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Background: Alzheimer's disease (AD) heritability is estimated to be around 70–80%. Yet, much of it remains to be explained. Studying transmission patterns may help in understanding other factors contributing to the development of AD. Objective: In this study, we aimed to search for evidence of autosomal recessive or X- and Y-linked inheritance of risk factors in a large cohort of Portuguese AD patients. Methods: We collected family history from patients with AD and cognitively healthy controls over 75 years of age. We compared the proportions of maternal and paternal history in male and female patients and controls (to search for evidence of X-linked and Y-linked inherited risk factors). We compared the risk of developing AD depending on parents' birthplace (same vs. different), as a proxy of remote consanguinity. We performed linear regressions to study the association of these variables with different endophenotypes. Results: We included 3090 participants, 2183 cognitively healthy controls and 907 patients with AD. Men whose mother had dementia have increased odds of developing AD comparing to women whose mother had dementia. In female patients with a CSF biomarker-supported diagnosis of AD, paternal history of dementia is associated with increased CSF phosphorylated Tau levels. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated tau. Conclusions: Our study gives evidence supporting an increased risk of developing AD associated with an X-linked inheritance pattern and remote consanguinity. [ABSTRACT FROM AUTHOR]

Purpose: Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorly understood. This study focused on the neurological consequences of X-chromosome functional imbalances between sexes. Methods: Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated and contrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns and disease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus. Results: We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinically relevant genes in the context of rare genetic syndromes and brain waves modulation. Conclusion: Considering female-specific patterns on brain transcriptional programs becomes essential when designing health care strategies for mental and sleep illnesses with sex bias in prevalence. [ABSTRACT FROM AUTHOR]

Introduction: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. Aim: The present study aimed to trace the origin of the pathogenic variant in a well‐defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non‐carrier mothers. Methods: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two‐to‐three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique. Results: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather. Conclusion: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X‐chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant. [ABSTRACT FROM AUTHOR]

Population genetic inference of selection on the nucleotide sequence level often proceeds by comparison to a reference sequence evolving only under mutation and population demography. Among the few candidates for such a reference sequence is the 5' part of short introns (5SI) in Drosophila. In addition to mutation and population demography, however, there is evidence for a weak force favouring GC bases, likely due to GC -biased gene conversion (gBGC), and for the effect of linked selection. Here, we use polymorphism and divergence data of Drosophila melanogaster to detect and describe the forces affecting the evolution of the 5SI. We separately analyse mutation classes, compare them between chromosomes, and relate them to recombination rate frequencies. GC -conservative mutations seem to be mainly influenced by mutation and drift, with linked selection mostly causing differences between the central and the peripheral (i.e. telomeric and centromeric) regions of the chromosome arms. Comparing GC -conservative mutation patterns between autosomes and the X chromosome showed differences in mutation rates, rather than linked selection, in the central chromosomal regions after accounting for differences in effective population sizes. On the other hand, GC -changing mutations show asymmetric site frequency spectra, indicating the presence of gBGC, varying among mutation classes and in intensity along chromosomes, but approximately equal in strength in autosomes and the X chromosome. [ABSTRACT FROM AUTHOR]

Purpose: Analyze the relationship between changes in the proportion of Xchromosome deletions and clinical manifestations in children with Turner syndrome (TS). Methods: X-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence in situ hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed. Results: A total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis (r = 0.26, p = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease (p = 0.26), central nervous system, thyroid, or liver disease. Conclusion: The mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: A study was conducted to investigate five semen traits in Egyptian buffalo bulls using a single-step genome-wide association study for genomic evaluation. The study aimed to identify associated genomic regions and potential candidate genes. The X-chromosome was the most crucial, accounting for 23.43% of the overall genomic variance observed in these semen traits. Numerous potential candidate genes associated with the examined semen traits were identified within the genomic regions under investigation. In addition, a total of five new candidate genes were discovered within the genomic area examined for semen traits in Egyptian buffalo bulls. The present study aimed to contribute to the limited research on buffalo (Bubalus bubalis) semen traits by incorporating genomic data. A total of 8465 ejaculates were collected. The genotyping procedure was conducted using the Axiom® Buffalo Genotyping 90 K array designed by the Affymetrix Expert Design Program. After conducting a quality assessment, we utilized 67,282 SNPs genotyped in 192 animals. We identified several genomic loci explaining high genetic variance by employing single-step genomic evaluation. The aforementioned regions were located on buffalo chromosomes no. 3, 4, 6, 7, 14, 16, 20, 22, and the X-chromosome. The X-chromosome exhibited substantial influence, accounting for 4.18, 4.59, 5.16, 5.19, and 4.31% of the genomic variance for ejaculate volume, mass motility, livability, abnormality, and concentration, respectively. In the examined genomic regions, we identified five novel candidate genes linked to male fertility and spermatogenesis, four in the X-chromosome and one in chromosome no. 16. Additional extensive research with larger sample sizes and datasets is imperative to validate these findings and evaluate their applicability for genomic selection. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has uncovered many mysteries about SARS-CoV-2, including its potential to trigger abnormal autoimmune responses. Emerging evidence suggests women may face higher risks from COVID-induced autoimmunity manifesting as persistent neurological symptoms. Elucidating the mechanisms underlying this female susceptibility is now imperative. We synthesize key insights from existing studies on how COVID-19 infection can lead to immune tolerance loss, enabling autoreactive antibodies and lymphocyte production. These antibodies and lymphocytes infiltrate the central nervous system. Female sex hormones like estrogen and X-chromosome mediated effects likely contribute to dysregulated humoral immunity and cytokine profiles among women, increasing their predisposition. COVID-19 may also disrupt the delicate immunological balance of the female microbiome. These perturbations precipitate damage to neural damage through mechanisms like demyelination, neuroinflammation, and neurodegeneration – consistent with the observed neurological sequelae in women. An intentional focus on elucidating sex differences in COVID-19 pathogenesis is now needed to inform prognosis assessments and tailored interventions for female patients. From clinical monitoring to evaluating emerging immunomodulatory therapies, a nuanced women-centered approach considering the hormonal status and immunobiology will be vital to ensure equitable outcomes. Overall, deeper insights into the apparent female specificity of COVID-induced autoimmunity will accelerate the development of solutions mitigating associated neurological harm. [ABSTRACT FROM AUTHOR]

