Analysis of goat PPP6C mRNA profile, detection of genetic variations, and their associations with litter size.

The Protein Phosphatase 6 Catalytic Subunit (PPP6C) is evolutionarily a conserved gene in eukaryotes known to play a significant role in mammalian reproduction. This study aimed to investigate expression patterns of PPP6C and explore its association with litter size in Shaanbei white cashmere (SBWC) goats. Initially, we determined the mRNA expression levels of PPP6C in both male and female goats across multiple tissues. The results showed that PPP6C mRNA was expressed in multiple tissues, with higher levels in the testis and fallopian tubes, suggesting its involvement in goat reproduction. Additionally, we identified a novel 19 bp InDel within the PPP6C gene in a population of 1030 SBWC goats, which exhibited polymorphism. Statistical analysis revealed a significant association between the19 bp InDel mutation and litter size (P < 0.05). Subsequent, bioinformatics analysis, including linkage disequilibrium (LD) block and selective scanning, highlighted the linkage tendency among most InDel loci did not stand out within B-8 block, there were still some InDel loci linked to the 19 bp within a relatively narrow region. Furthermore, comparative analysis with Bezoars, these selective signals all indicated that this gene was under higher selection pressure, implying that the 19 bp InDel locus within the PPP6C is potentially associated with domesticated traits, particularly in relation to litter size. The results of the present study suggest that the PPP6C is a vital candidate gene affecting prolificacy in goats, with implications for selective breeding programs for goat breeds.

Ancestry analysis using a self-developed 56 AIM-InDel loci and machine learning methods.

Insertion/deletion (InDel) polymorphisms can be used as one of the ancestry-informative markers in ancestry analysis. In this study, a self-developed panel consisting of 56 ancestry-informative InDels was used to investigate the genetic structures and genetic relationships between Chinese Inner Mongolia Manchu group and 26 reference populations. The Inner Mongolia Manchu group was closely related in genetic background to East Asian populations, especially the Han Chinese in Beijing. Moreover, populations from northern and southern East Asia displayed obvious variations in ancestral components, suggesting the potential value of this panel in distinguishing the populations from northern and southern East Asia. Subsequently, four machine learning models were performed based on the 56 AIM-InDel loci to evaluate the performance of this panel in ancestry prediction. The random forest model presented better performance in ancestry prediction, with 91.87% and 99.73% accuracy for the five and three continental populations, respectively. The individuals of the Inner Mongolia Manchu group were assigned to the East Asian populations by the random forest model, and they exhibited closer genetic affinities with northern East Asian populations. Furthermore, the random forest model distinguished 87.18% of the Inner Mongolia Manchus from the East Asian populations, suggesting that the random forest model based on the 56 ancestry-informative InDels could be a potential tool for ancestry analysis.

The Detection of a Functional 168 bp Deletion of the HOXB13 Gene Determining Short Tail and Its Association with Senior Growth Traits in Sheep Breeds Worldwide.

In recent years, genome-wide association studies (GWAS) have uncovered that the HOXB13 gene is a key regulatory factor for the tail length trait of sheep. Further research has found that there is a functional 168 bp SINE element insertion upstream of the HOXB13 gene, which leads to the occurrence of long tails in sheep. However, the frequency of mutations in the 168 bp SINE element of the HOXB13 gene among different sheep breeds around the world and its relationship with growth traits are still unclear. This study used whole-genome sequencing (WGS) data, including 588 samples from 33 different sheep breeds around the world, to evaluate the frequency of HOXB13 gene mutations in different sheep breeds globally. At the same time, this study also selected 3392 sheep samples from six breeds. The genetic variation in the 168 bp InDel locus in the HOXB13 gene was determined through genotyping, and its association with the growth traits of Luxi black-headed sheep was analyzed. The research results indicate that the polymorphism of the 168 bp InDel locus is significantly correlated with the hip width of adult ewes in the Luxi black-headed sheep breed (p < 0.05) and that the hip width of adult ewes with the DD genotype is significantly larger than that of adult ewes with the ID genotype (p < 0.05). This study indicates that there is consistency between the research results on the sheep tail length trait and growth traits, which may contribute to the promotion of sheep breed improvement.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

Developing an SNP dataset for efficiently evaluating soybean germplasm resources using the genome sequencing data of 3,661 soybean accessions.

