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Neurosurgery Aug 2023Diffuse idiopathic skeletal hyperostosis (DISH) is an incompletely defined disease process with no known unifying pathophysiological mechanism.
BACKGROUND
Diffuse idiopathic skeletal hyperostosis (DISH) is an incompletely defined disease process with no known unifying pathophysiological mechanism.
OBJECTIVE
To our knowledge, no genetic studies have been performed in a North American population. To summarize genetic findings from previous studies and to comprehensively test for these associations in a novel and diverse, multi-institutional population.
METHODS
Cross-sectional, single nucleotide polymorphism (SNP) analysis was performed in 55 of 121 enrolled patients with DISH. Baseline demographic data were available on 100 patients. Based on allele selection from previous studies and related disease conditions, sequencing was performed on COL11A2, COL6A6, fibroblast growth factor 2 gene, LEMD3, TGFB1, and TLR1 genes and compared with global haplotype rates.
RESULTS
Consistent with previous studies, older age (mean 71 years), male sex predominance (80%), a high frequency of type 2 diabetes (54%), and renal disease (17%) were observed. Unique findings included high rates of tobacco use (11% currently smoking, 55% former smoker), a higher predominance of cervical DISH (70%) relative to other locations (30%), and an especially high rate of type 2 diabetes in patients with DISH and ossification of the posterior longitudinal ligament (100%) relative to DISH alone (100% vs 47%, P < .001). Compared with global allele rates, we found higher rates of SNPs in 5 of 9 tested genes ( P < .05).
CONCLUSION
We identified 5 SNPs in patients with DISH that occurred more frequently than a global reference. We also identified novel environmental associations. We hypothesize that DISH represents a heterogeneous condition with both multiple genetic and environmental influences.
Topics: Humans; Male; Hyperostosis, Diffuse Idiopathic Skeletal; Alleles; Diabetes Mellitus, Type 2; Cross-Sectional Studies
PubMed: 36802217
DOI: 10.1227/neu.0000000000002417 -
The Journal of Molecular Diagnostics :... Sep 2023Twin pregnancy constitutes significant risks for maternal and fetal health, which is usually detected by ultrasound examination at early gestation. However, the...
Twin pregnancy constitutes significant risks for maternal and fetal health, which is usually detected by ultrasound examination at early gestation. However, the imaging-based approach may not accurately identify all twins confounded by practical or clinical variables. The analysis of fetal cell-free DNA in noninvasive prenatal screening assays can completement the ultrasound method for twin detection, which differentiates fraternal or identical twins based on their distinct genotypes. Here, a new noninvasive prenatal screening employing high-coverage next-generation sequencing for targeted nucleotide polymorphisms was developed for detection of zygosity and determination of fetal fraction in twin pregnancies. This method utilizes a binary analysis of both the number and allelic fraction of fetus-specific single-nucleotide polymorphisms to infer the zygosity. In 323 samples collected from 215 singleton, 90 dizygotic, and 18 monozygotic twin pregnancies, all 90 dizygotic twins were correctly detected, with a 100% sensitivity and a 100% specificity. In addition, this method can detect complex pregnancies, such as egg donors, contamination, and twins with complete hydatidiform mole. The fetus-specific fetal fraction change was monitored in nine dizygotic twin pregnancies, which demonstrated highly variable dynamics of fetal cell-free DNA turnover up to 7 weeks after twin reduction. Overall, this study provides a new noninvasive prenatal screening strategy for the accurate identification of twin zygosity and quantification of fetal fraction, which has important clinical implications for the management of twin pregnancies.
Topics: Female; Pregnancy; Humans; Pregnancy, Twin; Polymorphism, Single Nucleotide; Fetus; Alleles; Cell-Free Nucleic Acids
PubMed: 37599029
DOI: 10.1016/j.jmoldx.2023.06.003 -
BMC Biology Aug 2023Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional...
BACKGROUND
Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional changes that occur in autopolyploids after WGD. Cyclocarya paliurus (Juglandaceae) is a natural diploid-autotetraploid species. We generated an allele-aware autotetraploid genome, a chimeric chromosome-level diploid genome, and whole-genome resequencing data for 106 autotetraploid individuals at an average depth of 60 × per individual, along with 12 diploid individuals at an average depth of 90 × per individual.
