Screening of the Combined Risk of Genetics and Epidemiology on Infertility Among Indian Men: Synergistic Effect of AZFc Partial Deletions and Habits of Smokeless Chewing Tobacco.

The AZFc partial deletions of Y chromosome and lifestyle/epidemiological factors such as the use of smokeless chewing tobacco (SCT) exhibit intriguing variations in their association with male infertility across the population, ethnicity, and genetic background. Here, a pioneering attempt has been made to elucidate the interactions of such deletions with the habits of SCT consumption among the participating individuals, using their large epidemiological data. This screening program was conducted among Bengali-speaking men in West Bengal, India. We screened the prevalence and association of distinct partial deletions (gr/gr, b1/b3, and b2/b3) of the AZFc region using locus-specific sequence-tagged site (STS) markers among 728 case subjects and compared them with 264 ethnicity- and age-matched proven-fertile control men. The recorded epidemiological data of the study group and the outcome of partial deletion analysis were compiled to frame the plausible Gene × Epidemiological factor (G × E) interactions. The gr/gr deletion was reported to be significantly associated with azoospermic (p = .0015, odds ratio [OR] = 3.413) and oligozoospermic (p = .0382, OR = 3.012) case subgroups, and b1/b3 deletions were also detected among the infertile persons only. The G × E model revealed that men who carried microdeletions as well as were SCT users had an elevated risk of infertility (p = .002, OR = 6.38). The study highlights the fact that AZFc partial deletions and SCT, when co-occurred, synergistically increase the risk of infertility among men. This work helps to get more insight into the etiology of male infertility in the light of gene-environmental interaction.

Y-Chromosomal insights into the paternal genealogy of the Kerey tribe have called into question their descent from the Stepfather of Genghis Khan.

The Kerey is one of the prominent Kazakh tribes and has long been a subject of ethnographic scrutiny, with a lack of consensus on its origin and traditional genealogy. Their historical significance, intertwined with the emergence of the empire established by Genghis Khan, necessitates a comprehensive understanding of their genetic history. This study focuses on unraveling the genetic heritage of the Kerey tribe. We conducted a comprehensive analysis of Y-chromosome data from genetic genealogy as citizen science and genetic screening of 23 Y-STRs and 37 Y-SNPs on 207 males from the Kerey tribe within academic science. Our results reveal two prevalent phylogenetic lineages within the C2a1a3a-F3796 haplogroup, also known as the C2*-Star Cluster (C2*-ST), which is one of the founding paternal lineages of the ancient Niru'un clan of the Mongols: C2-FT411734 and C2-FT224144, corresponding to the Abak and Ashamaily clans. While indicating a common male ancestry for them, our findings challenge the notion that they are full siblings. Additionally, genetic diversity analysis of the Y-chromosomes in the Kerey tribe and Kazakhs confirms their kinship with the Uissun tribe but refutes the claim of the Abak clan's progenitor originating from this tribe. Furthermore, genetic evidence fails to support popular historical and ethnographic hypotheses regarding the Kerey tribe's kinship with the Uak, Sirgeli, Adai, Törtkara, Karakerey, and Kereyit Kazakh tribes. The absence of a genetic paternal connection with the Kereyt tribe raises doubts about the genealogical link between the Kerey tribe and the stepfather of Genghis Khan.

Evaluating the efficacy of three Y-STRs commercial kits in degraded skeletal remains.

Y chromosome short tandem repeats (Y-STRs) typing is a useful tool in scenarios such as mass graves analysis or disaster victim identification and has become a routine analysis in many laboratories. Not many comparisons have been performed with the currently available commercial kits, much less with degraded skeletal remains. This research aims to evaluate the performance of three commercial Y-STR kits: Yfiler™ Plus, PowerPlex® Y23, and Investigator® Argus Y-28 in 63 degraded skeletal remains from mass graves. PowerPlex® Y23 yields more reportable markers and twice the RFU on average, while Yfiler™ Plus and Investigator® Argus Y-28 exhibited a similar behaviour. Additionally, Argus Y-28, which has not been tested with this kind of samples in literature before, showed a good performance. Finally, a predictive model was attempted to be developed from quantification and autosomal STR data. However, no acceptable model could be obtained. Nevertheless, good Y-STR typing results may be expected if at least 50 pg DNA input is used or 13 autosomal markers were previously obtained.

Characterization of sequence variations in the extended flanking regions using massively parallel sequencing in 21 A-STRs and 21 Y-STRs.