Objectives: The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. Methods: A serological analysis of humoral immune response against SARS-CoV-2, phenotypic characterization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed. Results: Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-γ production by cluster of differentiation (CD)4+ and CD8+ T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phorbol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8+ and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity. Conclusion: Following previous reports in the literature for other conditions, our data showed that patients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19.

The forensic DNA profiling technique has tremendously contributed to forensic human identification, an important aspect in forensic investigations. In instances whereby comparison samples are unavailable, utilization of short tandem repeats of X chromosome (X-STRs) may prove useful to resolve complex kinship investigations involving missing persons and mass disasters. Despite such evidential values, the use of X-STRs during investigations remains scarce in many Southeast Asian countries including Malaysia, requiring concerted efforts for establishing forensic statistical support for its diverse populations (especially the admixture populations), standardizing core loci and procedure, improving the knowledge among practitioners as well as developing suitable standard operating procedure for incorporating X-STRs analysis in the overall DNA profiling framework. Hence, this review paper aims to highlight the developments, applications and population data of X-STRs, as well as its challenges and future insights for forensic casework.

• Delayed or insufficient humoral immune response to SARS-CoV-2 in patients with Turner syndrome (TS). • Lower interferon-γ production in volunteers with TS after stimulation with toll-like receptors 7/8 agonists. • Higher cytotoxic activity by cluster of differentiation 8+ and natural killer cells after phorbol myristate acetate (PMA)/ionomycin stimuli in TS. The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. A serological analysis of humoral immune response against SARS-CoV-2, phenotypic characterization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed. Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-γ production by cluster of differentiation (CD)4+ and CD8+ T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phorbol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8+ and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity. Following previous reports in the literature for other conditions, our data showed that patients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19. [ABSTRACT FROM AUTHOR]

Abstract Background The X-chromosome short tandem repeat (STR) polymorphisms are a particular tool in the fields of human population genetics and personal identification. It was necessary in investigating complex kinship or deficiency cases in conditions where information on mitochondrial DNA (mtDNA) or Y chromosome polymorphisms have been used to explore their direct paternal line. This study aimed to investigate the allele frequency of (12X-STR) of 200 unrelated males from different region of Baghdad City to serve as a reference data base for individual identification in Iraqi population. Results Twelve X-STR loci (DXS7424, HPRTB, DXS8377, GATA31E08, DXS7423, DXS8378, DXS9895, DXS10074, DXS6809, DXS7133, DXS101, DXS6807) were successfully amplified by multiplex PCR and divided into four groups. According to measures of allele frequency, the higher alleles frequency were 16, 11, 46, 11, 14, 10, 15, 15.2, 35, 11, 25, and 11 while the lowest alleles frequency were 11, 9, 52,53, 7, 17, 14, 13, 12.2,17, 36, 15, 16, 22, 29, and 17 that observed at the 12 loci respectively. Forensic efficiency parameter for DXS8377 locus in the first group showed highest polymorphic allele in the Iraqi Arab population with the frequencies ranging from 0.005 to 0.16%. The power of discrimination (PD) value ranged from 0.663 for DXS7423 locus and 0.9066 for DXS8377 locus. In addition, the polymorphism information content (PIC) value ranged from 0.602974 for DXS7423 locus to 0.899206 for DXS8377 locus. Conclusions Overall the X-STR markers become used as an important source of information beside the autosomal and Y-STR markers, especially for kinship testing and haplotype analysis.

Background: The insertion/deletion polymorphism (InDel), an ideal forensic genetic marker with a low spontaneous mutation rate and small amplification product fragments, is widely distributed in the genome, combining the advantages of STR and SNP genetic markers. The X-chromosome has high application value in complex paternity testing, and it is an excellent system for evaluating population admixture and studying evolutionary anthropology. However, further research is needed on the population genetics of X-chromosome InDels (X-InDels). Methods: In this article, a system composed of 38 X-InDel loci was utilized to analyse and evaluate the forensic parameters of the Guizhou Han population in order to explore its forensic application efficiency. Results: The results showed that expected heterozygosities spanned from 0.0189 to 0.5715, and the cumulative power of discrimination of the 32 X-InDels and three linkage blocks was 0.9999999954 and 0.999999999999741 for males and females, respectively. The combined mean exclusion chance of these loci for trios and duos is 0.999999 and 0.999747, respectively. Multiple methods like principal component analysis, Fst genetic distance, and phylogenetic reconstruction were employed for dissecting the genetic structure of the Guizhou Han population by comparing it with previously reported populations. As expected, the studied Han population displayed relatively close genetic affinities with the East Asian populations. At the same time, there were obvious genetic differentiations between the Guizhou Han population and other continental populations that were discerned, especially for the African populations. Conclusions: This study further verified the applicability of 38 X-InDels for human personal identification and kinship analyses of Han Chinese, and also showed the application potential of X-InDels in population genetics. [ABSTRACT FROM AUTHOR]

