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Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

XIST noncoding RNA promotes the initiation of X chromosome silencing by recruiting the protein SPEN to one X chromosome in female mammals. The SPEN protein is also called SHARP (SMRT and HDAC-associated repressor protein) and MINT (Msx-2 interacting nuclear target) in humans. SPEN recruits N-CoR2 and HDAC3 to initiate histone deacetylation on the X chromosome, leading to the formation of repressive chromatin marks and silencing gene expression. We dissected the contributions of different RNA and protein regions to the formation of a human XIST-SPEN complex in vitro and identified novel sequence and structure determinants that may contribute to X chromosome silencing initiation. Binding of SPEN to XIST RNA requires RRM 4 of the protein, in contrast to the requirement of RRM 3 and RRM 4 for specific binding to SRA RNA. Measurements of SPEN binding to full-length, dimeric, trimeric, or other truncated versions of the A-repeat region revealed that high-affinity binding of XIST to SPEN in vitro requires a minimum of four A-repeat segments. SPEN binding to XIST A-repeat RNA changes the accessibility of the RNA at specific nucleotide sequences, as indicated by changes in RNA reactivity through chemical structure probing. Based on computational modeling, we found that inter-repeat duplexes formed by multiple A-repeats can present an unpaired adenosine in the context of a double-stranded region of RNA. The presence of this specific combination of sequence and structural motifs correlates with high-affinity SPEN binding in vitro. These data provide new information on the molecular basis of the XIST and SPEN interaction.

Objective: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X‐linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. Methods: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. Results: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post‐fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. Interpretation: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X‐linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914–931 [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation—IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype–genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected. [ABSTRACT FROM AUTHOR]

STR loci localized on the X chromosome provide information additional to the autosomal markers routinely analyzed in forensic genetics, integrating genetic systems as Y-STRs and mitochondrial DNA in the investigation of complex kinship scenarios and mass disaster cases. In this study we genotyped 12 X-STR loci in 251 male samples from four populations of Namibia in southern Africa using the Investigator Argus X-12 kit (Qiagen, Hilden, Germany). Forensic efficiency parameters indicated high power of discrimination in the considered populations. As part of our investigation, we highlighted partial linkage associations between loci within known linkage groups (LGs) and identified several occurrences of previously unreported out-of-ladder (OL) alleles. Genetic distances between the Namibian populations here investigated and other African (Eritrea, Ethiopia, Somalia, Guinea, Cape Verde) and non-African (Germany, China, Philippines) populations using loci grouped in LGs mirrored their biogeographical distribution differently for each linkage group. Haplotype sharing within each LG revealed a high degree of population-specific types, hinting to the potential of these markers for ancestry applications. These results highlight the importance to produce specific and freely available population databases especially for multi-ethnic countries. This novel dataset is expected to be of interest for population studies that need an accessible reference dataset of African regions not currently well represented, as well as possible relevance for forensic applications focusing on the biogeographic origin of samples. [ABSTRACT FROM AUTHOR]

A female protective effect has long been postulated as the primary explanation for the four-fold increase of autism spectrum disorder (ASD) diagnoses in males versus females. However, genetic and epidemiological investigations of this hypothesis have so far failed to explain the large difference in ASD prevalence between the sexes. To address this knowledge gap, we examined sex chromosome aneuploidy in a large ASD case-control cohort to evaluate the relationship between X and Y chromosome dosage and ASD risk. From these data, we modeled three relationships between sex chromosome dosage and ASD risk: the extra Y effect, the extra X effect, and sex chromosome haploinsufficiency. We found that the extra Y effect increased ASD risk significantly more than the extra X effect. Among females, we observed a large association between 45, X and ASD, confirming sex chromosome haploinsufficiency as a strong ASD risk factor. These results provide a framework for understanding the relationship between X and Y chromosome dosage on ASD, which may inform future research investigating genomic contributors to the observed sex difference. Genetic and epidemiological investigations have yet to reveal what drives the large difference in ASD prevalence between the sexes. Here authors examine chromosome aneuploidy in a large ASD case-control cohort and report sex chromosome haploinsufficiency is a strong ASD risk factor, while the extra Y effect increases ASD risk significantly more than the extra X effect. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is a clinical condition characterized by ovarian dysfunction in women under 40. The etiology of most POI cases remains unidentified and is believed to be multifactorial, including factors such as autoimmunity, metabolism, infection, and genetics. POI exhibits significant genetic heterogeneity, and it can result from chromosomal abnormalities and monogenic defects. Case presentation: The study participant, a 33-year-old woman, presented with a history of irregular menstruation that commenced two years ago, progressing to prolonged menstrual episodes and eventual cessation. The participant exhibits a rearrangement of the X chromosome, characterized by heterozygosity duplication on the long arm and heterozygosity deletion on the short arm by whole exome sequencing(WES) combined with cell chromosome detection. Conclusions: This study expands the spectrum of mutations associated with POI resulting from X chromosomal abnormalities. WES-Copy number variation analysis, in conjunction with chromosome karyotype analysis and other detection techniques, can provide a more comprehensive understanding of the genetic landscape underlying complex single or multi-system diseases. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder marked by alpha-galactosidase-A (α-Gal A) deficiency, caused by pathogenic mutations in the GLA gene, resulting in the accumulation of glycosphingolipids within lysosomes. The current screening test relies on measuring α-Gal A activity. However, this approach is limited to males. Infrared (IR) spectroscopy is a technique that can generate fingerprint spectra of a biofluid's molecular composition and has been successfully applied to screen numerous diseases. Herein, we investigate the discriminating vibration profile of plasma chemical bonds in patients with FD using attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. Results: The Fabry disease group (n = 47) and the healthy control group (n = 52) recruited were age-matched (39.2 ± 16.9 and 36.7 ± 10.9 years, respectively), and females were predominant in both groups (59.6% and 65.4%, respectively). All patients had the classic phenotype (100%), and no late-onset phenotype was detected. A generated partial least squares discriminant analysis (PLS-DA) classification model, independent of gender, allowed differentiation of samples from FD vs. control groups, reaching 100% sensitivity, specificity and accuracy. Conclusion: ATR-FTIR spectroscopy harnessed to pattern recognition algorithms can distinguish between FD patients and healthy control participants, offering the potential of a fast and inexpensive screening test. [ABSTRACT FROM AUTHOR]

The Four Core Genotypes (FCG) is a mouse model system used to disentangle the function of sex chromosomes and hormones. We report that a copy of a 3.2 MB region of the X chromosome has translocated to the YSry- chromosome and thus increased the expression of X-linked genes including the single-stranded RNA sensor and autoimmune disease mediator Tlr7. This previously-unreported X-Y translocation complicates the interpretation of studies reliant on C57BL/6J FCG mice. Here the authors find a genetic alteration in the popular "Four Core Genotypes" mouse model that is used to distinguish sex-biased phenotypes caused by sex chromosomes and gonads. This alteration increases the expression of some X-linked genes, which might confound the interpretation of the model. [ABSTRACT FROM AUTHOR]

