Genes最新文献

This review synthesizes advances in nondestructive DNA extraction from teeth, emphasizing their importance in forensics and archaeogenetics. Because of their mineralized structure and resistance to diagenesis, teeth remain vital for human identification when other tissues are unavailable or degraded. Modern protocols targeting dental cementum have shown high success rates in retrieving nuclear DNA while maintaining specimen integrity, supporting ethical standards, and enabling additional morphological and isotopic analyses. Nondestructive extraction methods produce DNA yields comparable to-or in some archaeological cases, greater than-those of traditional destructive approaches, while ensuring strict contamination control and minimal physical impact. Cementum is a reliable source of DNA in aged and degraded teeth, although the petrous part of the temporal bone still represents the best option under extreme preservation conditions. These results highlight the need for context-specific sampling strategies that balance analytical goals with the preservation of museum collections. Future efforts include testing nondestructive protocols across various forensic scenarios and creating predictive models for DNA preservation. Overall, these developments promote ethical, effective, and sustainable practices in human genomic analysis.

Background: Intrachromosomal rearrangements in birds play a subtle but important role in shaping genomic evolution, phenotypic diversity and speciation. However, the avian sex chromosome system (homogametic ZZ males; heterogametic ZW females) remains relatively understudied, and evolutionary rearrangements of the Z chromosome have not been mapped in most species. To address this, we employed universally hybridizing avian Z chromosome probes to metaphases of 11 avian species from South America. Methods: Chromosome preparations were obtained from fibroblast cell cultures of 11 birds representing nine different orders; four bacterial artificial chromosome (BAC) probes were used in our interspecies fluorescence in situ hybridization (FISH) experiments. We identified chromosomal rearrangements in the species investigated, tracing the evolution of the Z chromosome in these species through comparison with reptiles from Southeast Asia (three snake species used as an outgroup), along with two reference species: chicken (Galliformes) and zebra finch (Passeriformes). Results: We observed high rates of intrachromosomal rearrangements in the avian Z chromosome, with most species showing different patterns from chicken and zebra finch. Nannopterum brasilianum (Suliformes) and Jacana jacana (Charadriiformes) showed the same BAC order as chicken, but centromere repositioning was evident. Apart from Piciformes, all other species exhibited a conserved Z chromosome size. The corresponding Z chromosome sequences were homologous to regions of the long arms of Chromosome 2 and W in snakes but not on the Z chromosomes. Conclusions: Comparative analysis of the Z chromosome across avian orders provides important insights into the dynamics of avian sex chromosomes and the evolution of sex chromosome systems in general.

Background/objectives: Pacing-induced cardiomyopathy (PiCM) is a recognized complication of chronic right ventricular pacing (RVP), characterized by left ventricular (LV) dysfunction, adverse remodeling, and progression to heart failure. MicroRNAs (miRs) regulate gene expression and play an important role in ventricular remodeling. This study aimed to observe whether dynamic changes in miRs according to a novel peripheral blood mononuclear cell (PBMC)-based approach could serve as early predictive biomarkers of PiCM.

Methods: A prospective, single-center cohort study was conducted in adult patients undergoing pacemaker implantation. Clinical characteristics, echocardiographic parameters and expression levels of miR-208b-3p and miR-9 were assessed immediately and 3 months post-pacemaker implantation. PiCM was defined as a ≥10% reduction in LVEF at one year, with no alternative cause. Statistical analyses included correlation testing, ROC curve analysis, and multivariate regression to identify factors associated with PiCM.