RESULTS
Autotetraploid C. paliurus had 64 chromosomes clustered into 16 homologous groups, and the majority of homologous chromosomes demonstrated similar chromosome length, gene numbers, and expression. The regions of synteny, structural variation and nonalignment to the diploid genome accounted for 81.3%, 8.8% and 9.9% of the autotetraploid genome, respectively. Our analyses identified 20,626 genes (69.18%) with four alleles and 9191 genes (30.82%) with one, two, or three alleles, suggesting post-polyploid allelic loss. Genes with allelic loss were found to occur more often in proximity to or within structural variations and exhibited a marked overlap with transposable elements. Additionally, such genes showed a reduced tendency to interact with other genes. We also found 102 genes with more than four copies in the autotetraploid genome, and their expression levels were significantly higher than their diploid counterparts. These genes were enriched in enzymes involved in stress response and plant defense, potentially contributing to the evolutionary success of autotetraploids. Our population genomic analyses suggested a single origin of autotetraploids and recent divergence (~ 0.57 Mya) from diploids, with minimal interploidy admixture.
CONCLUSIONS
Our results indicate the potential for genomic and functional reorganization, which may contribute to evolutionary success in autotetraploid C. paliurus.
Topics: Humans; Alleles; Tetraploidy; Gene Duplication; Polyploidy; Genomics
PubMed: 37553642
DOI: 10.1186/s12915-023-01668-1 -
International Journal of Molecular... Nov 2023Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin () gene. Juan de Acosta, Atlántico, a city located on the...
Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin () gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of < 0.05. We found that the average CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.
Topics: Adult; Female; Humans; Huntington Disease; Colombia; Alleles; DNA; Pedigree; Huntingtin Protein; Trinucleotide Repeat Expansion
PubMed: 38003344
DOI: 10.3390/ijms242216154 -
Genes Feb 2024Rapid climate changes, with higher warming rates during winter and spring seasons, dramatically affect the vernalization requirements, one of the most critical processes... (Review)
Review
Rapid climate changes, with higher warming rates during winter and spring seasons, dramatically affect the vernalization requirements, one of the most critical processes for the induction of wheat reproductive growth, with severe consequences on flowering time, grain filling, and grain yield. Specifically, the genes play a major role in the transition from vegetative to reproductive growth in wheat. Recent advances in wheat genomics have significantly improved the understanding of the molecular mechanisms of genes (, , , and ), unveiling a diverse array of natural allelic variations. In this review, we have examined the current knowledge of genes from a functional and structural point of view, considering the studies conducted on alleles at different ploidy levels (diploid, tetraploid, and hexaploid). The molecular characterization of alleles has been a focal point, revealing a diverse array of allelic forms with implications for flowering time. We have highlighted the structural complexity of the different allelic forms and the problems linked to the different nomenclature of some alleles. Addressing these issues will be crucial for harmonizing research efforts and enhancing our understanding of gene function and evolution. The increasing availability of genome and transcriptome sequences, along with the improvements in bioinformatics and computational biology, offers a versatile range of possibilities for enriching genomic regions surrounding the target sites of genes, paving the way for innovative approaches to manipulate flowering time and improve wheat productivity.
Topics: Triticum; Alleles; Vernalization; Tetraploidy; Phenotype
PubMed: 38397240
DOI: 10.3390/genes15020251 -
Journal of Immunology Research 202444 OSF patients and 44 healthy volunteers were included in this study. To detect the expression frequency of HLA-DQB1 alleles in the two groups and analyze significant...
METHODS
44 OSF patients and 44 healthy volunteers were included in this study. To detect the expression frequency of HLA-DQB1 alleles in the two groups and analyze significant allelic subtypes and their relative risk, polymerase chain reaction (PCR) sequence-specific primers were used. Subsequently, based on the identification of differential genes, we compare the gene expression levels of OSF patients and healthy volunteers expressing differential genes by real-time quantitative PCR.
RESULTS
The expression frequency of the HLA-DQB1 05 : 02 allele in the OSF group (36.4%) was significantly higher than in the controls (13.6%), and exposure to the HLA-DQB1 05 : 02 allele was strongly related to OSF (OR (95% CI) = 3.619 (1.257,10.421), Wald = 5.681, =0.017). However, there were no significant differences in the allele expression frequencies of DQB1 02 : 01, DQB1 03 : 03, DQB1 05 : 01, DQB1 05 : 03, DQB1 06 : 02, DQB1 06 : 03, and DQB1 06 : 04 in the OSF group compared with the controls (all > 0.05). Furthermore, the relative expression level of the HLA-DQB1 05 : 02 allele in the OSF group (3.98 ± 3.50) was significantly higher than in controls (0.70 ± 0.41).
CONCLUSIONS
There are differences in the HLA-DQB1 allele polymorphisms between the healthy population and patients with oral submucosal fibrosis. Preliminarily, it is suggested that the HLA-DQB1 05 : 02 allele, which has a strong correlation with OSF and great differential expression between patients with OSF and controls, might be a susceptibility gene for OSF in Hunan.