The goat, an early domesticated ruminant, is a reliable source of cashmere, meat and milk in global agricultural production. Despite this, the genome of cashmere-rich goats has yet to be characterized. Here, we assembled the nearly complete genome of a cashmere goat from a highly economically valuable Inner Mongolian Cashmere buck, utilizing a combination of PacBio HiFi, ONT ultra-long reads, and Hi-C technologies. The size of this genome is 2.76 Gb, with a contig N50 of 95.22 Mb. All assembled sequences were anchored onto 29 autosomes and both sex chromosomes, with only two gaps present on the X chromosome. We identified 1,333.29 Mb (48.26%) of repetitive sequences and predicted 22,480 protein-coding genes. Assembly quality assessment of the genome demonstrated that our assembled cashmere goat genome surpasses the continuity, completeness, and accuracy of other published goat genomes. Taken together, we provided the first cashmere goat assembly, bridging the gap in the genome of important economic breeds of domestic goats, and providing a valuable reference resource for goat genetics and genome research. [ABSTRACT FROM AUTHOR]

Background: 46,XX testicular disorder/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene (SRY) has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive. Methods: We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (n = 11), male controls (46,XY; variable cohort sizes) and female controls (46,XX; variable cohort sizes), in addition to RNA sequencing and DNA methylation analysis on blood samples from males with Klinefelter syndrome (47,XXY, n = 22). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (n = 10). Results: We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (n = 1), (2) with short Yp arms (breakpoint at 2.7–2.8 Mb, n = 2), (3) with medium Yp arms (breakpoint at 7.3 Mb, n = 1), and (4) with long Yp arms (n = 7), including deletions of AMELY, TBLY1 and in some cases PRKY. We also identified variable expression of the X-Y homologues PRKY and PRKX. The Y-chromosomal transcriptome and methylome reflected the Y chromosome segment lengths, while changes to autosomal and X-chromosomal regions indicated global effects. Furthermore, transcriptional changes tentatively correlated with phenotypic traits of 46,XX DSD, including reduced height, lean mass and testicular size. Conclusion: This study refines our understanding of the genetic composition in 46,XX DSD, describing the translocated Y chromosome segment in more detail than previously and linking variability herein to genome-wide changes in the transcriptome and methylome. Plain English summary: Our sex chromosome constitution determines our sex, with the presence of a Y chromosome causing male sex determination (typically 46,XY) and the lack hereof resulting in female sex development (typically 46,XX). However, individuals can become male despite of them presenting with the classical female chromosome constitution. We term this "46,XX testicular disorder/difference of sex development" or "46,XX DSD" for short. Individuals with this condition are affected by a number of traits, such as infertility, short stature and altered hormone levels. We know that most cases of 46,XX DSD are caused by the sex-determining region of the Y chromosome being moved to one of the X chromosomes. However, we do not know the more precise size of the Y-chromosomal section or its effects on the genome. In this study we investigated 11 individuals with 46,XX DSD using novel and precise techniques than previously applied. Analyzing DNA, we found that their Y-chromosomal sections varied. This was reflected in multiple types of additional genetic analyses, investigating modifications to DNA and expression of genes. Our findings are the most accurate description of the Y-chromosomal section in 46,XX DSD to date, and indicate that the genomes of individuals with 46,XX DSD differ, with many potential mechanisms of action. Highlights: • From a cohort of 11 individuals with 46,XX testicular DSD, the profile of Y chromosome segments was described in more detail than previously and used to sub-categorize subjects into four groups; SRY-negative, short Yp (2.7–2.8 Mb), medium Yp (7.3 Mb) and long Yp. • In individuals with long Yp segments, a characteristic loss of AMELY, TBL1Y and in some cases PRKY was observed. • Variable expression of the X-Y homologous gene pair PRKX and PRKY was observed, suggesting a compensatory mechanism. • The lengths of Y chromosome segments were reflected in the transcriptome and methylome. • Differential expression and methylation of autosomes suggested genome-wide effects. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease. Plain English summary: Lupus is a disease where the immune system mistakenly attacks the body's own tissues, leading to a range of complicated health issues. Interestingly, lupus is much more common in women (XX) than in men (XY), with women being up to 14 times more likely to develop the condition. Additionally, some genetic conditions involving extra or missing X chromosomes can also affect the chances of getting lupus: Klinefelter (XXY) and Triple X (XXX) syndromes show higher rates of lupus, while conditions like Turner syndrome (XO) have a lower risk. This suggests a link between the number of X chromosomes and the likelihood of developing the disease. In female cells, a process called X-chromosome inactivation (XCI) occurs, where one of the two X chromosomes in each cell is switched off to equalize X chromosome dosage with males. This process is regulated by a gene called XIST, which produces a long non-coding RNA. XIST helps to form a complex of RNA and proteins that silence the inactive X chromosome (Xi), ensuring stable gene expression patterns. Recent research suggests that molecular components or problems with this process might be linked to lupus. This review focuses on three hypotheses in which XCI or its dysregulation could impact lupus: nonrandom XCI, incomplete silencing of certain genes on the Xi, and the potential for the XIST ribonucleoprotein complex to activate the immune system. By investigating these mechanisms, researchers aim to better understand how variations in XCI mechanisms contribute to the development of lupus. Highlights: Lupus is an immune-mediated disease with higher prevalence in women than men. Individuals with supernumerary X chromosomes have a higher lupus susceptibility and there is lower prevalence in individuals with Turner syndrome (X0), suggesting that X chromosome dosage may be implicated in lupus pathogenesis. The X chromosome harbors several genes involved in immune responses, some of which are implicated in lupus pathogenesis. The X-linked content between female and male genomes is balanced by a dosage compensation mechanism regulated by the XIST non-coding RNA, known as X-chromosome inactivation (XCI), which silences one of the two X chromosomes in female cells. The molecular components involved in XCI or their dysregulation may actively contribute to lupus pathogenesis in several ways: 1) through the preferential inactivation of one X chromosome (XCI skewing); 2) by increasing XCI escape of X-linked genes involved in immune responses, such as TLR7, CXCR3, and CXorf21; 3) by being preferential targets for autoimmune responses, as it might be the case for XIST and its protein interactors. [ABSTRACT FROM AUTHOR]