X-chromosome and its independent loci recently gained importance in genetic investigations concerned with disease control-case studies, population genetic analyses, and phylogenetic investigations. Infertility and lack of normal reproduction are important issues in health. Aazoospermia is a kind of infertility in men whose semen contains no sperm and can affect about 1-20% of the male population. The majority of cases of spermatogenic failure in humans are idiopathic, and the underlying causes are postulated to be genetic. We analyze the potential association between seven X-Chromosome SNPs and the neighboring sequences with azoospermia in four ethnic populations in Iran. We also carried out population genetic analyses to produce data on genetic variability, population structure, gene flow, and time of divergence in these ethnic groups, for the first time. As the X-chromosome genes/SNPs are in homozygous condition, for the association study we used multivariate statistical methods, which revealed the potential role of variable sites close to the studied SNPs in male infertility. Haplotype groups were identified for each of the seven SNPs. The results showed gene flow among ethnic groups due to migration and inter-breeding and Bayesian analysis of sequence data suggested divergence time for ethnic populations to be between 2-30 KY. [ABSTRACT FROM AUTHOR]

Genes that are involved in the transcription process, mitochondrial function, glycoprotein metabolism, and ubiquitination dominate the list of 21 new genes associated with X‐linked intellectual disability since the last update in 2017. The new genes were identified by sequencing of candidate genes (2), the entire X‐chromosome (2), the whole exome (15), or the whole genome (2). With these additions, 42 (21%) of the 199 named XLID syndromes and 27 (25%) of the 108 numbered nonsyndromic XLID families remain to be resolved at the molecular level. Although the pace of discovery of new XLID genes has slowed during the past 5 years, the density of genes on the X chromosome that cause intellectual disability still appears to be twice the density of intellectual disability genes on the autosomes. [ABSTRACT FROM AUTHOR]

Males with X‐linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very long‐chain fatty acids (VLCFA), including C26:0‐lysophosphatidylcholine (C26:0‐LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives. The Dutch Health Council recommended to screen only male newborns for ALD without identifying untreatable conditions associated with elevated C26:0‐LPC, like Zellweger spectrum disorders and single peroxisomal enzyme defects. Here, we present the results of the SCAN (Screening for ALD in the Netherlands) study which is the first sex‐specific newborn screening program worldwide. Males with ALD are identified based on elevated C26:0‐LPC levels, the presence of one X‐chromosome and a variant in ABCD1, in heel prick dried bloodspots. Screening of 71 208 newborns resulted in the identification of four boys with ALD who, following referral to the pediatric neurologist and confirmation of the diagnosis, enrolled in a long‐term follow‐up program. The results of this pilot show the feasibility of employing a boys‐only screening algorithm that identifies males with ALD without identifying untreatable conditions. This approach will be of interest to countries that are considering ALD newborn screening but are reluctant to identify girls with ALD because for girls there is no direct health benefit. We also analyzed whether gestational age, sex, birth weight and age at heel prick blood sampling affect C26:0‐LPC concentrations and demonstrate that these covariates have a minimal effect. [ABSTRACT FROM AUTHOR]

The forensic DNA profiling technique has tremendously contributed to forensic human identification, an important aspect in forensic investigations. In instances whereby comparison samples are unavailable, utilization of short tandem repeats of X chromosome (X-STRs) may prove useful to resolve complex kinship investigations involving missing persons and mass disasters. Despite such evidential values, the use of X-STRs during investigations remains scarce in many Southeast Asian countries including Malaysia, requiring concerted efforts for establishing forensic statistical support for its diverse populations (especially the admixture populations), standardizing core loci and procedure, improving the knowledge among practitioners as well as developing suitable standard operating procedure for incorporating X-STRs analysis in the overall DNA profiling framework. Hence, this review paper aims to highlight the developments, applications and population data of X-STRs, as well as its challenges and future insights for forensic casework. [ABSTRACT FROM AUTHOR]

The present study aimed to contribute to the limited research on buffalo (Bubalus bubalis) semen traits by incorporating genomic data. A total of 8465 ejaculates were collected. The genotyping procedure was conducted using the Axiom® Buffalo Genotyping 90 K array designed by the Affymetrix Expert Design Program. After conducting a quality assessment, we utilized 67,282 SNPs genotyped in 192 animals. We identified several genomic loci explaining high genetic variance by employing single-step genomic evaluation. The aforementioned regions were located on buffalo chromosomes no. 3, 4, 6, 7, 14, 16, 20, 22, and the X-chromosome. The X-chromosome exhibited substantial influence, accounting for 4.18, 4.59, 5.16, 5.19, and 4.31% of the genomic variance for ejaculate volume, mass motility, livability, abnormality, and concentration, respectively. In the examined genomic regions, we identified five novel candidate genes linked to male fertility and spermatogenesis, four in the X-chromosome and one in chromosome no. 16. Additional extensive research with larger sample sizes and datasets is imperative to validate these findings and evaluate their applicability for genomic selection.

In many domains, including cognition and personality, greater variability is observed in males than in females in humans. However, little is known about how variability differences between sexes are represented in the brain. The present study tested whether there is a sex difference in variance in brain structure using a cohort of 643 males and 591 females aged between 3 and 21 years. The broad age-range of the sample allowed us to test if variance differences in the brain differ across age. We observed significantly greater male than female variance for several key brain structures, including cerebral white matter and cortex, hippocampus, pallidum, putamen, and cerebellar cortex volumes. The differences were observed at both upper and lower extremities of the distributions and appeared stable across development. These findings move beyond mean levels by showing that sex differences were pronounced for variability, thereby providing a novel perspective on sex differences in the developing brain.