Results: Among 126 patients, 11.1% developed PiCM. Compared with the non-PiCM group, those who developed PiCM exhibited more pronounced 3-month changes in miR-208b-3p (median Δ₃log miR: +1.3 vs. -0.4, p = 0.013) and miR-9 (median Δ₃log miR: -1.7 vs. +0.21, p = 0.011). In multivariate analyses, Δ₃LV-GLS, Δ₃logmiR-208b-3p, and Δ₃logmiR-9 were associated with a higher likelihood of PiCM. Among PiCM patients, Δ₃logmiR-208b-3p correlated inversely with Δ₃LV-GLS (r = -0.73, p = 0.016), while Δ₃logmiR-9 correlated positively (r = 0.88, p < 0.001). ROC analyses demonstrated good predictive ability for Δ₃LV-GLS (AUC = 0.924), Δ₃log miR-208b-3p (AUC = 0.783), and Δ₃log miR-9 (AUC = 0.835), with no significant differences between curves.

Conclusions: Early LV-GLS deterioration and dynamic changes in expression of miR-208b-3p and miR-9 in PBMCs precede overt LV systolic dysfunction. These miRs may serve as early predictive biomarkers for PiCM.

Background: Short tandem repeats (STRs) are highly variable sequences present along the human genome, including the Y-chromosome. Y-STRs are exclusive to males, and the haplotypes they define are informative. Objectives: Twenty-six Y-STR loci were genotyped in 252 males from Northern Portugal to characterise Y-chromosome genetic variation using the Investigator Argus Y28 QS Kit. Methods: The kit mentioned was used to amplify male DNA samples, and capillary electrophoresis was used to analyze the fragments. Forensic parameters and haplotype diversity were computed, and samples' haplogroups were predicted. A multidimensional scaling (MDS) plot was used to graphically represent the R_ST genetic distances, including reference populations. Results: A total of 250 different haplotypes were observed, including 248 unique ones, yielding a very high haplotype diversity (HD = 0.999) and discriminatory power (DP = 0.992). Haplogroup analysis indicated a predominance of R1b (58.7%), followed by E1b1b, I and J, pointing to a population history shaped by Mediterranean and North African gene flow. Comparative analysis between Portugal and 5 other populations showed greater genetic affinity with Spain and Italy, while revealing marked differentiation from Greece, Morocco, and former Portuguese colonies. Conclusions: The results confirm that the Northern Portuguese Population exhibits high Y-STR variability and robust forensic resolution. The dataset was submitted to the YHRD database, enhancing the representation of the Portuguese population and underscoring the value of the 26 locus panel for applications in forensic science, genealogy, and population genetics.

Background/Objectives: Whole exome sequencing (WES) is an effective method for detecting disease-causing variants. However, copy number variation (CNV) detection using WES data often has limited sensitivity and high false-positive rates. Methods: In this study, we constructed a reference CNV set using chromosomal microarray analysis (CMA) data from 44 of 180 individuals who underwent WES and CMA and evaluated four WES-based CNV callers (CNVkit, CoNIFER, ExomeDepth, and cn.MOPS) against this benchmark. For each tool, we first defined software-specific problematic genomic regions across the full WES cohort and filtered out the CNVs that overlapped these regions. Results: The four algorithms showed low mutual concordance and distinct distributions in the problematic regions. On average, 2210 sequencing target baits (1.23%) were classified as problematic; these baits had lower mappability scores and higher coefficients of variation in RPKM than the remaining probes. After the supplementary filtration step, all tools demonstrated improved performance. Notably, ExomeDepth achieved gains of 14.4% in sensitivity and 7.9% in positive predictive value. Conclusions: We delineated software-specific problematic regions and demonstrated that targeted filtration markedly reduced false positives in WES-based CNV detection.