Somatic copy number variations (CNVs), including abnormal chromosome numbers and structural changes leading to gain or loss of genetic material, play a crucial role in initiation and progression of cancer. CNVs are believed to cause gene dosage imbalances and modify cis-regulatory elements, leading to allelic expression imbalances in genes that influence cell division and thereby contribute to cancer development. However, the impact of CNVs on allelic gene expression in cancer remains unclear. Allele-specific expression (ASE) analysis, a potent method for investigating genome-wide allelic imbalance profiles in tumors, assesses the relative expression of two alleles using high-throughput sequencing data. However, many existing methods for gene-level ASE detection rely on only RNA sequencing data, which present challenges in interpreting the genetic mechanisms underlying ASE in cancer. To address this issue, we developed a robust framework that integrates allele-specific copy number calls into ASE calling algorithms by leveraging paired genome and transcriptome data from the same sample. This integration enhances the interpretability of the genetic mechanisms driving ASE, thereby facilitating the identification of driver events triggered by CNVs in cancer. In this study, we utilized BASE to conduct a comprehensive analysis of ASE in high hyperdiploid acute lymphoblastic leukemia (HeH ALL), a prevalent childhood malignancy characterized by gains of chromosomes X, 4, 6, 10, 14, 17, 18, and 21. Our analysis unveiled the comprehensive ASE landscape in HeH ALL. Through a multi-perspective examination of HeH ASEs, we offer a systematic understanding of how CNVs impact ASE in HeH, providing valuable insights to guide ASE studies in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: A genome-wide copy number variations (CNVs) analysis using high-density Ovine BeadChip array data in 288 Chinese Merino sheep was conducted. A total of 656 CNV regions (CNVRs) with an average size of 66.88 Kbps were identified. These CNVRs contain 519 losses, 60 gains, and 77 gain–losses ranging from 1.5 Kbps to 646 Kbps and covering 43 Mbps (1.58%) of the whole Ovine genome. To validate these results, we performed a quantitative PCR to detect 11 randomly selected CNVRs and successfully verified 8 (72.7%). The gene functional enrichment analysis revealed that a total of 1592 genes in 465 CNVRs were identified as related to biological functions such as ATP binding activity. Our results expand the current CNV map of the sheep genome and provide preliminary fundamental information for carrying out CNV studies of fine wool sheep in the future. Sheep are a vital species in the global agricultural economy, providing essential resources such as meat, milk, and wool. Merino sheep (Junken type) are a key breed of fine wool sheep in China. However, research on fine wool traits has largely overlooked the role of SNPs and their association with phenotypes. Copy number variations (CNVs) have emerged as one of the most important sources of genetic variation, influencing phenotypic traits by altering gene expression and dosage. To generate a comprehensive CNVR map of the ovine genome, we conducted genome-wide CNV detection using genotyping data from 285 fine wool sheep. This analysis revealed 656 CNVRs, including 628 on autosomes and 28 on the X chromosome, covering a total of 43.9 Mbs of the sheep genome. The proportion of CNVRs varied across chromosomes, from 0.45% on chromosome 26 to 3.72% on chromosome 10. Functional annotation through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses highlighted significantly enriched GO terms, including odorant binding, ATP binding, and sulfuric ester hydrolase activity. The KEGG analysis identified involvement in pathways such as neuroactive ligand–receptor interaction, axon guidance, ECM–receptor interaction, the one-carbon pool by folate, and focal adhesion (p < 0.05). To validate these CNVRs, we performed quantitative real-time PCR experiments to verify copy number predictions made by PennCNV software (v1.0.5). Out of 11 selected CNVRs with predicted gain, loss, or gain–loss statuses, 8 (IDs 68, 156, 201, 284, 307, 352, 411, 601) were successfully confirmed. This study marks a significant step forward in mapping CNVs in the ovine genome and offers a valuable resource for future research on genetic variation in sheep. [ABSTRACT FROM AUTHOR]

Simple Summary: Chromosome diversification represents a fundamental driver of biological evolution. Here we present and discuss the results of a comparative chromosome analysis on different species of the Malagasy chameleons of the genera Brookesia and Furcifer. We show that the study species are characterized by different karyotypes in terms of chromosome number (2n = 36–22), ratio of micro- and macrochromosomes, and the variable presence of differentiated sex chromosomes. Considering our new data together with those from previous studies, we describe a chromosome evolutionary scenario in the studied taxa. Specifically, while genus Brookesia has a fixed chromosome number (2n = 36) and no differentiated sex chromosomes, which corresponds to the hypothesized ancestral chameleon karyotype, Furcifer shows a high diversity in chromosome number (2n = 20–34), morphology, and the independent raising of simple and multiple sex chromosomes with female heterogamety. The karyotypes in Furcifer with a relatively low chromosome count likely evolved from a chromosome complement similar to that of F. balteatus (2n = 34), mostly via a progressive number of chromosome fusions involving distinct micro- and macrochromosome pairs. Similarly, the diversification of simple and multiple sex chromosome systems occurred in Furcifer via independent (non-homologous) sex chromosome-autosome fusions and heterochromatinization. In this work, we performed a preliminary molecular analysis and a comparative cytogenetic study on 5 different species of Malagasy chameleons of the genus Brookesia (B. superciliaris) and Furcifer (F. balteautus, F. petteri, F. major and F. minor). A DNA barcoding analysis was first carried out on the study samples using a fragment of the mitochondrial gene coding for the cytochrome oxidase subunit 1 (COI) in order to assess the taxonomic identity of the available biological material. Subsequently, we performed on the studied individuals a chromosome analysis with standard karyotyping (5% Giemsa solution at pH 7) and sequential C-banding + Giemsa, + CMA3, and + DAPI. The results obtained indicate that the studied species are characterized by a different chromosome number and a variable heterochromatin content and distribution, with or without differentiated sex chromosomes. In particular, B. superciliaris (2n = 36) and F. balteatus (2n = 34) showed a similar karyotype with 6 macro- and 12–11 microchromosome pairs, without differentiated sex chromosomes. In turn, F. petteri, F. major, and F. minor showed a karyotype with a reduced chromosome number (2n = 22–24) and a differentiated sex chromosome system with female heterogamety (ZZ/ZW). Adding our newly generated data to those available from the literature, we highlight that the remarkable chromosomal diversification of the genus Furcifer was likely driven by non-homologous chromosome fusions, including autosome–autosome, Z–autosome, and W–autosome fusions. The results of this process resulted in a progressive reduction in the chromosome number and partially homologous sex chromosomes of different shapes and sizes. [ABSTRACT FROM AUTHOR]

Chromosome alignment on the metaphase plate is a conserved phenomenon and is an essential function for correct chromosome segregation for many organisms. Organisms with naturally-occurring trivalent chromosomes provide a useful system for understanding how chromosome alignment is evolutionarily regulated, as they align on the spindle with one kinetochore facing one pole and two facing the opposite pole. We studied chromosome alignment in a praying mantid that has not been previously studied chromosomally, the giant shield mantis Rhombodera megaera. R. megaera has a chromosome number of 2n = 27 in males. Males have X1, X2, and Y chromosomes that combine to form a trivalent in meiosis I. Using live-cell imaging of spermatocytes in meiosis I, we document that sex trivalent Y chromosomes associate with one spindle pole and the two X chromosomes associate with the opposing spindle pole. Sex trivalents congress alongside autosomes, align with them on the metaphase I plate, and then the component chromosomes segregate alongside autosomes in anaphase I. Immunofluorescence imaging and quantification of brightness of kinetochore–microtubule bundles suggest that the X1 and X2 kinetochores are associated with fewer microtubules than the Y kinetochore, likely explaining the alignment of the sex trivalent at the spindle equator with autosomes. These observations in R. megaera support the evolutionary significance of the metaphase alignment of chromosomes and provide part of the explanation for how this alignment is achieved. [ABSTRACT FROM AUTHOR]

Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy causing progressive vision loss due to mutations in the CHM gene, leading to Rab escort protein 1 loss of function. CHM disease is characterized by a progressive degeneration of the choroid, the retinal pigment epithelium (RPE), and the retina. The RPE is a monolayer of polarized cells that supports photoreceptors, providing nutrients, growth factors, and ions, and removes retinal metabolism waste products, having a central role in CHM pathogenesis. Commonly used models such as ARPE-19 cells do not reproduce accurately the nature of RPE cells. Human induced pluripotent stem cells (hiPSCs) can be differentiated into RPE cells (hiPSC-RPE), which mimic key features of native RPE, being more suited to study retinal diseases. Therefore, we took advantage of hiPSCs to generate new human-based CHM models. Two isogenic hiPSC lines were generated through CRISPR/Cas9: a CHM knock-out line from a healthy donor and a corrected CHM patient line using a knock-in approach. The differentiated hiPSC-RPE lines exhibited critical morphological and physiological characteristics of native RPE, including the presence of the tight junction markers Claudin-19 and Zonula Occludens-1, phagocytosis of photoreceptor outer segments, pigmentation, a postmitotic state, and the characteristic polygonal shape. In addition, all the studied cells were able to form retinal organoids. This work resulted in the establishment of isogenic hiPSC lines, representing a new and important CHM cellular model. To our knowledge, this is the first time that isogenic cell lines have been developed to model CHM disease, providing a valuable tool for studying the mechanisms at the onset of RPE degeneration. [ABSTRACT FROM AUTHOR]

Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in‐house, molecular diagnostic platform using Senshin‐Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin‐Iryo as "Drug resistance gene testing for anticancer chemotherapy" and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation‐dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin‐Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin‐Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system. [ABSTRACT FROM AUTHOR]

IntroductionAimMethodsResultsConclusionRetinoblastoma is initiated by inactivation of RB1 gene, but additional alterations may be required for tumor progression. Substitution and INDEL variants in different genes, aside RB1, are infrequent, while large copy number variants (CNVs) like gains on 1q, 2p, 6p and loss on 16q are common, they include oncogenes or tumor suppressors and are typical of retinoblastoma.To provide the molecular profile that is useful for prognosis and understanding of retinoblastoma development.To identify genomic variants in six retinoblastoma tumors whole exome sequencing and informatic analysis were performed.RB1 was the only gene with nonsense or frameshift mutations. SNVs in other 11 genes were missense and at non-canonical splice-sites, all nonpathogenic. CNVs, similar to those reported, were identified in all retinoblastoma tumors. The most frequent were 1q gain and 16q loss. Additionally, deletions were identified on 13q, including RB1 gene, and on the X chromosome, including BCOR gene, the most frequently mutated, after RB1, in retinoblastoma. The number of CNVs detected in each tumor was between 1 and 7, depending on the age at diagnosis.The analysis of genomic alterations in retinoblastoma is useful to understand the severity of tumor progression and to apply appropriate treatments. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a genetic condition in phenotypic females in which the individual has 1 intact X chromosome and the second sex chromosome is absent or structurally altered Components of Y chromosome (eg, 45,X/46,XY) have been found in 5%-15% of patients with TS; these patients are often referred to as having "Turner syndrome with Y" (TS+Y). The presence of Y chromosome material increases risk for development of gonadal tumors. Historically, prophylactic gonadectomy has been recommended in this population to prevent malignancy, and patients were presumed infertile due to the presence of streak gonads with no germ cells (GCs). More recently, studies have reported on spontaneous puberty and menarche in TS+Y patients suggesting the presence of viable GC and ovarian function. Our institution offers patients with TS+Y the option of experimental gonadal tissue cryopreservation (GTC) at the time of gonadectomy. We present a unique case of a young girl with TS+Y who had GCs present in her gonads and underwent experimental GTC at the time of gonadectomy. [ABSTRACT FROM AUTHOR]

Background: Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the long arm (q) of the X chromosome. Objective: Trofinetide is a recently developed drug that has a neuroprotective effect on neurons, and it is our aim in this meta-analysis to evaluate its efficacy and safety in treating Rett syndrome patients. Methods: We searched 5 databases (PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases) to identify randomized controlled trials (RCTs) comparing Trofinetide and placebo in patients with Rett syndrome until August 13, 2023.Our primary outcomes were the Clinical Global Impression-Improvement (CGI) and the Rett syndrome Behavior Questionnaire (RSBQ). We used Risk of Bias Assessment tool-2 (ROB2) to assess the methodological quality of the included randomized controlled trials. Results: Three RCTs with a total of 325 patients were included with a follow-up duration ranging from one month to three months. 186 patients received the intervention drug (Trofinetide) and 138 received the placebo. Trofinetide was found to reduce CGI and RSBQ significantly more than placebo (MD = -0.35, 95% CI [-0.52 to -0.18], P 0.0001), (MD = -3.40, 95% CI [-3.69 to -3.12], P 0.00001) respectively. Most adverse events did not show any statistical difference between Trofinetide and the placebo. Conclusion: Trofinetide offers promise as a potential effective and safe therapeutic opportunity for a population without many available treatments, with improvements seen on both CGI and RSBQ assessments and no severe adverse effects reported. [ABSTRACT FROM AUTHOR]

The fermentative model yeast Saccharomyces cerevisiae has been extensively used to study the genetic basis of stress response and homeostasis. In this study, we performed quantitative trait loci (QTL) analysis of the high-temperature fermentation trait of the progeny from the mating of the S. cerevisiae natural isolate BCC39850 (haploid#17) and the laboratory strain CEN.PK2-1C. A single QTL on chromosome X was identified, encompassing six candidate genes (GEA1, PTK2, NTA1, NPA3, IRT1, and IML1). The functions of these candidates were tested by reverse genetic experiments. Deletion mutants of PTK2, NTA1, and IML1 showed growth defects at 42 °C. The PTK2 knock-out mutant also showed significantly reduced ethanol production and plasma membrane H+ ATPase activity and increased sensitivity to acetic acid, ethanol, amphotericin B (AMB), and β-1,3-glucanase treatment. The CRISPR-Cas9 system was used to construct knock-in mutants by replacement of PTK2, NTA1, IML1, and NPA3 genes with BCC39850 alleles. The PTK2 and NTA1 knock-in mutants showed increased growth and ethanol production titers at 42 °C. These findings suggest an important role for the PTK2 serine/threonine protein kinase in regulating plasma membrane H+ ATPase activity and the NTA1 N-terminal amidase in protein degradation via the ubiquitin-proteasome system machinery, which affects tolerance to heat stress in S. cerevisiae. [ABSTRACT FROM AUTHOR]

Background: Reproductive performance plays an important role in animal welfare, health and profitability in animal husbandry and breeding. It is well established that there is a negative correlation between performance and reproduction in dairy cattle. This relationship is being increasingly considered in breeding programs. By elucidating the genetic architecture of underlying reproduction traits, it will be possible to make a more detailed contribution to this. Our study followed two approaches to elucidate this area; in a first part, variance components were estimated for 14 different calving and fertility traits, and then genome-wide association studies were performed for 13 reproduction traits on imputed sequence-level genotypes with subsequent enrichment analyses. Results: Variance components analyses showed a low to moderate heritability (h2) for the traits analysed, ranging from 0.014 for endometritis up to 0.271 for stillbirth, indicating variable degrees of variation within the reproduction traits. For genome-wide association studies, we were able to detect genome-wide significant association signals for nine out of 13 analysed traits after Bonferroni correction on chromosome 6, 18 and the X chromosome. In total, we detected over 2700 associated SNPs encircling more than 90 different genes using the imputed whole-genome sequence data. Functional associations were reviewed so far known and potential candidate regions in the proximity of reproduction events were hypothesised. Conclusion: Our results confirm previous findings of other authors in a comprehensive cohort including 13 different traits at the same time. Additionally, we identified new candidate genes involved in dairy cattle reproduction and made initial suggestions regarding their potential impact, with special regard to the X chromosome as a putative information source for further research. This work can make a contribution to reveal the genetic architecture of reproduction traits in context of trait specific interactions. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are essential regulatory elements of sex chromosomes that act to equalize gene expression levels between males and females. XIST, RSX, and roX2 regulate X chromosomes in placental mammals, marsupials, and Drosophila, respectively. Because the green anole (Anolis carolinensis) shows complete dosage compensation of its X chromosome, we tested whether a lncRNA was involved. We found an ancient lncRNA, MAYEX, that gained male-specific expression more than 89 million years ago. MAYEX evolved a notable association with the acetylated histone 4 lysine 16 (H4K16ac) epigenetic mark and the ability to loop its locus to the totality of the X chromosome to increase expression levels. MAYEX is the first lncRNA in reptiles linked to a dosage compensation mechanism that balances the expression of sex chromosomes. [ABSTRACT FROM AUTHOR]

