. In addition, the pheasant Sho protein sequence showed 100% identity with the chicken Sho protein sequence. Furthermore, amino acid substitutions were predicted to affect the hydrogen bond distribution in the 3D structure of the pheasant Sho protein.
CONCLUSION
To the best of our knowledge, this is the first report of the genetic and structural features of the pheasant gene.
PubMed: 38812560
DOI: 10.3389/fvets.2024.1399548 -
Frontiers in Immunology 2024While conventional in silico immunogenicity risk assessments focus on measuring immunogenicity based on the potential of therapeutic proteins to be processed and...
HYPOTHESIS
While conventional in silico immunogenicity risk assessments focus on measuring immunogenicity based on the potential of therapeutic proteins to be processed and presented by a global population-wide set of human leukocyte antigen (HLA) alleles to T cells, future refinements might adjust for HLA allele frequencies in different geographic regions or populations, as well for as individuals in those populations. Adjustment by HLA allele distribution may reveal risk patterns that are specific to population groups or individuals, which current methods that rely on global-population HLA prevalence may obscure.
KEY FINDINGS
This analysis uses HLA frequency-weighted binding predictions to define immunogenicity risk for global and sub-global populations. A comparison of assessments tuned for North American/European versus Japanese/Asian populations suggests that the potential for anti-therapeutic responses (anti-therapeutic antibodies or ATA) for several commonly prescribed Rheumatoid Arthritis (RA) therapeutic biologics may differ, significantly, between the Caucasian and Japanese populations. This appears to align with reports of differing product-related immunogenicity that is observed in different populations.
RELEVANCE TO CLINICAL PRACTICE
Further definition of population-level (regional) and individual patient-specific immunogenic risk profiles may enable prescription of the RA therapeutic with the highest probability of success to each patient, depending on their population of origin and/or their individual HLA background. Furthermore, HLA-specific immunogenicity outcomes data are limited, thus there is a need to expand HLA-association studies that examine the relationship between HLA haplotype and ATA in the clinic.
Topics: Humans; Arthritis, Rheumatoid; Biological Products; Gene Frequency; HLA-DR Antigens; Antirheumatic Agents; Alleles
PubMed: 38812524
DOI: 10.3389/fimmu.2024.1377911