Spermatogenesis is regulated by complex tissue specific gene expression in the testis to achieve normal male fertility. X‐chromosome specific TATA binding protein (TBP)‐associated factor 7L (hTAF7L) is one of the transcriptional regulator genes considered essential for spermatogenesis. The aim of this study was to evaluate the role of variants/mutations in the testis‐specific hTAF7L gene in non‐obstructive azoospermia and severe oligozoospermia male infertility. We studied 156 idiopathic non‐obstructive azoospermic, severe oligozoospermic infertile males and 50 fertile proven controls. Infertile males and control subjects were genotyped for variants of the hTAF7L gene using polymerase chain reaction and a direct Sanger sequencing approach. The odds ratio evaluated the association of hTAF7L gene variants with idiopathic male infertility. The variants found in the hTAF7L gene were subjected to an in‐silico analysis study. In infertile study subjects, we observed 11 single base pair nucleotide changes at various exons and three frameshift variants at exon 10 in the hTAF7L gene. We also found more than one variant in some non‐obstructive azoospermia and severe oligozoospermia infertile males along with control subjects. All these variants changed the amino acid sequences in the hTAF7L gene. However, similar changes were also seen in fertile subjects, and the differences were not statistically significant. In‐silico tools also predicted that the variants were likely to be benign. The variants in cDNA of the hTAF7L gene were typical SNPs. It is found that the hTAF7L gene is highly polymorphic and these missense variants are not directly associated with male infertility. However, we feel that more studies are needed to elucidate the role of multiple variants of the hTAF7L gene in the process of normal spermatogenesis. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILD) are a group of heterogeneous progressive pulmonary disorders, characterised by tissue remodelling and/or fibrotic scarring of the lung parenchyma. ILD patients experience lung function decline with progressive symptoms, poor response to treatment, reduced quality of life and high mortality. ILD can be idiopathic or associated with systemic or connective tissue diseases (CTD) but idiopathic pulmonary fibrosis (IPF) is the most common form. While IPF has a male predominance, women are affected more greatly by CTD and therefore associated ILDs. The mechanisms behind biological sex differences in these progressive lung diseases remain unclear. However, differences in environmental exposures, variable expression of X-chromosome related inflammatory genes and sex hormones play a role. Here, we will outline sex-related differences in the incidence, progression and mechanisms of action of these diseases and discuss existing and novel cellular and pre-clinical studies. Furthermore, we will highlight how sex-differences are not adequately considered in pre-clinical disease models, how gender bias exists in clinical diagnosis and how women are underrepresented in clinical trials. Future action on these observations will hopefully shed light on the role of biological sex in disease development, identify potential targets for intervention and increase female participant numbers in clinical trials. [ABSTRACT FROM AUTHOR]

Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular diagnosis. Here, we report our experimental work that aimed to uncover the developmental and genetic basis of the anophthalmia characterising the X-linked Ie (eye-ear reduction) X-ray-induced allele in mouse that was first identified in 1947. Histological analysis of the embryonic phenotype showed failure of normal eye development after the optic vesicle stage with particularly severe malformation of the ventral retina. Linkage analysis mapped this mutation to a ~6 Mb region on the X chromosome. Short- and long-read whole-genome sequencing (WGS) of affected and unaffected male littermates confirmed the Ie linkage but identified no plausible causative variants or structural rearrangements. These analyses did reduce the critical candidate interval and revealed evidence of multiple variants within the ancestral DNA, although none were found that altered coding sequences or that were unique to Ie. To investigate early embryonic events at a genetic level, we then generated mouse ES cells derived from male Ie embryos and wild type littermates. RNA-seq and accessible chromatin sequencing (ATAC-seq) data generated from cultured optic vesicle organoids did not reveal any large differences in gene expression or accessibility of putative cis-regulatory elements between Ie and wild type. However, an unbiased TF-footprinting analysis of accessible chromatin regions did provide evidence of a genome-wide reduction in binding of transcription factors associated with ventral eye development in Ie, and evidence of an increase in binding of the Zic-family of transcription factors, including Zic3, which is located within the Ie-refined critical interval. We conclude that the refined Ie critical region at chrX: 56,145,000–58,385,000 contains multiple genetic variants that may be linked to altered cis regulation but does not contain a convincing causative mutation. Changes in the binding of key transcription factors to chromatin causing altered gene expression during development, possibly through a subtle mis-regulation of Zic3, presents a plausible cause for the anophthalmia phenotype observed in Ie, but further work is required to determine the precise causative allele and its genetic mechanism. [ABSTRACT FROM AUTHOR]

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Condensins are molecular motors that compact DNA via linear translocation. In Caenorhabditis elegans, the X-chromosome harbors a specialized condensin that participates in dosage compensation (DC). Condensin DC is recruited to and spreads from a small number of recruitment elements on the X-chromosome (rex) and is required for the formation of topologically associating domains (TADs). We take advantage of autosomes that are largely devoid of condensin DC and TADs to address how rex sites and condensin DC give rise to the formation of TADs. When an autosome and X-chromosome are physically fused, despite the spreading of condensin DC into the autosome, no TAD was created. Insertion of a strong rex on the X-chromosome results in the TAD boundary formation regardless of sequence orientation. When the same rex is inserted on an autosome, despite condensin DC recruitment, there was no spreading or features of a TAD. On the other hand, when a ‘super rex’ composed of six rex sites or three separate rex sites are inserted on an autosome, recruitment and spreading of condensin DC led to the formation of TADs. Therefore, recruitment to and spreading from rex sites are necessary and sufficient for recapitulating loop-anchored TADs observed on the X-chromosome. Together our data suggest a model in which rex sites are both loading sites and bidirectional barriers for condensin DC, a one-sided loop-extruder with movable inactive anchor.