BACKGROUND: Single nucleotide polymorphism (SNP) markers play significant roles in accelerating breeding and basic crop research. Several soybean SNP panels have been developed. However, there is still a lack of SNP panels for differentiating between wild and cultivated populations, as well as for detecting polymorphisms within both wild and cultivated populations. RESULTS: This study utilized publicly available resequencing data from over 3,000 soybean accessions to identify differentiating and highly conserved SNP and insertion/deletion (InDel) markers between wild and cultivated soybean populations. Additionally, a naturally occurring mutant gene library was constructed by analyzing large-effect SNPs and InDels in the population. CONCLUSION: The markers obtained in this study are associated with numerous genes governing agronomic traits, thus facilitating the evaluation of soybean germplasms and the efficient differentiation between wild and cultivated soybeans. The natural mutant gene library permits the quick identification of individuals with natural mutations in functional genes, providing convenience for accelerating soybean breeding using reverse genetics.

Genetic variant of the sheep E2F8 gene and its associations with litter size.

The economic efficiency of sheep breeding, aiming to enhance productivity, is a focal point for improvement of sheep breeding. Recent studies highlight the involvement of the Early Region 2 Binding Factor transcription factor 8 (E2F8) gene in female reproduction. Our group's recent genome-wide association study (GWAS) emphasizes the potential impact of the E2F8 gene on prolificacy traits in Australian White sheep (AUW). Herein, the purpose of this study was to assess the correlation of the E2F8 gene with litter size in AUW sheep breed. This work encompassed 659 AUW sheep, subject to genotyping through PCR-based genotyping technology. Furthermore, the results of PCR-based genotyping showed significant associations between the P1-del-32bp bp InDel and the fourth and fifth parities litter size in AUW sheep; the litter size of those with genotype ID were superior compared to those with DD and II genotypes. Thus, these results indicate that the P1-del-32bp InDel within the E2F8 gene can be useful in marker-assisted selection (MAS) in sheep.

Angiotensin-converting enzyme I/D gene polymorphism and risk of type 2 diabetes mellitus in Iranian individuals.

This study aimed to examine the relationship between type 2 diabetes mellitus (T2DM) and renin-angiotensin system gene polymorphisms in the Iranian population. Additionally, we performed a straightforward meta-analysis of the present articles to better understand this role. A total of 100 Iranian individuals, 50 patients with T2DM, and 50 age-matched healthy individuals were included in this study. DNA was extracted using the salting-out approach, polymerase chain reaction was used to amplify the angiotensin-converting enzyme (ACE) gene, electrophoresis techniques were used, and genotyping was performed. We also searched PubMed, Web of Science, Scopus, and Google Scholar databases for papers published in 2023. We found a significantly higher frequency of I/D genotype in the patient group than in the control group, and the risk of T2DM was 10 times higher in individuals with the I/D genotype (OR, 10 [95% CI, 3.7 to 27]; p < 0.0001) and also 2.85 time higher in individuals with the D allele OR, 2.85 [95% CI, 1.55 to 5.24]; p < 0.001). The ACE polymorphism alleles D and I/D genotypes may increase the risk of developing T2DM in an Iranian population.

Systematical explorations of forensic feature and population genetic diversity of the Chinese Mongolian group from northwest China via a self-constructed Multi-InDel panel.