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation sequencing (NGS), and immunogenetic assessment of immunoglobulin heavy chain variable region (IGHV) somatic hypermutation status, each of which interrogates only a limited aspect of disease biology. Methods: We retrospectively evaluated fifty patients with CLL using OGM and integrated these findings with cytogenomics, targeted NGS, IGHV mutational status, and clinical time-to-first-treatment (TTFT) data. Structural variants were detected using OGM and pathogenic NGS variants were derived from a clinical heme malignancy panel. Clinical outcomes were extracted from the electronic medical record. Results: OGM identified reportable structural variants in 82% (41/50) of cases. The most frequent abnormality was del(13q), observed in 29/50 (58%) and comprising 73% (29/40) of all OGM-detected deletions with pathologic significance. Among these, 12/29 (42%) represented large RB1-spanning deletions, while 17/29 (58%) were focal deletions restricted to the miR15a/miR16-1 minimal region, mapping to the non-coding host gene DLEU2. Co-occurrence of adverse lesions, including deletion 11q/ATM, BIRC3 loss, trisomy 12, and deletion 17p/TP53, were recurrent and strongly associated with shorter TTFT. OGM also uncovered multiple cryptic rearrangements involving chromosomal loci that are not represented in the canonical CLL FISH probe panel, including IGL::CCND1, IGH::BCL2, IGH::BCL11A, IGH::BCL3, and multi-chromosomal copy-number complexity. IGHV data were available in 37/50 (74%) of patients; IGHV-unmutated status frequently co-segregated with OGM-defined high-risk profiles (del(11q), del(17p), trisomy 12 with secondary hits, and complex genomes whereas mutated IGHV predominated in OGM-negative or structurally simple del(13q) cases and aligned with indolent TTFT. Integration of OGM with NGS further improved genomic risk classification, particularly in cases with discordant or inconclusive routine testing. Conclusions: OGM provides a comprehensive, genome-wide view of structural variation in CLL, resolving deletion architecture, identifying cryptic translocations, and defining complex multi-hit genomic profiles that tracked closely with clinical behavior. Combining OGM and NGS analysis refined risk stratification beyond standard FISH panels and supports more precise, individualized management strategies in CLL. Prospective studies are warranted to evaluate the clinical utility of OGM-guided genomic profiling in contemporary treatment paradigms.

Background/objectives: In 2023, we reported that the tamarins (genus Saguinus) Saguinus imperator and Saguinus midas have had an extensive independent expansion of Platy-1 SINEs compared to previously characterized platyrrhine genomes among traditional cebids. This study investigates the amplification dynamics of Platy-1 insertions across thirteen diverse genomes representing each Platyrrhini family, including two from Pitheciidae and three from Atelidae.

Methods: By comparing the distribution of Platy-1 subfamily content, total interspersed repeat content and the proximity of Platy-1 insertions to, or within, other repeats across evolutionary taxa, this study begins to identify genomic landscape features that are unique to family Callithrichidae that correlate with LINE (L1).

Results: Platy-1 radiation in non-callithrichid taxa derives primarily from older subfamilies 1-4, 1-4a (as reported here for genus Alouatta) and 1-5, whereas callithrichids proliferate higher numbers of Platy-1 copies via independent bursts from much younger sources. Linage-specific Platy-1 activity was notable in two of the new genomes studied, Bolivian titi and mantled howler monkey, both with a relatively low copy number. Variable presence/absence patterns across evolutionary taxa support the traditional platyrrhine branching order Pitheciidae-Atelidae-Cebidae. Only one Platy-1-4a insertion polymorphism placed Aotidae between Atelidae and Cebidae, as opposed to between Cebidae and Callithrichidae.

Conclusions: This study shows that callithrichids, and Saguinus tamarins in particular, are unique among platyrrhines with regard to their extensive rate of Platy-1 mobilization, a dynamic that appears to be correlated with LINE (L1) genomic content. Alouatta has two young lineage-specific Platy-1 subfamilies. With strong evidence of incomplete lineage sorting (ILS) and rapid radiation, the accurate placement of Aotus remains elusive.

Background: Interstitial deletions of the short arm of chromosome 12 are rare, and very little is known about the potential genetic basis of the most common phenotypic presentations to date described in the literature.

Methods: In the present study, we present a new patient carrying a heterozygous de novo 12p deletion, identified by a-CGH.

Results: Comparison between the new case with phenotypically similar 12p-deleted patients drawn from the literature and from the DECIPHER (the DatabasE of Chromosomal Imbalances and Phenotypes using Ensembl Resources) database allowed us to analyze 22 cases and to define a revised minimal critical region not previously considered.