Aim: Among the severe organ complications occurring in patients with Turner syndrome (TS), ophthalmic dysmorphia and visual impairment are usually marginalized. There are only a few studies that take into account the prevalence of ophthalmic disorders in female patients with TS. Material and methods: Articles in PubMed, Scholar, and Website were reviewed, considering the prevalence of various ocular disorders in patients with X chromosome deficiency. Current standards for the management of patients with TS in the context of the prevalence of ophthalmic disorders were also analyzed. Results: Identification of visual impairment in people is important because it significantly impairs quality of life (QoL) along with other health problems. QoL affects cognitive and behavioral functioning and significantly increases self-esteem, acceptance of treatment, and, consequently, physical and mental health. Low self-esteem makes patients feel helpless and unable to plan their social development. Patients with TS are relatively more frequently diagnosed with various eye defects compared to the healthy population. Therefore, special attention should be paid to the early assessment of the visual system in people with TS to eliminate any factors that could potentially impair their QoL. Conclusions: Patients with TS should be referred to specialist ophthalmologists, pediatricians, or optometrists for preventive care or early treatment of visual impairment. The authors point out the need for comprehensive ophthalmological examinations as standard management in patients with TS. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease. [ABSTRACT FROM AUTHOR]

Background: Hearing loss (HL) is the most common sensory birth deficit worldwide, with causative variants in more than 150 genes. However, the etiological contribution and clinical manifestations of X-linked inheritance in HL remain unclear within the Chinese HL population. In this study, we focused on X-linked hereditary HL and aimed to assess its contribution to hereditary HL and identify the genotype–phenotype relationship. Methods: We performed a molecular epidemiological investigation of X-linked hereditary HL based on next-generation sequencing and third-generation sequencing in 3646 unrelated patients with HL. We also discussed the clinical features associated with X-linked non-syndromic HL-related genes based on a review of the literature. Results: We obtained a diagnostic rate of 52.72% (1922/3646) among our patients; the aggregate contribution of HL caused by genes on the X chromosome in this cohort was ~ 1.14% (22/1922), and POU3F4 variants caused ~ 59% (13/22) of these cases. We found that X-linked HL was congenital or began during childhood in all cases, with representative audiological profiles or typical cochlear malformations in certain genes. Genotypic and phenotypic analyses showed that causative variants in PRPS1 and AIFM1 were mainly of the missense type, suggesting that phenotypic variability was correlated with the different effects that the replaced residues exert on structure and function. Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy. No phenotypic differences were identified in patients carrying POU3F4 or COL4A6 variants. Conclusions: Our work constitutes a preliminary evaluation of the molecular contribution of X-linked genes in heritable HL (~ 1.14%). The 15 novel variants reported here expand the mutational spectrum of these genes. Analysis of the genotype–phenotype relationship is valuable for X-linked HL precise diagnostics and genetic counseling. Elucidation of the pathogenic mechanisms and audiological profiles of HL can also guide choices regarding treatment modalities. [ABSTRACT FROM AUTHOR]

Brontispa longissima is a highly destructive pest that affects coconut and ornamental palm plants. It is widely distributed across Southeast and East Asia and the Pacific region, causing production losses of up to 50–70%. While control methods and ecological phenomena have been the primary focus of research, there is a significant lack of studies on the molecular mechanisms underlying these ecological phenomena. The absence of a reference genome has also hindered the development of new molecular-targeted control technologies. In this study, we conducted a karyotype analysis of B. longissima and assembled the first high-quality chromosome-level genome. The assembled genome is 582.24 Mb in size, with a scaffold N50 size of 63.81 Mb, consisting of 10 chromosomes and a GC content of 33.71%. The BUSCO assessment indicated a completeness estimate of 98.1%. A total of 23,051 protein-coding genes were predicted. Our study provides a valuable genomic resource for understanding the mechanisms of adaptive evolution and facilitates the development of new molecular-targeted control methods for B. longissima. [ABSTRACT FROM AUTHOR]

Morabine grasshoppers in the Vandiemenella viatica species group, which show karyotype diversity, have been studied for their ecological distribution and speciation in relation to their genetic and chromosomal diversity. They are good models for studying sex chromosome evolution as "old" and newly emerged sex chromosomes co-exist within the group. Here we present a reference genome for the viatica19 chromosomal race, that possesses the ancestral karyotype within the group. Using PacBio HiFi and Hi-C sequencing, we generated a chromosome-level assembly of 4.09 Gb in span, scaffold N50 of 429 Mb, and complete BUSCO score of 98.1%, containing 10 pseudo-chromosomes. We provide Illumina datasets of males and females, used to identify the X chromosome. The assembly contains 19,034 predicted protein-coding genes, and a total of 75.21% of repetitive DNA sequences. By leveraging HiFi reads, we mapped the genome-wide distribution of methylated bases (5mC and 6 mA). This comprehensive assembly offers a robust reference for morabine grasshoppers and supports further research into speciation and sex chromosome diversification within the group and its related species. [ABSTRACT FROM AUTHOR]

X chromosome inactivation (XCI) is an epigenetic process that results in the transcriptional silencing of one X chromosome in the somatic cells of females. This phenomenon is common to both eutherian and marsupial mammals, but there are fundamental differences. In eutherians, the X chosen for silencing is random. DNA methylation on the eutherian inactive X is high at transcription start sites (TSSs) and their flanking regions, resulting in universally high DNA methylation. This contrasts XCI in marsupials where the paternally derived X is always silenced, and in which DNA methylation is low at TSSs and flanking regions. Here, we examined the DNA methylation status of the tammar wallaby X chromosome during spermatogenesis to determine the DNA methylation profile of the paternal X prior to and at fertilization. Whole genome enzymatic methylation sequencing was carried out on enriched flow-sorted populations of premeiotic, meiotic, and postmeiotic cells. We observed that the X displayed a pattern of DNA methylation from spermatogonia to mature sperm that reflected the inactive X in female somatic tissue. Therefore, the paternal X chromosome arrives at the egg with a DNA methylation profile that reflects the transcriptionally silent X in adult female somatic tissue. We present this epigenetic signature as a candidate for the long sought-after imprint for paternal XCI in marsupials. [ABSTRACT FROM AUTHOR]