Genetic association studies have been very successful at elucidating the genetic background of many complex diseases/traits. However, the X-chromosome is often neglected in these studies because of technical difficulties and the fact that most tools only utilize genetic data from autosomes. In this review, we aim to provide an overview of different practical approaches that are followed to incorporate the X-chromosome in association analysis, such as Genome-Wide Association Studies and Expression Quantitative Trait Loci Analysis. In general, the choice of which test statistics is most appropriate will depend on three main criteria: (1) the underlying X-inactivation model, (2) if Hardy–Weinberg equilibrium holds and sex-specific allele frequencies are expected and (3) whether adjustment for confounding variables is required. All in all, it is recommended that a combination of different association tests should be used for the analysis of X-chromosome. [ABSTRACT FROM AUTHOR]

Background: The X-chromosome short tandem repeat (STR) polymorphisms are a particular tool in the felds of human population genetics and personal identifcation. It was necessary in investigating complex kinship or def‑ ciency cases in conditions where information on mitochondrial DNA (mtDNA) or Y chromosome polymorphisms have been used to explore their direct paternal line. This study aimed to investigate the allele frequency of (12X-STR) of 200 unrelated males from diferent region of Baghdad City to serve as a reference data base for individual identifcation in Iraqi population. Results: Twelve X-STR loci (DXS7424, HPRTB, DXS8377, GATA31E08, DXS7423, DXS8378, DXS9895, DXS10074, DXS6809, DXS7133, DXS101, DXS6807) were successfully amplifed by multiplex PCR and divided into four groups. According to measures of allele frequency, the higher alleles frequency were 16, 11, 46, 11, 14, 10, 15, 15.2, 35, 11, 25, and 11 while the lowest alleles frequency were 11, 9, 52,53, 7, 17, 14, 13, 12.2,17, 36, 15, 16, 22, 29, and 17 that observed at the 12 loci respectively. Forensic efciency parameter for DXS8377 locus in the frst group showed high‑ est polymorphic allele in the Iraqi Arab population with the frequencies ranging from 0.005 to 0.16%. The power of discrimination (PD) value ranged from 0.663 for DXS7423 locus and 0.9066 for DXS8377 locus. In addition, the poly‑ morphism information content (PIC) value ranged from 0.602974 for DXS7423 locus to 0.899206 for DXS8377 locus. Conclusions: Overall the X-STR markers become used as an important source of information beside the autosomal and Y-STR markers, especially for kinship testing and haplotype analysis. [ABSTRACT FROM AUTHOR]

Background During the early 3rd millennium BCE migration from Pontic Steppe, mainly related to Yamnaya culture, has affected European populations both culturally and genetically, however, it has long been debated to what extent this migration was male-driven, and how this replacement process took place which eliminated partially/largely Neolithic male lines over time. Aim This paper aims to evaluate the influence of the Steppe migration on European Bronze Age populations by calculating both male and female genetic contributions of the Steppe-related ancestry to the European Bronze Age populations. With this approach, we will be able to clarify the hypotheses on whether it was male-biased migration or not. Subjects and methods To evaluate the genetic impact and the proportion of the Steppe-related ancestry to the European Bronze Age populations, we performed PCA and qpAdm analyses by using published genome-wide data. In addition, we quantified male and female genetic contribution into Europe by using the analysis of uniparental markers and the X-chromosome. Results The Steppe migration had a considerable impact on the genetic makeup of the Bronze Age European populations. The data suggest that the Steppe-related ancestry arriving into Central Europe was male-driven, dominantly in the Corded Ware culture populations and lesser in the Bell Beaker populations. In fact, there is no evidence that this migration had a significant input on the mitochondrial genetic pool of all European Bronze Age populations. Conclusions Our analyses suggest that the Steppe-related ancestry had genetic impact on mainly Central-Eastern Europe. Moreover, this migration was male-driven for most of the Central European populations belonging to the Corded Ware groups, and to a lesser extent for the Bell Beaker groups.

Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune disease that can affect multiple organs. While the exact disease etiology remains incompletely understood, there is a suggested influence of X-chromosome dosage in the pathogenesis of lupus. Here, we report a rare case of a female patient diagnosed with mosaic Turner syndrome and subsequently presenting with juvenile-onset SLE. DNA methylation patterns were analyzed in this patient and compared with age-matched female SLE controls, revealing higher methylation levels in interferon-regulated genes previously shown to be hypomethylated in SLE. These data provide a potential link between a gene-dose effect from the X-chromosome and the lupus-defining epigenotype. We hypothesize that the attenuated demethylation in interferon-regulated genes might provide a protective effect explaining the rarity of SLE in Turner syndrome. • A rare coexistence of Turner syndrome and lupus is reported. • Turner syndrome is associated with an attenuated lupus-associated epigenetic signature. • Epigenetics suggests a mechanistic explanation for the rarity of lupus in Turner syndrome. • Autosomal DNA methylation is linked to the gene-dose effect on the X-chromosome. [ABSTRACT FROM AUTHOR]