This study aimed to investigate the genetic polymorphisms and population characteristics of Chinese Mongolian group from northwest China (NCM) through a self-developed panel including 43 autosomal insertion/deletion (A-InDel) polymorphism genetic markers. Herein, 288 unrelated healthy individuals from the NCM group were employed to obtain the genetic data of 43 A-InDels through multiplex PCR amplification and InDel genotyping using capillary electrophoresis platform. In addition, multiplex population genetic analyses were performed between the NCM group and 27 reference populations. There were no deviations at 43 loci from Hardy-Weinberg equilibrium in the NCM group. The observed heterozygosity (Ho) values ranged from 0.312 8 to 0.559 2, and the combined power of discrimination (CPD) and cumulative probability of exclusion (CPE) values in the NCM group were 0.999 999 999 999 999 998 77 and 0.999 814, respectively. The forensic parameter values indicated that this panel was polymorphic and informative in the NCM group and could be used as an effective tool for forensic personal identification. Furthermore, the results of pairwise genetic distances, principal component analysis, multidimensional scaling analysis, phylogenetic tree construction, and admixture analysis among the NCM group and 27 reference populations revealed that there were closer genetic relationships between the NCM group and East Asian populations, especially Chinese Hui group (CHH) from the northwest China, which is consistent with the geographical location. These present findings contributed to the ongoing genetic explorations and insights into the genetic architecture of the NCM group.

Exploration of the Polymorphism Distribution of Bovine HMGA2 Gene in Worldwide Breeds and Its Associations with Ovarian Traits.

The high-mobility group AT-hook 2(HMGA2) gene has been widely studied in the context of cancer and animal growth. However, recently, several studies have uncovered its critical role in cell proliferation. A genome-wide association study (GWAS) further suggests that the HMGA2 gene is a candidate gene in fertility, indicating its connection not only to growth traits but also to reproduction, specifically ovarian traits. Thus, this study aimed to analyze the distribution of the HMGA2 gene in 54 bovine breeds worldwide, identify important short fragment variants (indels), and investigate the relationship between HMGA2 and ovarian development. The dataset included genotypic information from a bovine population of 634 individuals (n = 634). After genotyping and analyzing four selected loci, we found that one out of four loci, rs133750033 (P4-D22-bp), was polymorphic. Our results also reveal that this indel of HMGA2 is significantly associated with certain ovarian traits (p < 0.05). Specifically, it has connection with ovarian length (p = 0.004) and ovarian height (p = 0.026) during diestrus. Additionally, we discovered a higher expression of the HMGA2 gene in Asian cattle breeds. In summary, this study suggests that HMGA2 has the potential to serve as an animal fertility testing marker gene. Moreover, these findings contribute to a more promising outlook for the bovine industry.

A developmental validation of the Quick TargSeq 1.0 integrated system for automated DNA genotyping in forensic science for reference samples.

Analysis of short tandem repeats (STRs) is a global standard method for human identification. Insertion/Deletion polymorphisms (DIPs) can be used for biogeographical ancestry inference. Current DNA typing involves a trained forensic worker operating several specialized instruments in a controlled laboratory environment, which takes 6-8 h. We developed the Quick TargSeq 1.0 integrated system (hereinafter abbreviated to Quick TargSeq) for automated generation of STR and DIP profiles from buccal swab samples and blood stains. The system fully integrates the processes of DNA extraction, polymerase chain reaction (PCR) amplification, and electrophoresis separation using microfluidic biochip technology. Internal validation studies were performed using RTyper 21 or DIP 38 chip cartridges with single-source reference samples according to the Scientific Working Group for DNA Analysis Methods guidelines. These results indicated that the Quick TargSeq system can process reference samples and generate STR or DIP profiles in approximately 2 h, and the profiles were concordant with those determined using traditional STR or DIP analysis methods. Thus, reproducible and concordant DNA profiles were obtained from reference samples. Throughout the study, no lane-to-lane or run-to-run contamination was observed. The Quick TargSeq system produced full profiles from buccal swabs with at least eight swipes, dried blood spot cards with two 2-mm disks, or 10 ng of purified DNA. Potential PCR inhibitors (i.e., coffee, smoking tobacco, and chewing tobacco) did not appear to affect the amplification reactions of the instrument. The overall success rate and concordance rate of 153 samples were 94.12% and 93.44%, respectively, which is comparable to other commercially available rapid DNA instruments. A blind test initiated by a DNA expert group showed that the system can correctly produce DNA profiles with 97.29% genotype concordance with standard bench-processing methods, and the profiles can be uploaded into the national DNA database. These results demonstrated that the Quick TargSeq system can rapidly generate reliable DNA profiles in an automated manner and has the potential for use in the field and forensic laboratories.