In female eutherian mammal development, X-chromosome inactivation (XCI) of one of the two X chromosomes is initiated early. Understanding the relationship between the initiation of XCI and cell fate is critical for understanding early female development and requires a system that can monitor XCI in single living cells. Traditional embryonic stem cells (ESCs) used for XCI studies often lose X chromosomes spontaneously during culture and differentiation, making accurate monitoring difficult. Additionally, most XCI assessment methods necessitate cell disruption, hindering cell fate tracking. We developed the Momiji (version 2) ESC line to address these difficulties, enabling real-time monitoring of X-chromosome activity via fluorescence. We inserted green and red fluorescent reporter genes and neomycin and puromycin resistance genes into the two X chromosomes of PGK12.1 ESCs, creating a female ESC line that retains two X chromosomes more faithfully during differentiation. Momiji (version 2) ESCs exhibit a more stable XX karyotype than other ESC lines, including the parental PGK12.1 line. This new tool offers valuable insights into the relationship between XCI and cell fate, improving our understanding of early female development. [ABSTRACT FROM AUTHOR]

Azoospermia (the complete absence of spermatozoa in the semen) is a common cause of male infertility. The etiology of azoospermia is poorly understood. Whole-genome analysis of azoospermic men has identified a number of candidate genes, such as the X-linked testis-expressed 11 (TEX11) gene. Using a comparative genomic hybridization array, an exonic deletion (exons 10–12) of TEX11 had previously been identified in two non-apparent azoospermic patients. However, the putative impact of this genetic alteration on spermatogenesis and the azoospermia phenotype had not been validated functionally. We therefore used a CRISPR/Cas9 system to generate a mouse model (Tex11Ex9-11del/Y) with a partial TEX11 deletion that mimicked the human mutation. Surprisingly, the mutant male Tex11Ex9-11del/Y mice were fertile. The sperm concentration, motility, and morphology were normal. Similarly, the mutant mouse line's testis transcriptome was normal, and the expression of spermatogenesis genes was not altered. These results suggest that the mouse equivalent of the partial deletion observed in two infertile male with azoospermia has no impact on spermatogenesis or fertility in mice, at least of a FVB/N genetic background and until 10 months of age. Mimicking a human mutation does not necessarily lead to the same human phenotype in mice, highlighting significant differences species. [ABSTRACT FROM AUTHOR]

Introduction: Pathogenic variants in the XK gene are associated with dysfunction or loss of XK protein leading to McLeod syndrome (MLS), a rare X-linked neuroacanthocytosis syndrome with multisystemic manifestation. Here we present clinical, genetic and immunological data on a patient originally admitted to our clinic for presumed post-COVID-19 syndrome, where thorough clinical work-up revealed a novel frameshift deletion in XK causal for the underlying phenotype. We additionally review the clinicogenetic spectrum of reported McLeod cases in the literature. Methods: We performed in-depth clinical characterization and flow cytometry of cerebrospinal fluid (CSF) in a patient where multi-gene panel sequencing identified a novel hemizygous frameshift deletion in XK. Additionally, Kell (K) and Cellano (k) antigen expression was analysed by Fluorescence-activated Cell Sorting (FACS). KEL gene expression was examined by RNA sequencing. Results: A novel hemizygous frameshift deletion in the XK gene resulting in premature termination of the amino acid chain was identified in a 46-year old male presenting with decrease in physical performance and persisting fatigue after COVID-19 infection. Examinations showed raised creatine kinase (CK) levels, neuropathy and clinical features of myopathy. FACS revealed the K-k+ blood type and reduced Cellano density. CSF flow cytometry showed elevation of activated T Cells. Conclusion: In-depth clinical, genetic, immunological and ribonucleic acid (RNA) expression data revealed axonal neuropathy, myopathy and raised levels of activated CSF-T-lymphocytes in a patient with a previously unpublished frameshift deletion in the XK gene. [ABSTRACT FROM AUTHOR]

Turner syndrome is a genetic disorder characterized by a partial or complete loss of one X chromosome in females. This case report describes a 16-year-old Aboriginal adolescent who presented with amenorrhea and developmental challenges in primary care on a community visit. The patient's medical history revealed a delay in speech development, poor academic performance, and limited literacy skills. Physical examination demonstrated characteristic Turner Syndrome features such as slanted eyes, a flat nasal bridge, a webbed neck, cubitus valgus, short metatarsals, and atrophic genitalia. Karyotyping confirmed the diagnosis of Turner Syndrome (45, X). In addition, the patient exhibited growth retardation, with height and weight measurements below the 3rd centile. Management included a referral to obstetrics and gynaecology for growth hormone therapy, aortic aneurysm and bone marrow density monitoring, and genetic counselling for the family. This case emphasizes the importance of early diagnosis, the challenges in diagnosing TS in rural areas and multidisciplinary care for patients with Turner Syndrome to address the condition's medical and developmental aspects. [ABSTRACT FROM AUTHOR]

Sex-biased gene expression differs across human populations; however, the underlying genetic basis and molecular mechanisms remain largely unknown. Here, we explore the influence of ancestry on sex differences in the human transcriptome and its genetic effects on a Eurasian admixed population: Uyghurs living in Xinjiang (XJU), by analyzing whole-genome sequencing data and transcriptome data of 90 XJU and 40 unrelated Han Chinese individuals. We identified 302 sex-biased expressed genes and 174 sex-biased cis -expression quantitative loci (sb- cis -eQTLs) in XJU, which were enriched in innate immune-related functions, indicating sex differences in immunity. Notably, approximately one-quarter of the sb- cis -eQTLs showed a strong correlation with ancestry composition; i.e. populations of similar ancestry tended to show similar patterns of sex-biased gene expression. Our analysis further suggested that genetic admixture induced a moderate degree of sex-biased gene expression. Interestingly, analysis of chromosome interactions revealed that the X chromosome acted on autosomal immunity-associated genes, partially explaining the sex-biased phenotypic differences. Our work extends the knowledge of sex-biased gene expression from the perspective of genetic admixture and bridges the gap in the exploration of sex-biased phenotypes shaped by autosome and X-chromosome interactions. Notably, we demonstrated that sex chromosomes cannot fully explain sex differentiation in immune-related phenotypes. [ABSTRACT FROM AUTHOR]

In organisms with the XY sex-determination system, there is an imbalance in the inheritance and transmission of the X chromosome between males and females. Unlike an autosomal allele, an X-linked recessive allele in a female will have phenotypic effects on its male counterpart. Thus, genes located on the X chromosome are of particular interest to researchers in molecular evolution and genetics. Here we present a model for selection with two alleles of X-linkage to understand fitness components associated with genes on the X chromosome. We apply this model to the fitness analysis of an X-linked gene, OdsH (16D), in the fruit fly Drosophila melanogaster. The function of OdsH is involved in sperm production and the gene is rapidly evolving under positive selection. Using site-directed gene targeting, we generated functional and defective OdsH variants tagged with the eye-color marker gene white. We compare the allele frequency changes of the two OdsH variants, each directly competing against a wild-type OdsH allele in concurrent but separate experimental populations. After 20 generations, the two genetically modified OdsH variants displayed a 40% difference in allele frequencies, with the functional OdsH variant demonstrating an advantage over the defective variant. Using maximum likelihood estimation, we determined the fitness components associated with the OdsH alleles in males and females. Our analysis revealed functional aspects of the fitness determinants associated with OdsH , and that sex-specific fertility and viability consequences both contribute to selection on an X-linked gene. [ABSTRACT FROM AUTHOR]

