The genetic structure of the Turkish population reveals high levels of variation and admixture

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes

Spatial and temporal heterogeneity in human mobility patterns in Holocene Southwest Asia and the East Mediterranean

We present a spatiotemporal picture of human genetic diversity in Anatolia, Iran, Levant, South Caucasus, and the Aegean, a broad region that experienced the earliest Neolithic transition and the emergence of complex hierarchical societies. Combining 35 new ancient shotgun genomes with 382 ancient and 23 present-day published genomes, we found that genetic diversity within each region steadily increased through the Holocene. We further observed that the inferred sources of gene flow shifted in time. In the first half of the Holocene, Southwest Asian and the East Mediterranean populations homogenized among themselves. Starting with the Bronze Age, however, regional populations diverged from each other, most likely driven by gene flow from external sources, which we term “the expanding mobility model.” Interestingly, this increase in inter-regional divergence can be captured by outgroup-f$_3$-based genetic distances, but not by the commonly used F$_{ST}$ statistic, due to the sensitivity of F$_{ST}$, but not outgroup-f$_3$, to within-population diversity. Finally, we report a temporal trend of increasing male bias in admixture events through the Holocene

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH

Chylothorax, chylopericardium and lymphoedema - The presenting features of signet-ring cell carcinoma

PubMed ID: 10445630This report describes a patient with chylous pleural and pericardial effusions in conjunction with severe lymphoedema resembling elephantiasis. The chylous effusions and generalized lymphoedema were associated with a signet-ring cell carcinoma

DNA binding and cleavage activity of three new copper (II) complexes of chiral N-salicyl-ß-amino alcohol schiff bases

Three new copper(II) complexes (1-3) with general formula [Cu(HL)CH 3 COO] of N-salicyl-ß-amino alcohol Schiff bases containing, (S)-(+)-phenyl glycinol, (1S, 2R)-2-amino-1, 2-diphenylethanol and 1, 1, 3-triphenyl-(R)-(+)-2-amino propanol, were synthesized. Their structures were characterized by FTIR, LCMS, magnetic moment, molar conductance and elemental analysis data. DFT calculations proposed distorted square planar geometries for the complexes. The calculated IR spectra are in good agreement with the experimental IR spectra, confirming the proposed structures. Their interactions with calf thymus DNA were investigated and their binding constants K b were found. Gel electrophoresis reveals that all complexes display significant nuclease activity against supercoiled pentry/d-topo plasmid DNA. © 2018, Sociedad Química de México.FEF.A3.16.015 --This study was supported by Ahi Evran University Scientific Research Foundation under grant No FEF.A3.16.015 -

Three new copper (II) complexes with chiral Schiff bases: Synthesis, characterization, DNA binding and DNA-cleavage studies

Summary: New mononuclear copper (II) complexes (1, 2 and 3) were synthesized from Schiff bases (H2L) of chiral amino alcohols. The structures of the copper complexes were proposed by a combination of elemental analyses, FTIR, LCMS, magnetic susceptibility and molar conductance measurement methods. Spectroscopic and analytical data of the complexes suggest four-coordinated structures. Geometry optimization carried out with DFT/6-31G (d,p) were proposed to be distorted square planar geometry for the complexes. The similarity between experimental and theoretical IR spectra confirms the proposed structures. The interaction of copper (II) complexes with calf thymus (CT-DNA) was investigated using absorption titration method. The results suggest that the complex 1 and 2 can bind to DNA by intercalation. Binding constants Kb were found to be 2.46×10 5 for 1, 5.41×10 5 for 2 and 7.00×10 4 for 3. Moreover, agarose gel electrophoresis assay demonstrates that all complexes were found to cleavage of plasmid pentry/d-topo plasmid DNA. Complex 2 shows the best cleavage activity (5 µM). © 2019 Chemical Society of Pakistan. All rights reserved.FEF.A3.16.015 --This study was supported by Ahi Evran University Scientific Researchs Foundation under grant No FEF.A3.16.015 -

Determination of T-cell clonality and expression profiles of Toll-like receptors signaling pathway genes and related miRNAs in patients with mycosis fungoides

Cutaneous T-cell lymphomas (CTCL) encompass a group of diseases characterized by the presence of malignant clonal CD4+ T lymphocytes in the skin. Mycosis fungoides (MF) is the most prevalent form of CTCL, accounting for approximately 60 % of cutaneous T-cell lymphomas and 50 % of all primary cutaneous lymphomas. Despite ongoing research, the precise pathogenesis of MF remains incompletely understood. Toll-like receptors (TLRs) have the ability to specifically recognize ligands, subsequently induce the expression of diverse genes and activate innate immunity within the cell. Furthermore, miRNAs play a crucial role in regulating various aspects of immune cell function. The aim of our study was to explore the potential roles of TLRs and the genes implicated in their signal transduction, along with the expression status of miRNAs in the mechanisms underlying MF. Additionally, we assessed the clonal status and compared it with clinicopathological data using a T-cell clonality assay. To determine the expression status of TLR pathway genes and miRNAs, we conducted RT-PCR analysis on 52 MF samples and 50 control paraffin block materials. Pathway analysis were conducted using the KEGG database. T-cell receptor (TCR) gamma clonality changes were evaluated. Results from the study revealed increased expressions of TLR-1, -4, -8, IRF7, TRAF3, MEK1, MEK2, Elk1, NFkB, hsa-miR-21-5p, and hsa-miR-155-5p, as well as decreased expressions of hsa-miR-130a-3p, hsa-miR-210-3p, and hsa-let-7e-5p in the MF group. TCR gamma clonal change analysis demonstrated that 55.5 % of the analysed DNAs exhibited monoclonal and biallelic patterns, while 45.5 % displayed polyclonality. These findings collectively suggest the potential influence and therapeutic possibilities of the TLR signalling pathway in the molecular pathogenesis of MF. © 2023 Elsevier B.V.Funding: This research was produced from the PhD thesis of M.S and supported by the Scientific Research Coordinatorship of Pamukkale University as the project numbered as 2018SABE004).Pamukkale Üniversitesi, PAÜ: 2018SABE00