Discussion: Within the new minimal critical region, we identified genes intolerant to haploinsufficiency, highlighting the involvement of PTHLH and CCDC91 in the onset of skeletal abnormalities and proposing the involvement of PPFIBP1 in neurodevelopmental disorders (although it has previously been associated only with autosomal recessive conditions).

Conclusions: We suggest that clinical severity in cases with 12p deletions varies depending on the cytobands involved, being more moderate when they occur at 12p11-where the gene DENND5B (12p11.23) has recently been associated with a dominant neurodevelopmental disorder-than at 12p12.

Background: Molecular testing is recommended to refine risk stratification in indeterminate thyroid nodules (Bethesda III-IV), but data on dual-gene (BRAF and RAS) testing using fresh FNA washout specimens are limited. We aimed to evaluate the performance of BRAF and RAS mutation analysis from fresh thyroid FNA washout material, with a focus on indeterminate cytology.

Methods: We retrospectively analyzed 1139 patients who underwent washout-based molecular testing between May 2022 and October 2024 at a tertiary endocrine center. Of these, 307 had available histopathologic results after surgery. Primary outcomes were sample adequacy, mutation spectrum, and diagnostic metrics (sensitivity, specificity, PPV, NPV, and accuracy). Analyses were repeated under two assumptions that classified borderline/low-risk neoplasms as benign vs. malignant, and within the Bethesda III-IV subset.

Results: Adequate material for molecular analysis was obtained in 1037/1139 samples (90.9%). In the operated cohort (n = 307), malignant lesions comprised 31.9% and low-risk neoplasms 8.5%. When borderline lesions were considered benign, mutation positivity yielded a sensitivity of 48.0%, a specificity of 89.6%, a PPV of 75.9%, an NPV of 71.9%, and an accuracy of 72.9%. In Bethesda III-IV nodules (n = 153), sensitivity, specificity, and accuracy were 41.0%, 85.2%, and 66.0% (malignant assumption). Isolated BRAF positivity showed high specificity (~96.7%) with modest sensitivity.

Conclusions: Our findings extend current diagnostic approaches by showing that dual-gene (BRAF and RAS) testing from fresh FNA washouts is technically feasible (≥90% adequacy) and provides high specificity with modest sensitivity for malignancy in indeterminate nodules. In settings lacking comprehensive commercial panels, this low-complexity approach offers a practical adjunct to cytology and imaging for preoperative decision-making.

Aim: To report on the clinical and genetic spectrum of retinopathy associated with CDHR1 variants in a Hungarian cohort. Methods: A retrospective cohort study was conducted at a single tertiary care referral center. The study enrolled nine patients harboring biallelic variants in the CDHR1 gene. Detailed clinical history, multimodal imaging, electroretinography, and molecular genetics are presented. Results: We identified four CDHR1 variants predicted to cause loss-of-function and five phenotypes (cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy, rod-cone dystrophy, and late-onset macular dystrophy). The most frequent variant was the synonymous CDHR1 c.783G>A (p.Pro261=) variant (10/18 alleles, 55.6%). A novel splice acceptor site variant, CDHR1 c.349-1G>A, and a novel intronic variant, CDHR1 c.1168-10A>G, were also detected. Fundus examination revealed macular atrophy with or without peripheral retinal changes. Full-field electroretinography, available in seven patients, demonstrated decreased light-adapted and extinguished dark-adapted responses in both the rod-cone dystrophy group and patients with macular involvement. OCT imaging indicated ellipsoid zone disruption with foveal sparing in two out of nine patients and severe retinal damage in rod-cone dystrophy cases. Conclusions: The predominant clinical manifestations of cone dystrophy, cone-rod dystrophy, and macular dystrophy in the Hungarian patient cohort showed heterogeneity, with a rod-cone dystrophy phenotype observed in five of nine cases (55.6%). The natural history of CDHR1-associated retinopathy typically follows a slow progression, providing a therapeutic window, which makes the disease a candidate for gene therapy.