Although age-dependent alterations in urinary magnesium (Mg2+) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg2+ excretion, we measured urinary Mg2+ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared with animals aged 6 mo, an increase in Mg2+ excretion was observed at 12 and 18 mo. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg2+ excretion at 6 mo of age, with Oit3 (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg2+ handling, we generated and characterized Oit3 knockout (Oit3−/−) mice. Although a slightly lower serum Mg2+ concentration was present in male Oit3−/− mice, this effect was not observed in female Oit3−/− mice. In addition, urinary Mg2+ excretion and the expression of renal magnesiotropic genes were unaltered in Oit3−/− mice. For animals aged 12 and 18 mo, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg2+ channel involved in renal Mg2+ reabsorption. Comparison with RNA sequencing (RNA-Seq) data revealed that Trpm6 mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg2+ excretion in mice. In conclusion, we show here that variants in Oit3 and Trpm6 are associated with urinary Mg2+ excretion at distinct periods of life, although OIT3 is unlikely to affect renal Mg2+ handling. NEW & NOTEWORTHY: Aging increased urinary magnesium (Mg2+) excretion in mice. We show here that variation in Oit3, a candidate gene for the locus associated with Mg2+ excretion in young mice, is unlikely to be involved as knockout of Oit3 did not affect Mg2+ excretion. Differences in the expression of the renal Mg2+ channel TRPM6 may contribute to the variation in urinary Mg2+ excretion in older mice. [ABSTRACT FROM AUTHOR]

Histone variants are the paralogs of core histones (H2A, H2B, H3 and H4). They are stably expressed throughout the cell cycle in a replication-independent fashion and are capable of replacing canonical counterparts under different fundamental biological processes. Variants have been shown to take part in multiple processes, including DNA damage repair, transcriptional regulation and X chromosome inactivation, with some of them even specializing in lineage-specific roles like spermatogenesis. Several reports have recently identified some unprecedented variants from different histone families and exploited their prognostic value in distinct types of cancer. Among the four classes of canonical histones, the H2A family has the greatest number of variants known to date, followed by H2B, H3 and H4. In our prior review, we focused on summarizing all 19 mammalian histone H2A variants. Here in this review, we aim to complete the full summary of the roles of mammalian histone variants from the remaining histone H2B, H3, and H4 families, along with an overview of their roles in cancer biology and their prognostic value in a clinical context. [ABSTRACT FROM AUTHOR]

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model. [ABSTRACT FROM AUTHOR]

X chromosome centromeric drive may explain the prevalence of polycystic ovary syndrome and contribute to oocyte aneuploidy, menopause, and other conditions. The mammalian X chromosome may be vulnerable to meiotic drive because of X inactivation in the female germline. The human X pericentromeric region contains genes potentially involved in meiotic mechanisms, including multiple SPIN1 and ZXDC paralogs. This is consistent with a multigenic drive system comprising differential modification of the active and inactive X chromosome centromeres in female primordial germ cells and preferential segregation of the previously inactivated X chromosome centromere to the polar body at meiosis I. The drive mechanism may explain differences in X chromosome regulation in the female germlines of the human and mouse and, based on the functions encoded by the genes in the region, the transmission of X pericentromeric genetic or epigenetic variants to progeny could contribute to preeclampsia, autism, and differences in sexual differentiation. [ABSTRACT FROM AUTHOR]

ZC4H2 -associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual. The ZC4H2 -Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ 2, and Mann-Whitney tests were utilized. Males tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05). Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells play a crucial role in both innate immunity and the activation of adaptive immunity. The activating effect of Mn2+ on cyclic GMP‐AMP(cGAS)–stimulator of interferon genes (STING signaling has been well known, but its effect on NK cells remains elusive. In this study, we identified the vital role of manganese (Mn2+) in NK cell activation. Mn2+ directly boosts cytotoxicity of NK cells and promotes the cytokine secretion by NK cells, thereby activating CD8+ T cells and enhancing their antitumor activity. Furthermore, Mn2+ can simultaneously activate NK‐cell intrinsic cGAS and STING and consequently augment the expression of ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX to promote the responsiveness of NK cells. Our results contribute to a broader comprehension of how cGAS–STING regulates NK cells. As a potent agonist of cGAS–STING, Mn2+ provides a promising option for NK cell‐based immunotherapy of cancers. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML harboring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. Methods: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46, Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. Results: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCRABL1 levels were elevated above the MMR. Conclusions: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations. [ABSTRACT FROM AUTHOR]

Simple Summary: The process of acquiring sexed sperm involves the separation of sperm with X and Y chromosomes, allowing for the production of offspring of the desired sex. However, this process can negatively affect the quality of semen due to biochemical and physical stresses. ProAKAP4 is a major component of the sperm flagellum structure. In this study, sexed bull semen samples were evaluated using the proAKAP4 biomarker for the first time. Based on CASA and flow cytometry analysis of spermatozoa after thawing and incubation for 3 h, proAKAP4 is considered a practical biomarker for estimating the longevity of sexed sperm quality. ProAKAP4 is a sperm structural protein that regulates motility through the PKA-dependent cAMP signaling pathway, which is synthesized as an X chromosome-linked member of the gene family. This study aims to determine the optimal level of proAKAP4 for evaluating sexed semen through investigating its relationship with the longevity of sperm quality in sexed Holstein bull sperm. A total of 30 sexed sperm samples (bearing X chromosomes) from 30 distinct Holstein bulls (n = 30) were analyzed. The frozen bull sperm samples were assessed for their proAKAP4 levels, mitochondrial membrane potential, plasma membrane and acrosome integrity (PMAI), and spermatozoa movement parameters at hours 0 and 3 after thawing. The proAKAP4 levels in the sexed sperm samples ranged from 16.35 to 72.10 ng/10 M spz, with an average of 37.18 ± 15.1 ng/10 M spz. A strong positive correlation was observed between proAKAP4 levels and total motility, progressive motility, PMAI, high mitochondrial membrane potential, VAP, and VCL values after 3 h of incubation, when compared to post-thaw analyses. The results also reveal that spermatozoa with proAKAP4 levels of ≥40 ng/10 M spz exhibit higher quality. In conclusion, the level of proAKAP4 in sexed sperm aligns with previous studies and shows potential as a biomarker for assessing the longevity of sexed sperm quality. [ABSTRACT FROM AUTHOR]

X-chromosomal genetic markers are frequently employed in forensic parentage determination owing to their distinctive inheritance patterns. The kinship analysis revealed that two sisters who were not identical twins had identical genotypes on the X chromosome, encompassing 36 X-chromosomal short tandem repeats (X-STRs) and 29 X-chromosomal single-nucleotide polymorphisms (X-SNPs) that spanned the whole X chromosome from the p-telomere to the q-telomere. The identical X-STRs and X-SNPs in the daughters could be the result of linkage or a rare chance of occurrence. This highlights the need for careful analysis and interpretation when dealing with X chromosome markers and that in individual cases, even if two women share an allele at each locus, this does not necessarily mean that they are paternal sisters. The likelihood of random concordance due to maternal alleles must be taken into account.