In forensic genetics, utilizing massively parallel sequencing (MPS) to analyze short tandem repeats (STRs) has demonstrated several advantages compared to conventional capillary electrophoresis (CE). Due to the current technical limitations, although flanking region polymorphisms had been mentioned in several previous studies, most studies focused on the core repeat regions of STRs or the variations in the adjacent flanking regions. In this study, we developed an MPS system consisting of two sets of multiplex PCR systems to detect not only the STR core repeat regions but also to observe variants located at relatively distant positions in the flanking regions. The system contained 42 commonly used forensic STRs, including 21 autosomal STRs (A-STRs) and 21 Y-chromosomal STRs (Y-STRs), and a total of 350 male individuals from a Chinese Han population were genotyped. The length and sequence variants per locus were tallied and categorized based on length (length-based, LB), sequence without flanking region (core repeat regions sequence-based, RSB), and sequence with flanking region (core repeat and flanking regions sequence-based, FSB), respectively. Allele frequencies, Y-haplotype frequencies, and forensic parameters were calculated based on LB, RSB, and FSB, respectively, to evaluate the improvement in discrimination power, heterozygosity, and effectiveness of forensic systems. The results suggested the sequence variations have more influence on A-STRs and could improve the identification ability of MPS-STR genotyping. Concordance between MPS and CE methods was confirmed by using commercial CE-based STR kits. The impact of flanking region variations on STR genotype analysis and potential factors contributing to discordances were discussed. A total of 58 variations in the flanking regions (53 SNPs/SNVs and 5 InDels) were observed and most variations (48/58) were distributed in A-STRs. In summary, this study delved deeper into the genetic information of forensic commonly used STR and advanced the application of massively parallel sequencing in forensic genetics.

Genetic profile and ancestral polymorphism research of the Guizhou Shui and Dong ethnic groups using a novel self-developed AIM-InDel panel.

Insertion or deletion (InDel), a genetic marker with short insertion/deletion fragment length polymorphism, is widely used in the field of forensic biological research. The Guizhou Shui (Shui) ethnic group and Guizhou Dong (Dong) ethnic group are located in the southwestern region of China, with rich historical and cultural background. In this study, a self-developed panel included 56 ancestry informative marker (AIM)-InDel loci on the autosomes, three InDel loci on the Y chromosome, and one sex-determined Amelogenin locus. Firstly, we used the 56 autosomal loci to assess the forensic individual identification and paternity testing abilities in both the Shui and Dong groups. The cumulative probability of match and probability of exclusion for the Shui and Dong groups were 2.228×10-15 and 0.991518139; 7.604×10-16 and 0.992253273, respectively. In addition, we also conducted in-depth analyses for the genetic backgrounds and structures of the Shui and Dong groups based on 56 AIM-InDel loci. This research has found that the Shui and Dong groups have close genetic relationships with the East Asian populations. Meanwhile, we also found that the Shui group has a close genetic distance with Chinese Dai in Xishuangbanna (CDX). These insights provide vital information for the genetic structures of the Shui and Dong groups, as well as basic population data and molecular biological evidence support for individual identification and biogeographic ancestry inference in forensic genetic field.

Sex chromosome-encoded protein homologs: current progress and open questions.

The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the 'X-Y pairs.' The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X-Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease.

[Genetic analysis of a fetus with with 45,X/46,X,idic(Y)(q11.2) mosaicism].

OBJECTIVE: To explore the genetic characteristics of a fetus with sex chromosome abnormality indicated by non-invasive prenatal testing (NIPT) at 25+ gestational weeks. METHODS: A pregnant woman who was admitted to the Taizhou Hospital for abnormal NIPT result on January 6, 2023 was selected as the study subject. Relevant clinical data was collected. The fetus was subjected to chromosomal karyotyping analysis, copy number variation sequencing (CNV-seq), fluorescence in situ hybridization (FISH), and multiplex PCR assays. RESULTS: NIPT had suggested monosomy of X chromosome. The fetus was found to have a chromosomal karyotype of 45,X[59]/46,X,del(Y)(q11.2)[17] at 30+ weeks of gestational age. CNV-seq suggested the presence a 7.98 Mb deletion at Yq11.222q12 and a mosaicism 16.92 Mb deletion. FISH suggested that the fetus harbored two SRY genes and a mosaicism sex chromosomal abnormality, and multiplex PCR revealed that its AZF b+c region was completely deleted. C-banded karyotyping showed darkly stained dense mitotic granules at both ends of the Y chromosome. The fetus was ultimately determined as a 45,X/46,X,idic(Y)(q11.2) mosaicism. Following elected abortion, testing of the fetal tissue confirmed the presence of 45,X/46,XY mosaicism, and CNV-seq result of the placental tissue was compatible with that of NIPT. CNV-seq analysis of the couple revealed no obvious abnormality. CONCLUSION: With combined NIPT, karyotyping, CNV-seq, FISH and multiplex PCR assays, the fetus was diagnosed as a 45,X/46,X,idic(Y)(q11.2) mosaicism with deletion of the AZF b+c region. Above finding has enabled prenatal diagnosis for the fetus.