Development of a novel five dye insertion/deletion (INDEL) panel for ancestry determination.

The use of genetic markers, specifically Short Tandem Repeats (STRs), has been a valuable tool for identifying persons of interest. However, the ability to analyze additional markers including Single Nucleotide Polymorphisms (SNPs) and Insertion/Deletion (INDELs) polymorphisms allows laboratories to explore other investigative leads. INDELs were chosen in this study because large panels can be differentiated by size, allowing them to be genotyped by capillary electrophoresis. Moreover, these markers do not produce stutter and are smaller in size than STRs, facilitating the recovery of genetic information from degraded samples. The INDEL Ancestry Informative Markers (AIMs) in this study were selected from the 1000 Genomes Project based on a fixation index (FST) greater than 0.50, high allele frequency divergence, and genetic distance. A total of 25 INDEL-AIMs were optimized and validated according to SWGDAM guidelines in a five-dye multiplex. To validate the panel, genotyping was performed on 155 unrelated individuals from four ancestral groups (Caucasian, African, Hispanic, and East Asian). Bayesian clustering and principal component analysis (PCA) were performed revealing clear separation among three groups, with some observed overlap within the Hispanic group. Additionally, the PCA results were compared against a training set of 793 samples from the 1000 Genomes Project, demonstrating consistent results. Validation studies showed the assay to be reproducible, tolerant to common inhibitors, robust with challenging casework type samples, and sensitive down to 125 pg. In conclusion, our results demonstrated the robustness and effectiveness of a 25 loci INDEL system for ancestry inference of four ancestries commonly found in the United States.

Exploring the Sheep MAST4 Gene Variants and Their Associations with Litter Size.

The economic efficiency of sheep breeding can be improved by enhancing sheep productivity. A recent genome-wide association study (GWAS) unveiled the potential impact of the MAST4 gene on prolificacy traits in Australian White sheep (AUW)). Herein, whole-genome sequencing (WGS) data from 26 different sheep breeds worldwide (n = 1507), including diverse meat, wool, milk, or dual-purpose sheep breed types from China, Europe, and Africa, were used. Moreover, polymerase chain reaction (PCR) genotyping of the MAST4 gene polymorphisms in (n = 566) Australian white sheep (AUW) was performed. The 3 identified polymorphisms were not homogeneously distributed across the 26 examined sheep breeds. Findings revealed prevalent polymorphisms (P3-ins-29 bp and P6-del-21 bp) with varying frequencies (0.02 to 0.97) across 26 breeds, while P5-del-24 bp was presented in 24 out of 26 breeds. Interestingly, the frequency of the P3-ins-29 bp variant was markedly higher in Chinese meat or dual-purpose sheep breeds, while the other two variants also showed moderate frequencies in meat breeds. Notably, association analysis indicated that all InDels were associated with AUW sheep litter size (p < 0.05). These results suggest that these InDels within the MAST4 gene could be useful in marker-assisted selection in sheep breeding.

Bases-dependent Rapid Phylogenetic Clustering (Bd-RPC) enables precise and efficient phylogenetic estimation in viruses.