Sex-ratio meiotic drivers are selfish genes or gene complexes that bias the transmission of sex chromosomes resulting in skewed sex ratios. Existing theoretical models have suggested the maintenance of a four-chromosome equilibrium (with driving and standard X and suppressing and susceptible Y) in a cyclic dynamic, but studies of natural populations have failed to capture this pattern. Although there are several plausible explanations for this lack of cycling, interference from autosomal suppressors has not been studied using a theoretical population genetic framework even though autosomal suppressors and Y-linked suppressors coexist in natural populations of some species. In this study, we use a simulation-based approach to investigate the influence of autosomal suppressors on the cycling of sex chromosomes. Our findings demonstrate that the presence of an autosomal suppressor can hinder the invasion of a Y-linked suppressor under some parameter space, thereby impeding the cyclic dynamics, or even the invasion of Y-linked suppression. Even when a Y-linked suppressor invades, the presence of an autosomal suppressor can prevent cycling. Our study demonstrates the potential role of autosomal suppressors in preventing sex chromosome cycling and provides insights into the conditions and consequences of maintaining both Y-linked and autosomal suppressors. [ABSTRACT FROM AUTHOR]

Maize, a one of the cereal crops, serves as the staple food for numerous people across the world. Maize breeding programmes primarily aim to enhance the yield potential of newly developed cultivars. This objective can be accomplished either by direct selection for increased grain yield or by indirect selection for traits closely associated with yield. The present study was carried out in two environments viz., Coimbatore (E1) and Vagarai (E2) to locate QTLs associated with yield-related traits in a recombinant inbred line (RIL) population that resulted from a cross between UMI79 and UMI 936(w). A total of seven yield-related traits (Ear weight, ear diameter, ear length, kernel row number, kernel number per row, 100-kernel weight, and grain yield) were evaluated across the two environments. The QTLs were mapped with the support of genotyping-by-sequencing based SNPs genetic linkage map which contains 1516 markers and spans 10 chromosomes and covers an overall distance of 6924.7 centimorgans. A total of 22 QTLs were discovered across these environments and best linear unbiased predictors, with four of these QTLs being common across them. The study pinpointed three stable QTLs (qEW-6, qEL-2, and qKRN-5), each contributing > 10% of the phenotypic variance in ear weight, ear length, and kernel row number, respectively. Within these QTL regions, 109 protein-coding genes were identified. Gene ontology analysis revealed these genes roles in development, reproduction, and growth. Several candidate genes, including MADS-box transcription factors, serine carboxypeptidase, and E3 ubiquitin-protein ligase, are well known for their role in yield-related traits of maize, and other cereal crops were among those identified. These findings provide valuable information for maize breeders aiming to enhance grain yield-related traits through marker-assisted breeding. [ABSTRACT FROM AUTHOR]

ABSTRACT Marked differences in survival from melanoma are noted between men and women that cannot be accounted for by behavioral differences. We and others have provided evidence that this difference may be due to increased expression of immune‐related genes from the second X chromosome because of failure of X inactivation. In the present review, we have examined evidence for the contrary view that survival differences are due to weaker immune responses in males. One reason for this may be the loss of Y chromosomes (LOY), particularly in older males. The genes involved may have direct roles in immune responses or be noncoding RNAs that regulate both sex and autosomal genes involved in immune responses or tumor growth. Loss of the KDM6C and KDM5D demethylases appeared to common genes involved. The second factor appears to be the activation of androgen receptors (AR) on melanoma cells that increase their invasiveness and growth. Induction of T‐cell exhaustion by AR that limits immune responses against melanoma appeared a common finding. The development of treatments to overcome effects related to gene loss on Y poses challenges, but several avenues related to AR signaling appear worthy of further study in the treatment of metastatic disease. [ABSTRACT FROM AUTHOR]

In order to identify the genetic stability in biology of bovine small intestinal epithelial cell line (BIECs-21), BIECs-21 cells were cultured in vitro by using adherent culture, and chromosome and G-band samples were prepared to analyze the chromosome karyotype and G-band of BIECs-21 cells. The results show that the number of chromosomes in BIECs-21 cells is 2n = 60, including 29 pairs of autosomes and 1 pair of sex chromosomes (X and Y chromosomes). Among them, 29 pairs of autosomes are all terminal centromere chromosomes, with X chromosome being the larger centromere chromosome and Y chromosome being the smaller centromere chromosome in the sex chromosome. There is no significant difference in the number and position of G-bands pattern on the autosomes of BIECs-21 cells, except for X and Y sex chromosome. Compared with the normal chromosome karyotype of Holstein cattle, there is no significant change in the number and morphological structure of chromosomes in BIECs-21 cells, indicating that the genetic characteristics of the cell line are stable, and it can be used for the research on the molecular mechanisms of bovine intestinal related diseases. [ABSTRACT FROM AUTHOR]

Sex determination in the nematode C. elegans is controlled by the master regulator XOL-1 during embryogenesis. Expression of xol-1 is dependent on the ratio of X chromosomes and autosomes, which differs between XX hermaphrodites and XO males. In males, xol-1 is highly expressed and in hermaphrodites, xol-1 is expressed at very low levels. XOL-1 activity is known to be critical for the proper development of C. elegans males, but its low expression was considered to be of minimal importance in the development of hermaphrodite embryos. Our study reveals that XOL-1 plays an important role as a regulator of developmental timing during hermaphrodite embryogenesis. Using a combination of imaging and bioinformatics techniques, we found that hermaphrodite embryos have an accelerated rate of cell division, as well as a more developmentally advanced transcriptional program when xol-1 is lost. Further analyses reveal that XOL-1 is responsible for regulating the timing of initiation of dosage compensation on the X chromosomes, and the appropriate expression of sex-biased transcriptional programs in hermaphrodites. We found that xol-1 mutant embryos overexpress the H3K9 methyltransferase MET-2 and have an altered H3K9me landscape. Some of these effects of the loss of xol-1 gene were reversed by the loss of met-2. These findings demonstrate that XOL-1 plays an important role as a developmental regulator in embryos of both sexes, and that MET-2 acts as a downstream effector of XOL-1 activity in hermaphrodites. Author summary: Various organisms have differing ways of determining, at a molecular level, what the sex of a developing embryo is supposed to be. The two sexes in the nematode C. elegans, hermaphrodite and male, have different numbers of X chromosomes. Hermaphrodites have two X chromosomes and males only have one. This mismatch raises an additional problem as hermaphrodites will have twice the amount of genes expressed from the X compared to males. This is solved by a process called dosage compensation, which equalizes gene expression between the sexes. A molecular sensor called XOL-1 detects the number of X chromosomes in an embryo and kick-starts the process of proper sexual development and/or dosage compensation. XOL-1 was known to be very important for activating male development but was believed to not have any role in the development of the hermaphrodite sex. We show that XOL-1 has some crucial roles in hermaphrodite embryos in controlling the rate of development of the embryo, and regulating the timing of dosage compensation. We also show that MET-2, a protein that deposits repressive methyl marks on DNA-bound histone proteins, is involved in this process. [ABSTRACT FROM AUTHOR]