Sheep are one of the most important livestock species in Croatia, found mainly in the Mediterranean coastal and mountainous regions along the East Adriatic coast, well adapted to the environment and mostly kept extensively. Our main objective was therefore to map the positive selection of the X-chromosome (18,983 SNPs that passed quality control), since nothing is known about the adaptation genes on this chromosome for any of the breeds from the Balkan cluster. Analyses were performed on a sample of eight native Croatian breeds (101 females and 100 males) representing the East Adriatic metapopulation and on 10 mouflons (five females and males), all sampled in Croatia. Three classical within-population approaches (extreme Runs of Homozygosity islands, integrated Haplotype Score, and number of Segregating Sites by Length) were applied along with our new approach called Haplotype Richness Drop (HRiD), which uses only the information contained in male haplotypes. We have also shown that phylogenetic analyses, such as the Median-joining network, can provide additional information when performed with the selection signals identified by HRiD. Our new approach identifies positive selection signals by searching for genomic regions that exhibit a sudden decline in haplotype richness. In total, we identified 14 positive selection signals, 11 using the classical approach and three using the HRiD approach, all together containing 34 annotated genes. The most reliable selection signal was mapped by all four approaches in the same region, overlapping between 13.17 and 13.60 Mb, and assigned to the CA5B, ZRSR2, AP1S2, and GRPR genes. High repeatability (86%) of results was observed, as 12 identified selection signals were also confirmed in other studies with sheep. HRiD offers an interesting possibility to be used complementary to other approaches or when only males are genotyped, which is often the case in genomic breeding value estimations. These results highlight the importance of the X-chromosome in the adaptive architecture of domestic ruminants, while our novel HRiD approach opens new possibilities for research. [ABSTRACT FROM AUTHOR]

Hemophilia A is an X-linked recessive bleeding disorder caused by different mutations in factor VIII gene. This gene is located on the distal end of the long arm of X-chromosome (Xq28). The commonest gene defect in FVIII gene is intron 22 inversion mutation followed by intron 1 inversion mutation, occurring in about 45% and 5% of the patients, respectively. This disease affects the health and life quality of the affected individuals. Aim: To identify FVIII gene rearrangement involving intron 1 and intron 22 inversions, using real time polymerase chain reaction analysis. New primers were designed for qPCR assessment of intron 22 inversion mutation and intron 1 inversion mutation of factor VIII gene. The procedure was accomplished with 60 known cases of severe hemophilia A, 10 carriers and 10 negative control individuals. Intron 22 inversion mutation was detected in 29 cases out of 60 patients (48.3%). Intron 1 inversion mutation was not detected in any of the 60 patients (0%). In conclusion, our newly designed primers could be used as a relatively fast and non-complicated routine test for intron 22 inversion mutation. [ABSTRACT FROM AUTHOR]

Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.

Insertion/deletion (InDel) polymorphisms, as ideal forensic markers, show useful characteristics of both SNPs and STRs, such as low mutation rate, short amplicon size and general applicability of genotyping platform, and have been used in human identification, population genetics and biogeographic research in recent years. X-chromosome genetic markers are significant in population genetic studies and indispensable complements in some complex forensic cases. However, the population genetic studies of X-chromosome InDel polymorphisms (X-InDels) still need to be explored. In this study, the forensic utility of a novel panel including 38 X-InDel markers was evaluated in a sample of Han population from Henan province in China. It is observed that the heterozygosities ranged from 0.0054 to 0.6133, and the combined discrimination power was 1–9.18 × 10−17 for males and 1–7.22 × 10−12 for females respectively. The mean exclusion chance in trios and duos were 0.999999319 and 0.999802969 respectively. Multiple biostatistics methods, such as principal component analysis, genetic distances analysis, phylogenetic reconstruction, and structure analysis was used to reveal the genetic relationships among the studied Henan Han group and other 26 reference groups from 1,000 Genomes Project. As expected, the Henan Han population was clustered with East Asian populations, and the most intimate genetic relationships existed in three Han Chinese populations from Henan, Beijing and South China, and showed significant differences compared with other continental groups. These results confirmed the suitability of the 38 X-InDel markers both in individual identification and parentage testing in Han Chinese population, and simultaneously showed the potential application in population genetics. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a challenging polygenic disease because the genes that cause PCa remain largely elusive and are affected by several causal factors. Consequently, research continuously strives to identify a genetic marker which could be used as an indicator to predict the most vulnerable (i.e., predisposed) segments of the population to the disease or for the gene which may be directly responsible for PCa. To enhance the genetic etiology of PCa, this research sought to discover the key studies conducted in this field using data from the main journal publication search engines, as it was hoped that this could shed light on the main research findings from these studies, which in turn could assist in determining these genes or markers. From the research highlighted, the studies primarily used two kinds of markers: short tandem repeats or single-nucleotide polymorphisms. These markers were found to be quite prevalent in all the chromosomes within the research carried out. It also became apparent that the studies differed in both quantity and quality, as well as being conducted in a variety of societies. Links were also determined between the degree and strength of the relationship between these markers and the occurrence of the disease. From the studies identified, most recommended a larger and more diverse survey for the parameters which had not been studied before, as well as an increase in the size of the community (i.e., the population) being studied. This is an indication that work in this field is far from complete, and thus, current research remains committed toward finding genetic markers that can be used clinically for the diagnosis and screening of patients with PCa.

Many studies exclude loci that exhibit linkage disequilibrium (LD); however, high LD can signal reduced recombination around genomic features such as chromosome inversions or sex-determining regions. Chromosome inversions and sex-determining regions are often involved in adaptation, allowing for the inheritance of co-adapted gene complexes and for the resolution of sexually antagonistic selection through sex-specific partitioning of genetic variants. Genomic features such as these can escape detection when loci with LD are removed; in addition, failing to account for these features can introduce bias to analyses. We examined patterns of LD using network analysis to identify an overlapping chromosome inversion and sex-determining region in chum salmon. The signal of the inversion was strong enough to show up as false population substructure when the entire dataset was analyzed, while the effect of the sex-determining region on population structure was only obvious after restricting analysis to the sex chromosome. Understanding the extent and geographic distribution of inversions is now a critically important part of genetic analyses of natural populations. Our results highlight the importance of analyzing and understanding patterns of LD in genomic dataset and the perils of excluding or ignoring loci exhibiting LD. Blindly excluding loci in LD would have prevented detection of the sex-determining region and chromosome inversion while failing to understand the genomic features leading to high-LD could have resulted in false interpretations of population structure.