Normal sperm quality despite partial deletion of sY84 in the AZFa region: A case report.

BACKGROUND: The complete absence of the azoospermia factor A (AZFa) region typically results in nonobstructive azoospermia. Partial deletions of the AZFa region are particularly noteworthy due to the limited and enigmatic reports of partial deletions in the AZFa region. Here, we present a rare case report of partial deletion of sY84 in the AZFa region but exhibiting normal sperm quality. The aim of this case report is to gain a deeper insight into the impact of AZFa region deletion on male fertility and to guide future clinical decisions and treatment strategies. METHODS AND RESULTS: A 25-year-old man presented to the hospital with his 25-year-old wife due to recurrent spontaneous abortions. Routine semen analysis, sperm morphology analysis, acrosomal enzyme analysis, sperm DNA fragmentation indexed, and peripheral blood karyotype analysis revealed no abnormalities. Y chromosome microdeletion was detected by real-time fluorescence polymerase chain reaction, which showed that sY84 could not be amplified and sY86 was amplified nonspecifically. The man was diagnosed with partial deletions in the AZFa region. The wife underwent in vitro fertilization treatment for tubal infertility and recurrent spontaneous abortions. The couple successfully delivered a healthy daughter weighing 2.7 kg at 39 weeks of gestation, following 2 assisted reproductive pregnancies. CONCLUSION: Our findings contribute to expanding our knowledge of the AZFa region. A sY84 deficiency in the AZFa region may not lead to spermatogenesis failure and may potentially be one of the factors causing recurrent miscarriages, which needs to be confirmed by further data.

Sex Dimorphism in Pulmonary Arterial Hypertension Associated With Autoimmune Diseases.

Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed.

Interbreeding between farmers and hunter-gatherers along the inland and Mediterranean routes of Neolithic spread in Europe.

The Neolithic (i.e., farming and stockbreeding) spread from the Near East across Europe since about 9000 years before the common era (BCE) until about 4000 yr BCE. It followed two main routes, namely a sea route along the northern Mediterranean coast and an inland one across the Balkans and central Europe. It is known that the dispersive behavior of farmers depended on geography, with longer movements along the Mediterranean coast than along the inland route. In sharp contrast, here we show that for both routes the percentage of farmers who interbred with hunter-gatherers and/or acculturated one of them was strikingly the same (about 3.6%). Therefore, whereas the dispersive behavior depended on the proximity to the Mediterranean sea, the interaction behavior (incorporation of hunter-gatherers) did not depend on geographical constraints but only on the transition in the subsistence economy (from hunting and gathering to farming) and its associated way of life. These conclusions are reached by analyzing the clines of haplogroup K, which was virtually absent in hunter-gatherers and the most frequent mitochondrial haplogroup in early farmers. Similarly, the most frequent Y-chromosome Neolithic haplogroup (G2a) displays an inland cline that agrees with the percentage of interbreeding reported above.

Circum-Mediterranean influence in the Y-chromosome lineages associated with prostate cancer in Mexican men: A Converso heritage founder effect?

Prostate cancer is the second most common neoplasia amongst men worldwide. Hereditary susceptibility and ancestral heritage are well-established risk factors that explain the disparity trends across different ethnicities, populations, and regions even within the same country. The Y-chromosome has been considered a prototype biomarker for male health. African, European, Middle Eastern, and Hispanic ancestries exhibit the highest incidences of such neoplasia; Asians have the lowest rates. Nonetheless, the contribution of ancestry patterns has been scarcely explored among Latino males. The Mexican population has an extremely diverse genetic architecture where all the aforementioned ancestral backgrounds converge. Trans-ethnic research could illuminate the aetiology of prostate cancer, involving the migratory patterns, founder effects, and the ethnic contributions to its disparate incidence rates. The contribution of the ancestral heritage to prostate cancer risk were explored through a case-control study (152 cases and 372 controls) study in Mexican Mestizo males. Seventeen microsatellites were used to trace back the ancestral heritage using two Bayesian predictor methods. The lineage R1a seems to contribute to prostate cancer (ORadjusted:8.04, 95%CI:1.41-45.80) development, whereas E1b1a/E1b1b and GHIJ contributed to well-differentiated (Gleason ≤ 7), and late-onset prostate cancer. Meta-analyses reinforced our findings. The mentioned lineages exhibited a connection with the Middle Eastern and North African populations that enriched the patrilineal diversity to the southeast region of the Iberian Peninsula. This ancestral legacy arrived at the New World with the Spanish and Sephardim migrations. Our findings reinforced the contribution of family history and ethnic background to prostate cancer risk, although should be confirmed using a large sample size. Nonetheless, given its complex aetiology, in addition to the genetic component, the lifestyle and xenobiotic exposition could also influence the obtained results.