Understanding phylogenetic relationships among species is essential for many biological studies, which call for an accurate phylogenetic tree to understand major evolutionary transitions. The phylogenetic analyses present a major challenge in estimation accuracy and computational efficiency, especially recently facing a wave of severe emerging infectious disease outbreaks. Here, we introduced a novel, efficient framework called Bases-dependent Rapid Phylogenetic Clustering (Bd-RPC) for new sample placement for viruses. In this study, a brand-new recoding method called Frequency Vector Recoding was implemented to approximate the phylogenetic distance, and the Phylogenetic Simulated Annealing Search algorithm was developed to match the recoded distance matrix with the phylogenetic tree. Meanwhile, the indel (insertion/deletion) was heuristically introduced to foreign sequence recognition for the first time. Here, we compared the Bd-RPC with the recent placement software (PAGAN2, EPA-ng, TreeBeST) and evaluated it in Alphacoronavirus, Alphaherpesvirinae, and Betacoronavirus by using Split and Robinson-Foulds distances. The comparisons showed that Bd-RPC maintained the highest precision with great efficiency, demonstrating good performance in new sample placement on all three virus genera. Finally, a user-friendly website (http://www.bd-rpc.xyz) is available for users to classify new samples instantly and facilitate exploration of the phylogenetic research in viruses, and the Bd-RPC is available on GitHub (http://github.com/Bin-Ma/bd-rpc).

TIROSEC: Molecular, Clinical and Histopathological Profile of Papillary Thyroid Carcinoma in a Colombian Cohort.

INTRODUCTION: In Colombia, thyroid cancer ranks among the highest incidences, yet our population lacks studies on its molecular profile. This study aims to characterize clinical, histopathologic and molecular data in a Colombian cohort with papillary thyroid carcinoma (PTC). METHODS: A retrospective review of clinical history, clinicopathologic characteristics, treatment and 5-10-year follow-up for all patients was done. DNA and RNA were extracted from formalin-fixed paraffin-embedded (FFPE) tissue using the Quick-DNA & RNA FFPE Min iPrep kit (Zymo Research). Next-generation sequencing (NGS) analysis was performed with SOPHiA Solid Tumor Solutions kit (SOPHiA GENETICS). Tumor mutation genomic analysis used SOPHiA DDM™ platform, with descriptive analysis reporting frequencies, means and associations via chi-square analysis. RESULTS: Among 231 sequenced patients, mean age at diagnosis was 46 (± 12.35) years, with higher frequency in women (81.82%). Two cases were reclassified as non-invasive follicular thyroid neoplasm (NIFT-P); an NRAS mutation was found in one of them. Predominant histologic subtype was classic PTC (57.64%) followed by tall cell (28.82%). Of the 229 sequenced carcinomas, mutations were identified in 186 cases, including BRAF, IDH1, RAS and PIK3CA. Notable copy number variations (CNVs) were PDGFRA, CDK4 and KIT, with RET being the most frequent gene fusion, including CCDC6-RET in two classic subtype cases. CONCLUSION: This is the first study in Colombia (TIROSEC) to our knowledge that integrates molecular and histopathologic profiles enriching our local comprehension and knowledge of PTC. The identification of target mutations such as BRAF, RET and NTRK fusions holds the potential to guide targeted therapies for tumor recurrence and predict aggressive behavior.

Development of a novel five-dye panel for human identification insertion/deletion (INDEL) polymorphisms.

DNA analysis of forensic case samples relies on short tandem repeats (STRs), a key component of the combined DNA index system (CODIS) used to identify individuals. However, limitations arise when dealing with challenging samples, prompting the exploration of alternative markers such as single nucleotide polymorphisms (SNPs) and insertion/deletion (INDELs) polymorphisms. Unlike SNPs, INDELs can be differentiated easily by size, making them compatible with electrophoresis methods. It is possible to design small INDEL amplicons (<200 bp) to enhance recovery from degraded samples. To this end, a set of INDEL Human Identification Markers (HID) was curated from the 1000 Genomes Project, employing criteria including a fixation index (FST) ≤ 0.06, minor allele frequency (MAF) >0.2, and high allele frequency divergence. A panel of 33 INDEL-HIDs was optimized and validated following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines, utilizing a five-dye multiplex electrophoresis system. A small sample set (n = 79 unrelated individuals) was genotyped to assess the assay's performance. The validation studies exhibited reproducibility, inhibition tolerance, ability to detect a two-person mixture from a 4:1 to 1:6 ratio, robustness with challenging samples, and sensitivity down to 125 pg of DNA. In summary, the 33-loci INDEL-HID panel exhibited robust recovery with low-template and degraded samples and proved effective for individualization within a small sample set.

