Journal of Applied Genetics最新文献

Infertility presents a substantial challenge for women of reproductive age, exerting profound effects on both individual well-being and healthcare systems. Despite its critical role in folate and homocysteine pathways, the influence of methylenetetrahydrofolate reductase (MTHFR) on the success of assisted reproductive techniques (ART) remains insufficiently understood. This knowledge gap impedes the development of personalized therapeutic strategies. Our study seeks to elucidate the relationship between MTHFR and ART outcomes, exploring potential mediators to enhance treatment efficacy. A cohort of 311 women with infertility was recruited for our study. Multivariate linear models were utilized to evaluate the relationship between the MTHFR 677T allele (a missense mutation resulting in an alanine to valine substitution) and the efficacy of ART, including both treatment outcomes and the number of ART cycles required. Sequential mediation analysis was conducted to elucidate the potential mediators influencing ART efficacy. The MTHFR 677T allele carried by infertile women was associated with a 17-51% reduction in ART efficacy (P < 0.05). This encompassed poorer overall ART outcomes, such as clinical pregnancy and live birth rates, as well as an increased number of ART cycles. Sequential mediation analysis suggested that anti-Müllerian hormone (AMH) and age may act as mediators modulating the impact of the MTHFR 677T allele on ART treatment efficacy. This study has unveiled the intricate connection between MTHFR 677T allele and ART treatment efficacy in infertile women, shedding light on the mediating role of AMH and age.

Endometrial cancer (EC) is the second most frequent gynecological malignancy and the sixth most common women's cancer worldwide. EC incidence rate is increasing rapidly. Apart from the classical, we should consider angiogenesis and hypoxia-related genes as a reason for EC manifestation and progression. We compared the patterns of HIF1A, EPAS1, and VEGFA (genes of interest - GOIs) mRNA expression in 92 cases. HIF1A and VEGFA levels were higher in EC patients than in controls. VEGFA differed significantly between controls and both tumor grades G2 and G3, and we observed a positive correlation for HIF1A and VEGFA with EC grading. VEGFA levels were significantly higher in post-menopausal compared to pre-menopausal patients. All GOIs demonstrated strong correlations in pre-menopausal cases and weak correlations in post-menopausal cases. A positive correlation was observed in pre-menopausal controls for all GOIs and in post-menopausal patients for only EPAS1 and VEGFA. HIF1A and EPAS1 positively correlated with VEGFA in post-menopausal EC cases. Multiple linear regression analyses revealed that menopause, body mass index (BMI), and HIF1A expression are significant stimulating factors for EC occurrence. HIF1A levels were higher in EC patients after BMI and comorbidity number adjustment. The gene-to-gene relation could be seen as either a diagnostic or a therapeutic target in EC. Physicians should inform patients about modifiable risk factors such as BMI. Second, more attention should be paid to diagnosing patients with comorbidities in older age and after menopause. These factors should be considered in designing angiogenesis and hypoxia-related gene-targeting therapies.

Chromosome number abnormalities is one of the hallmarks of cancer. DNA copy number alterations (CNA) are studied using various genome-wide methods. In our study, we investigated CNA in human pituitary tumors using three platforms CytoSNP-850 K microarrays, low-pass whole-genome sequencing (average × 7 coverage, LPWGS), and Infinium Methylation EPIC array. Virtual karyotypes based on each dataset were generated using open-source software packages for each sample. Concordant CNA profiles were found for most of tumor. Surprisingly, substantial discrepancies between results from SNP arrays and LPWGS/EPIC arrays were identified in 20% of tumors, for which discrimination of true karyotype was required. B-allelic frequency data from SNP arrays was crucial to adjust normal ploidy level as ultimately verified with FISH. The discrepancy between virtual karyotypes was more pronounced the more CNAs were found. When CNAs covered around half of genome, the level of normal/diploid copy number was incorrectly set with methods, based solely on signal intensity/read-counts coverage. To conclude, CNA analyses with methods such as LPWGS and methylation arrays in highly aneuploid tumors are prone to a bias from improper normal ploidy level setting. These methods are commonly used therefore, we aimed to aware the scientific community about this underestimated methodological problem.

Enzootic bovine leukosis (EBL) caused by the bovine leukosis virus (BLV) disturbs the immune response in bovines, leading to severe economic losses, with a possible impact on public health. EBL has no treatment or vaccine available, making the identification of genetic polymorphisms related to BLV resistance in locally adapted breeds like Crioula Lageana cattle valuable perspectives. This study aims to determine the presence of the BoLA-DRB3 alleles associated with susceptibility or resistance to BLV in Crioula Lageana cattle. For that, 208 Crioula Lageana bovines, spanning various ages, categories, and sexes, were subjected to blood sampling for DNA extraction for genetic characterization. The PCR targeted the 440-bp fragment of the env gene of the BLV and 284-bp for the alleles of the BoLA-DRB3 gene. The alleles were identified using Sanger sequencing, and the allele amount and frequency were determined by direct counting. For the determination of resistance or susceptibility, firstly the association between each allele and infection by BLV was determined using the chi-square test (p < 0.05), and then it was followed by an odds ratio analysis. The occurrence of BLV was 38.46% (80/208). The DRB3*12:01 allele was associated with resistance to BLV infection (p = 0.035, O.R. = 0.000. The presence of alleles linked to resistance to disease incidence highlights the potential to enhance genetic approaches in formulating management and control strategies for EBL in diverse cattle populations, with potential implications for livestock production, food safety, and public health.

Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues. To date, the disease has been linked to 15 pathogenic variants in the ACVR1 gene, which encodes a type I receptor for bone morphogenetic proteins. Most patients with FOP carry a recurrent single-nucleotide substitution (c.617G>A; p.Arg206His) in the ACVR1 gene. The genotype-phenotype correlations for atypical pathogenic variants of ACVR1 are poorly understood. In this study, we report the largest population of Polish patients affected by FOP and analyze their phenotypes and genotypes. We screened the whole ACVR1 coding sequence of 16 patients affected by FOP to confirm the presence of pathogenic variants. Thirteen individuals carried the classic pathogenic variant (p.Arg206His) and had a classic or FOP-plus phenotype. In agreement with the findings of previous studies, one patient with a p.Gly356Asp pathogenic variant had a variant FOP phenotype. We point to an unusual phenomenon in two patients who carried atypical pathogenic variants (p.Gly356Asp and p.Arg258Ser) and displayed a classic FOP phenotype. Our study extends the understanding of FOP's genotype-phenotype correlation, suggesting that classic FOP phenotypes are associated with non-classic pathogenic variants. We also summarize the recent advances in drug development for this condition. Therefore, the study may be valuable for clinicians consulting patients with FOP.

Recurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more pregnancies before reaching viability. Diagnosis for couples with RPL usually involves only the female partner. However, it is seen that male partners contribute equally to the occurrence of spontaneous abortions as the Y chromosome harbors several genes that control spermatogenesis and the quality of sperms. Three non-overlapping regions (AZFa, AZFb, AZFc) in the distal half of Y chromosome have been reported to be associated with spermatogenesis in males with normal karyotype. Microdeletions in these three regions have been identified in many male partners with repeated abortions. The STS regions of the Y chromosome are prone to self-recombination, making it susceptible to deletions, thereby leading to poor sperm quality and fetal implantation failure. The present study aimed to identify the frequency and type of microdeletions among male partners of RPL women. Analysis revealed nearly 76% of cases revealed microdeletions, whereas no deletions were observed among controls in Y chromosome, suggesting a strong link between RPL and microdeletion in the AZF regions of the Y chromosome in the male partner.

The planet hosts half a million plant species exhibiting a spectacular diversity of plant forms with genomes driving phenotypic variations. The genome information exists for less than 1% of species, limiting quantitative genomic studies in natural populations. This review explores how recent advances in cutting-edge genomic and phenomic techniques extended genome-wide association studies (GWAS) to wild, non-model species and other natural populations. We also discuss the incorporation of diverse bioinformatic tools into comprehensive in-silico pipelines and recommend implementing machine learning algorithms to address methodological challenges. The critical literature synthesis highlights several scopes of GWAS, bringing natural populations into the spotlight of genomic research. Thus, the study presents GWAS as a cornerstone for advancing quantitative genomics in natural populations. This shift holds great promise for understanding adaptation, trait evolution, and conservation genetics across diverse plant germplasm.

Multiple sclerosis (MS) is a central nervous system (CNS) disorder defined by inflammation, demyelination, and neuronal damage. Several independent studies have confirmed the prevalence of EBV infection in MS and the presence of elevated anti-EBV antibody titers in serum prior to and throughout the clinical period of MS. EBV stands out from other human-infecting viruses in that it can activate, infect, and clone the B cells and remain a latent infection inside them. The prevalence of EBV-positive B cell lymphoproliferative diseases in immunocompromised individuals demonstrates the critical significance of immune surveillance in managing EBV infection. It has also been postulated that a deficiency in EBV-specific CD8⁺ T cell regulation predisposes to MS by allowing EBV-infected autoreactive B cells and plasma cells to concentrate in the CNS. Thus, EBV-specific T-cell therapy might have the potential to eradicate B lymphocytes infected by EBV in the CNS, preventing disease development and leading to enhanced clinical outcomes. One of the effective approaches for treating MS patients is application of EBV-specific T cells. In this method, peripheral blood mononuclear cells (PBMCs) are isolated from patients and expanded with EBV-specific antigens, resulting in antiviral cytotoxic response. This review discusses the significance of EBV in the pathogenesis of MS, the impact of disease-modifying T-cell treatments targeting EBV, therapeutic implications to target EBV in MS pathogenesis, and several novel EBV-targeting gene therapies.

The Sieve Element Occlusion (SEO) proteins are subunits that assemble into structural filamentous phloem proteins, commonly referred to as P-proteins. These proteins in Arabidopsis play a structural role and contribute to plant defense by reversible sieve plate (SP) sealing. This mechanism could be particularly important also in Citrus trees affected by Huanglongbing (HLB), as SEO genes are highly induced in susceptible species C. sinensis upon Candidatus Liberibacter asiaticus (CLas) colonization. Given the limited information on this gene family in Citrus, we analyzed 27 SEO genes within the Rutaceae family, with a focus on genera closely related to Citrus, to better understand their potential roles in HLB tolerance. Genomic sequences revealed conserved exon-intron structures similar to Arabidopsis thaliana, while promoter regions contained a higher number of light-responsive Cis-elements, along with elements associated with growth, development, stress responses, and phloem-specific gene expression. Subcellular localization identified the cytoplasm as the primary site, with additional predictions for the plasma membrane and mitochondria. Phylogenetic analysis categorized SEO proteins into five subgroups, refining their classification in Citrus. Lately, protein interaction networks indicated strong connections with proteins involved in coordinated immune responses. These findings improve the understanding of SEO protein dynamics and evolutionary conservation, highlighting their role in phloem biology. Further investigation of these SEO genes and their promoters in the plant response to HLB could help identify specific targets for developing disease-tolerant Citrus varieties through genetic engineering.