Developmental validation of the AGCU YNFS Y Kit: A new 6-dye multiplex system with 44 Y-STRs and 5 Y-InDels for forensic application.

With the widespread use of the Y chromosome in genetics, a lot of commercially available Y chromosome kits were developed, validated, and applied to forensic science practice. The AGCU YNFS Y Kit is a new Y chromosome system containing forty-four preferred Y short tandem repeats (Y-STRs) and five common Y-InDels. In this study, the AGCU YNFS Y system was validated to verify its performance by following the guidelines of the Scientific Working Group on DNA Analysis Methods (SWGDAM). A series of validation experiments included the following parameters: PCR-based studies, sensitivity studies, species specificity studies, stability studies, mixture studies, precision studies, stutter calculation, mutation and statistical analysis, population study, and case samples and degradation studies. The results suggested that appropriately changing PCR amplification conditions did not affect genotyping; the kit had good sensitivity for trace amounts of DNA (0.0625 ng), mixtures of multiple male individuals (minor: major = 1: 9), and three PCR inhibitors (more than 250 µM hematin, 250 ng/µL humic acid and 50 ng/µL tannic acid). The maximum standard deviation of allele size did not exceed 0.1552 reflecting the high accuracy of the system. By this, 87 DNA-confirmed pairs of father-son pairs were also analyzed for mutations. A total of 18 loci were mutated, with mutation rates ranging from 11.5×10-3 to 34.5×10-3 (95% CI 7.2×10-3-97.5×10-3, DYS627 and DYF404S1). In the population study, the haplotype diversity of 87 unrelated individuals was 0.9997, and discrimination capacity was 0.9885. Degradation studies have demonstrated that UV-C light exposure for up to 120 hours has no effect on male blood and semen-vaginal secretion mixtures. However, complete typing could no longer be obtained after 48 hours of UV exposure in single male saliva and in male saliva and female blood mixed samples. Collectively, the AGCU YNFS Y Kit is sensitive and accurate and can play its application value in forensic science practice.

Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure.

Heart failure affects millions of people worldwide, with men exhibiting a higher incidence than women. Our previous work has shown that mosaic loss of the Y chromosome (LOY) in leukocytes is causally associated with an increased risk for heart failure. Here, we show that LOY macrophages from the failing hearts of humans with dilated cardiomyopathy exhibit widespread changes in gene expression that correlate with cardiac fibroblast activation. Moreover, we identify the ubiquitously transcribed t et ratricopeptide Y-linked (Uty) gene in leukocytes as a causal locus for an accelerated progression of heart failure in male mice with LOY. We demonstrate that Uty disruption leads to epigenetic alterations in both monocytes and macrophages, increasing the propensity of differentiation into profibrotic macrophages. Treatment with a transforming growth factor-ß-neutralizing antibody prevented the cardiac pathology associated with Uty deficiency in leukocytes. These findings shed light on the mechanisms that contribute to the higher incidence of heart failure in men.

Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types.

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (∼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.

Loss of Y Chromosome and Cardiovascular Events in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease. METHODS: LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study, n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed. RESULTS: In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events. CONCLUSIONS: LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.

Comparing the roles of sex chromosome-encoded protein homologs in gene regulation.

The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.

Promoter hypermethylation of Y-chromosome gene PRKY as a potential biomarker for the early diagnosis of prostate cancer.

Aim: To develop a methylation marker of Y-chromosome gene in the early diagnosis of prostate cancer (PCa).Materials & methods: We utilized bioinformatics analysis to identify the expression and promoter methylation of Y-chromosome gene PRKY in PCa and other common malignancies. Single-center experiments were conducted to validate the diagnostic value of PRKY promoter methylation in PCa.Results:  PRKY expression was significantly down-regulated in PCa and its mechanism may be related to promoter methylation. PRKY promoter methylation is highly specific for the diagnosis of early PCa, which may be superior to prostate-specific antigen, mpMRI and other excellent molecular biomarkers.Conclusion:  PRKY promoter methylation may be a potential marker for the early and accurate diagnosis of PCa.

Developing excellent diagnostic methylation markers for #prostate cancer! Bioinformatics analysis and experimental verification revealing promoter methylation of Y-chromosome gene PRKY is helpful to identify early prostate cancer, which may be superior to other molecular biomarkers.