ACE Gene I/D Polymorphism and Cardiometabolic Risk Factors: A Cross Sectional Study of Rural Population.

The D allele has been identified as being linked to cardiovascular disease since the discovery of an insertion/deletion (I/D) polymorphism in the ACE gene, this polymorphism has been found to have significant associations with a variety of cardiovascular risk factors. Recent findings indicate a rising prevalence of metabolic disorders among rural populations in developing nations. Research on health matters has been predominantly focused on urban populations, with relatively less attention given to their rural counterparts Hence, the present study attempts to estimate the prevalence of ACE gene I/D polymorphism and explore its association with various cardiovascular risk factors among Rural Yadav population from India. In the present study, 207 (Male 47, Female 160) members of the Yadav community participated in the cross-sectional study. All the socio-demographic factors, somatometric (anthropometric) variables, and the intravenous blood was collected and Physiological (blood pressure), and biochemical (fasting glucose and lipid profile) parameters were measured as recommended by the American Heart Association, allele-specific PCR of the ACE gene I/D polymorphism was carried out, the PCR products were genotyped on 2% agarose gel Electrophoresis and ACE gene polymorphism was analysed for its association with various cardiovascular risk factors. Among the analysed individuals, 34 (16.4%) were found to have the II genotype, 58 (28.0%) had the ID genotype, and 115 (55.6%) had the DD genotype. The allele frequency of the I allele was found to be 0.31, and the frequency of the D allele was 0.69. The frequency of the DD genotype was found to be significantly higher among individuals with high TC, high TG, and low non-HDL levels (p value < 0.05). When considered collectively, the findings of this study are consistent with the hypothesis that the DD genotype of ACE polymorphism represents a correlation with cardiovascular disease risk factors in this population.

An integrative framework for clinical diagnosis and knowledge discovery from exome sequencing data.

Non-silent single nucleotide genetic variants, like nonsense changes and insertion-deletion variants, that affect protein function and length substantially are prevalent and are frequently misclassified. The low sensitivity and specificity of existing variant effect predictors for nonsense and indel variations restrict their use in clinical applications. We propose the Pathogenic Mutation Prediction (PMPred) method to predict the pathogenicity of single nucleotide variations, which impair protein function by prematurely terminating a protein's elongation during its synthesis. The prediction starts by monitoring functional effects (Gene Ontology annotation changes) of the change in sequence, using an existing ensemble machine learning model (UniGOPred). This, in turn, reveals the mutations that significantly deviate functionally from the wild-type sequence. We have identified novel harmful mutations in patient data and present them as motivating case studies. We also show that our method has increased sensitivity and specificity compared to state-of-the-art, especially in single nucleotide variations that produce large functional changes in the final protein. As further validation, we have done a comparative docking study on such a variation that is misclassified by existing methods and, using the altered binding affinities, show how PMPred can correctly predict the pathogenicity when other tools miss it. PMPred is freely accessible as a web service at https://pmpred.kansil.org/, and the related code is available at https://github.com/kansil/PMPred.

Relationships between the mutations of the goat GATA binding protein 4 gene and growth traits.