Abstract Background Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. Methods Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. Results Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR

Insertion/deletion (InDel) polymorphisms, as ideal forensic markers, show useful characteristics of both SNPs and STRs, such as low mutation rate, short amplicon size and general applicability of genotyping platform, and have been used in human identification, population genetics and biogeographic research in recent years. X-chromosome genetic markers are significant in population genetic studies and indispensable complements in some complex forensic cases. However, the population genetic studies of X-chromosome InDel polymorphisms (X-InDels) still need to be explored. In this study, the forensic utility of a novel panel including 38 X-InDel markers was evaluated in a sample of Han population from Henan province in China. It is observed that the heterozygosities ranged from 0.0054 to 0.6133, and the combined discrimination power was 1–9.18 × 10−17 for males and 1–7.22 × 10−12 for females respectively. The mean exclusion chance in trios and duos were 0.999999319 and 0.999802969 respectively. Multiple biostatistics methods, such as principal component analysis, genetic distances analysis, phylogenetic reconstruction, and structure analysis was used to reveal the genetic relationships among the studied Henan Han group and other 26 reference groups from 1,000 Genomes Project. As expected, the Henan Han population was clustered with East Asian populations, and the most intimate genetic relationships existed in three Han Chinese populations from Henan, Beijing and South China, and showed significant differences compared with other continental groups. These results confirmed the suitability of the 38 X-InDel markers both in individual identification and parentage testing in Han Chinese population, and simultaneously showed the potential application in population genetics.

Background: Microduplications are a rare cause of disease in X‐linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation. Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder. Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8‐kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223‐ and 204‐kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re‐arrangement. Conclusion: In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X‐chromosome can be helpful in undiagnosed cases of neurodevelopmental disease. [ABSTRACT FROM AUTHOR]

Abstract Background Microduplications are a rare cause of disease in X‐linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation. Methods We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder. Results Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8‐kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223‐ and 204‐kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re‐arrangement. Conclusion In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X‐chromosome can be helpful in undiagnosed cases of neurodevelopmental disease.

Interstitial lung diseases (ILD) are a group of heterogeneous progressive pulmonary disorders, characterised by tissue remodelling and/or fibrotic scarring of the lung parenchyma. ILD patients experience lung function decline with progressive symptoms, poor response to treatment, reduced quality of life and high mortality. ILD can be idiopathic or associated with systemic or connective tissue diseases (CTD) but idiopathic pulmonary fibrosis (IPF) is the most common form. While IPF has a male predominance, women are affected more greatly by CTD and therefore associated ILDs. The mechanisms behind biological sex differences in these progressive lung diseases remain unclear. However, differences in environmental exposures, variable expression of X-chromosome related inflammatory genes and sex hormones play a role. Here, we will outline sex-related differences in the incidence, progression and mechanisms of action of these diseases and discuss existing and novel cellular and pre-clinical studies. Furthermore, we will highlight how sex-differences are not adequately considered in pre-clinical disease models, how gender bias exists in clinical diagnosis and how women are underrepresented in clinical trials. Future action on these observations will hopefully shed light on the role of biological sex in disease development, identify potential targets for intervention and increase female participant numbers in clinical trials.

The ability of detecting adaptive (positive) selection in the genome has opened the possibility of understanding the genetic basis of population-specific adaptations genome-wide. Here, we present the analysis of recent selective sweeps, specifically in the X chromosome, in human populations from the third phase of the 1,000 Genomes Project using three different haplotype-based statistics. We describe instances of recent positive selection that fit the criteria of hard or soft sweeps, and detect a higher number of events among sub-Saharan Africans than non-Africans (Europe and East Asia). A global enrichment of neural-related processes is observed and numerous genes related to fertility appear among the top candidates, reflecting the importance of reproduction in human evolution. Commonalities with previously reported genes under positive selection are found, while particularly strong new signals are reported in specific populations or shared across different continental groups. We report an enrichment of signals in genes that escape X chromosome inactivation, which may contribute to the differentiation between sexes. We also provide evidence of a widespread presence of soft-sweep-like signatures across the chromosome and a global enrichment of highly scoring regions that overlap potential regulatory elements. Among these, enhancers-like signatures seem to present putative signals of positive selection which might be in concordance with selection in their target genes. Also, particularly strong signals appear in regulatory regions that show differential activities, which might point to population-specific regulatory adaptations.

The ability of detecting adaptive (positive) selection in the genome has opened the possibility of understanding the genetic basis of population-specific adaptations genome-wide. Here, we present the analysis of recent selective sweeps, specifically in the X chromosome, in human populations from the third phase of the 1,000 Genomes Project using three different haplotype-based statistics. We describe instances of recent positive selection that fit the criteria of hard or soft sweeps, and detect a higher number of events among sub-Saharan Africans than non-Africans (Europe and East Asia). A global enrichment of neural-related processes is observed and numerous genes related to fertility appear among the top candidates, reflecting the importance of reproduction in human evolution. Commonalities with previously reported genes under positive selection are found, while particularly strong new signals are reported in specific populations or shared across different continental groups. We report an enrichment of signals in genes that escape X chromosome inactivation, which may contribute to the differentiation between sexes. We also provide evidence of a widespread presence of soft-sweep-like signatures across the chromosome and a global enrichment of highly scoring regions that overlap potential regulatory elements. Among these, enhancers-like signatures seem to present putative signals of positive selection which might be in concordance with selection in their target genes. Also, particularly strong signals appear in regulatory regions that show differential activities, which might point to population-specific regulatory adaptations. [ABSTRACT FROM AUTHOR]