Topics: Humans; HLA-DQ beta-Chains; Male; Female; Genetic Predisposition to Disease; Alleles; China; Gene Frequency; Adult; Polymorphism, Genetic; Middle Aged; Oral Submucous Fibrosis; Genotype; Case-Control Studies; Young Adult; Genetic Association Studies
PubMed: 38799118
DOI: 10.1155/2024/8757860 -
Cell Reports Methods Sep 2023Reconstructing diploid sequences of human leukocyte antigen (HLA) genes, i.e., full-resolution HLA typing, from sequencing data is challenging. The high homogeneity...
Reconstructing diploid sequences of human leukocyte antigen (HLA) genes, i.e., full-resolution HLA typing, from sequencing data is challenging. The high homogeneity across HLA genes and the high heterogeneity within HLA alleles complicate the identification of genomic source loci for sequencing reads. Here, we present SpecHLA, which utilizes fine-tuned reads binning and local assembly to achieve accurate full-resolution HLA typing. SpecHLA accepts sequencing data from paired-end, 10×-linked-reads, high-throughput chromosome conformation capture (Hi-C), Pacific Biosciences (PacBio), and Oxford Nanopore Technology (ONT). It can also incorporate pedigree data and genotype frequency to refine typing. In 32 Human Genome Structural Variation Consortium, Phase 2 (HGSVC2) samples, SpecHLA achieved 98.6% accuracy for G-group-resolution HLA typing, inferring entire HLA alleles with an average of three mismatches fewer, ten gaps fewer, and 590 bp less edit distance than HISAT-genotype per allele. Additionally, SpecHLA exhibited a 2-field typing accuracy of 98.6% in 875 real samples. Finally, SpecHLA detected HLA loss of heterozygosity with 99.7% specificity and 96.8% sensitivity in simulated samples of cancer cell lines.
Topics: Humans; Alleles; Genotype; Cell Line; Diploidy; Histocompatibility Testing
PubMed: 37714157
DOI: 10.1016/j.crmeth.2023.100589 -
HLA Jul 2023One nucleotide substitution in pseudoexon 5 of HLA-DQB1*06:02:01:01 results in a novel allele, HLA-DQB1*06:02:01:32.
One nucleotide substitution in pseudoexon 5 of HLA-DQB1*06:02:01:01 results in a novel allele, HLA-DQB1*06:02:01:32.
Topics: Humans; Alleles; HLA-DQ beta-Chains; Nucleotides; Russia
PubMed: 36961290
DOI: 10.1111/tan.15032 -
Proceedings. Biological Sciences Mar 2024Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance... (Review)
Review
Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance reversals are characterized by the beneficial allele for a given context (e.g. habitat, developmental stage, trait or sex) being dominant in that context but recessive where deleterious. This context dependence at least partially mitigates the fitness consequence of heterozygotes carrying one non-beneficial allele for their context and can result in balancing selection that maintains alternative alleles. Dominance reversals are theoretically plausible and are supported by mounting empirical evidence. Here, we highlight the importance of beneficial dominance reversals as a mechanism for the mitigation of genetic conflict and review the theory and empirical evidence for them. We identify some areas in need of further research and development and outline three methods that could facilitate the identification of antagonistic genetic variation (dominance ordination, allele-specific expression and allele-specific ATAC-Seq (assay for transposase-accessible chromatin with sequencing)). There is ample scope for the development of new empirical methods as well as reanalysis of existing data through the lens of dominance reversals. A greater focus on this topic will expand our understanding of the mechanisms that resolve genetic conflict and whether they maintain genetic variation.
Topics: Selection, Genetic; Phenotype; Heterozygote; Alleles; Genetic Variation; Models, Genetic; Genetic Fitness
PubMed: 38471544
DOI: 10.1098/rspb.2023.2816 -
Scientific Data Apr 2024The human mannose-binding lectin (MBL) gene encodes a polymorphic protein that plays a crucial role in the innate immune response. Human MBL deficiency is associated...
The human mannose-binding lectin (MBL) gene encodes a polymorphic protein that plays a crucial role in the innate immune response. Human MBL deficiency is associated with immunodeficiencies, and its variants have been linked to autoimmune and infectious diseases. Despite this significance, gene studies concerning MBL sequencing are uncommon in Malaysia. Therefore, we aimed to preliminary described the human MBL sequencing dataset based on the Kelantan population. Blood samples were collected from 30 unrelated individuals and underwent DNA extraction, genotyping, and sequencing. The sequencing data generated 886 bp, which were deposited in GenBank (ON619541-ON619546). Allelic variants were identified and translated into six MBL haplotypes: HYPA, HYPB, LYPB, LXPB, HXPA, and LXPA. An evolutionary tree was constructed using the haplotype sequences. These findings contribute to the expansion of MBL information within the country, providing a valuable baseline for future research exploring the association between the gene and targeted diseases.
Topics: Humans; Haplotypes; Malaysia; Mannose-Binding Lectin; Base Sequence; Alleles
PubMed: 38688916
DOI: 10.1038/s41597-024-03274-4