Osteogenesis is a complex multilevel process regulated by multiple genes. The GATA binding protein 4 (GATA4) gene has been extensively studied for its pivotal role in bone genesis and bone differentiation. However, its relationship with the growth traits of Shaanbei white cashmere (SBWC) and Guizhou black (GB) goats remains unclear. This work aims to investigate the potential influence of genetic mutations in the GATA4 gene on the growth traits goats. Thus, two Insertion/deletion (InDel) polymorphisms (8-bp-InDel and 9-bp-InDel) were screened and detected in a total of 1161 goats (including 980 SBWC goats and 181 GB goats) using PCR and agarose gel electrophoresis. The analyses revealed that there were two genotypes (ID and DD) for these two loci. In SBWC goats, 8-bp-InDel and 9-bp-InDel loci were significantly associated with heart girth (HG) and hip width (HW). Notably, individuals with DD genotype of 8-bp-InDel locus were superior while those with DD genotype of 9-bp-InDel locus were inferior. Correlation analyses of the four combined genotypes revealed significant associations with cannon circumference (CC), body height (BH), HG and HW. This work provides a foundation for the application of molecular marker-assisted selection (MAS) in goat breeding programs. Furthermore, the findings highlight the potential of the GATA4 gene and its genetic variations as valuable indicators for selecting goats with desirable growth traits.

Unravelling the Role of Iroquois Homeobox 4 and its Interplay with Androgen Receptor in Prostate Cancer.

Genome-wide association studies have linked Iroquois-Homeobox 4 (IRX4) as a robust expression quantitative-trait locus associated with prostate cancer (PCa) risk. However, the intricate mechanism and regulatory factors governing IRX4 expression in PCa remain poorly understood. Here, we unveil enrichment of androgen-responsive gene signatures in metastatic prostate tumors exhibiting heightened IRX4 expression. Furthermore, we uncover a novel interaction between IRX4 and the androgen receptor (AR) co-factor, FOXA1, suggesting that IRX4 modulates PCa cell behavior through AR cistrome alteration. Remarkably, we identified a distinctive short insertion-deletion polymorphism (INDEL), upstream of the IRX4 gene that differentially regulates IRX4 expression through the disruption of AR binding. This INDEL emerges as the most significant PCa risk-associated variant within the 5p15 locus, in a genetic analysis involving 82,591 PCa cases and 61,213 controls and was associated with PCa survival in patients undergoing androgen-deprivation therapy. These studies suggest the potential of this INDEL as a prognostic biomarker for androgen therapy in PCa and IRX4 as a potential therapeutic target in combination with current clinical management.

Angiotensin-converting enzyme insertion/deletion gene polymorphism and the progression of cerebral microbleeds.

Background and purpose: The angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been studied as a genetic candidate for cerebral small vessel disease (CSVD). However, no previous study has evaluated the relationship between the ACE I/D polymorphism and cerebral microbleed (CMB), an important CSVD marker. We evaluated the association between ACE I/D polymorphisms and 2-year changes in CMBs. Methods: The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Of 256 subjects, 186 participants who underwent a 2-year follow-up brain scan and ACE genotyping were included. Our analysis was conducted by dividing the ACE genotype into two groups (DD vs. ID/II) under the assumption of the recessive effects of the D allele. A linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between the DD and combined ID/II genotypes. Results: Among 186 patients included in this study, 24 (12.9%) had the DD genotype, 91 (48.9%) had the ID genotype, and 71 (38.2%) had the II genotype. Baseline clinical characteristics and cerebral small vessel disease markers were not different between the two groups (DD vs. ID/II) except for the prevalence of hypertension (DD 66.7% vs. ID/II 84.6%; p = 0.04). A multivariate linear mixed-effects model showed that the DD carriers had a greater increase in total CMB counts than the ID/II carriers after adjusting for the baseline number of CMBs, age, sex, and hypertension (estimated mean of difference [standard error (SE)] = 1.33 [0.61]; p = 0.03). When we performed an analysis of cases divided into deep and lobar CMBs, only lobar CMBs were significantly different between the two groups (estimated mean of difference [SE] = 0.94 [0.42]; p = 0.02). Conclusion: The progression of CMBs over 2 years was greater in the ACE DD carriers compared with the combined II/ID carriers. The results of our study indicate a possible association between the ACE I/D polymorphism and CMB. A study with a larger sample size is needed to confirm this association.