Introducción: La teoría de la mente refiere a la capacidad cognitiva de atribuir mente a los demás y de predecir y comprender su comportamiento en términos de entidades mentales como creencias, deseos e intenciones. Investigaciones recientes sugieren una distinción entre una teoría de la mente afectiva y una cognitiva, asignándoles un sustrato neuroanatómico específico. El Síndrome de Turner es un trastorno genético determinado por la deleción total o parcial del cromosoma X en el sexo femenino. Dadas las características biológicas, psicológicas y sociales encontradas en estas mujeres, pueden ser consideradas como una población relevante para el estudio de la teoría de la mente según parámetros biológicos como la expresión diferencial de los genes del cromosoma X. Objetivos y métodos: los objetivos de este estudio fueron describir la teoría de la mente cognitiva y afectiva en 22 mujeres con diagnóstico de Síndrome de Turner y determinar si existen perfiles distintivos de teoría de la mente asociados al cariotipo. Resultados y discusión: Los resultados indicaron que las mujeres con diagnóstico de Síndrome de Turner presentan dificultades generales en teoría de la mente, observándose un menor rendimiento en el aspecto cognitivo de esta capacidad. Asimismo, se encontró que un mayor daño genético se encuentra relacionado a mayores dificultades en la teoría de la mente cognitiva, vinculada a zonas corticales de procesamiento no automático.

Nowadays sexing of semen is slowly developing among dairy producers and farmers and benefit both the farmers and industry. Sexing of semen is used to sort out the healthy as well as more specific traits in which spermatozoa are separated into X-bearing or Y-bearing chromosome populations through either selection or sorting. The sex-sorted semen is collected from genetically superior animals so the result of milk production and quality of meat will get up to the expected level. The use of sex-sorted semen mainly produced the female heifer in dairy farms or herds which reduced the purchasing number and price of cattle from outside. Collectively, the rate of genetic change has been expected to increase by not more than 15% as a result of the increased selection of dams through sexed semen. [ABSTRACT FROM AUTHOR]

In this study, we investigate the forensic and population genetics properties of 21 X-chromosome markers (9 X-Alu insertions and 12 X-STRs) in a dataset composed of 716 individuals from 11 Western Mediterranean populations. The high values of combined forensic parameters indicate that this 21 X-loci panel can complement autosomal or uniparental markers in kinship analysis and complex deficient paternity testing in the populations studied. Population analyses revealed a lower differentiation between Western Mediterranean human groups for X-STRs than for X-Alu insertion polymorphisms. Moreover, X-chromosome markers suggest a sex-biased migration rate, confirming the predominance of patrilocality in this area. [ABSTRACT FROM AUTHOR]

Mammalian uniparental embryos are efficient models for genome imprinting research and allow studies on the contribution of the paternal and maternal genomes to early embryonic development. In this study, we analyzed different methods for production of bovine haploid androgenetic embryos (hAE) to elucidate the causes behind their poor developmental potential. Results indicate that hAE can be efficiently generated by using intracytoplasmic sperm injection and oocyte enucleation at telophase II. Although androgenetic haploidy does not disturb early development up to around the 8-cell stage, androgenetic development is disturbed after the time of zygote genome activation and hAE that reach the morula stage are less capable to reach the blastocyst stage of development. Karyotypic comparisons to parthenogenetic- and ICSI-derived embryos excluded chromosomal segregation errors as causes of the developmental constraints of hAE. However, analysis of gene expression indicated abnormal levels of transcripts for key long non-coding RNAs involved in X chromosome inactivation and genomic imprinting of the KCNQ1 locus, suggesting an association with X chromosome and some imprinted loci. Moreover, transcript levels of methyltransferase 3B were significantly downregulated, suggesting potential anomalies in hAE establishing de novo methylation. Finally, the methylation status of imprinted control regions for XIST and KCNQ1OT1 genes remained hypomethylated in hAE at the morula and blastocyst stages, confirming their origin from spermatozoa. Thus, our results exclude micromanipulation and chromosomal abnormalities as major factors disturbing the normal development of bovine haploid androgenotes. In addition, although the cause of the arrest remains unclear, we have shown that the inefficient development of haploid androgenetic bovine embryos to develop to the blastocyst stage is associated with abnormal expression of key factors involved in X chromosome activity and genomic imprinting.

Background: Androgen receptor (AR) has been described to play a prominent role in male breast cancer (MBC). It maps on chromosome X, and recent reports indicate that X-chromosome polysomy is frequent in MBC. Since the response to anti-androgen therapy may depend on AR polysomy and on its overexpression similarly to prostate cancer, the aim of the present study was to investigate the DNA methylation level of AR and its coregulators, especially those mapped on the X-chromosome, that may influence the activity of AR in MBC.Methods: The DNA methylation level of AR, MAGEA2, MAGEA11, MAGEC1, MAGEC2, FLNA, HDAC6, and UXT, mapped on the X-chromosome, was evaluated by quantitative bisulfite-NGS. Bioinformatic analysis was performed in a Galaxy Project environment using BWA-METH, MethylDackel, and Methylation Plotter tools. The study population consisted of MBC (41 cases) compared with gynecomastia (17 cases).Results:MAGEA family members, especially MAGEA2, MAGEA11, MAGEC, and UXT and HDAC6 showed hypomethylation of several CpGs, reaching statistical significance by the Kruskal–Wallis test (p < 0.01) in MBC when compared to gynecomastia. AR showed almost no methylation at all.Conclusions: Our study demonstrated for the first time that MAGEA family members mapped on the X-chromosome and coregulators of AR are hypomethylated in MBC. This may lead to their overexpression, enhancing AR activity.