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Sichuan donkeys are small-statured donkeys native to the plateau and mountainous regions of southwestern China. They are well-suited for transportation tasks in mountainous terrain and exhibit remarkable adaptability to the harsh environment, characterized by low temperatures and hypoxia. Adaptation to the local environment has shaped their unique genomic characteristics and is an important source of genetic variation. However, the genome-wide landscape of Sichuan donkeys remains undescribed. In this study, we obtained whole-genome sequencing data from 17 Sichuan donkeys and combined this data with published data of 99 donkeys from 9 other donkey breeds. We aimed to elucidate the population structure, genetic diversity, genetic differentiation, and selection pressure of Sichuan donkeys at the whole-genome level. Population structure and genetic diversity analysis showed that Sichuan donkeys were less influenced by the hybridization of foreign donkey breeds. They maintained a relatively pure lineage of Chinese native donkeys and exhibited higher genetic diversity. The study also found that Sichuan donkeys were genetically closest to Tibetan and Yunnan donkeys. Although their effective population size around 1000 years ago was smaller compared to Tibetan and Yunnan donkeys, it was still larger than that of other donkey breeds. Moreover, selective signature analysis (θπ, CLR, F This study clarified the genetic diversity, genetic differentiation, and effective population size of Sichuan donkeys by comparing them with other donkey breeds. Our findings contribute to deeper understanding of the high-altitude adaptability of Sichuan donkeys, and provide valuable information for the conservation and breeding of the breed. Show less

The clinical link between psoriasis (PsO) and cardiovascular diseases (CVDs) is well-established, yet the genetic underpinnings of their comorbidity remain unclear. This study aimed to systematically map the shared genetic architecture between PsO and CVDs to identify key risk loci, effector genes, and biological pathways. We analyzed large-scale genome-wide association study data for PsO and 11 CVDs to assess their genetic correlation. We then identified pleiotropic loci-variants associated with both PsO and CVDs-and applied colocalization analysis to test whether a single causal variant at each locus could explain the shared association. To interpret these findings, we performed functional annotation to map variants to genes and conducted heritability enrichment analysis to identify critical tissues. Finally, we performed an immune-specific colocalization analysis to investigate the role of distinct immune cell types in driving the shared disease risk. The findings revealed significant shared genetic risk between PsO and seven major CVDs (e.g., hypertension, myocardial infarction, and coronary artery disease). We identified 58 pleiotropic loci at the level of genome-wide significance (P < 5 × 10 Our systematic genetic analysis identifies shared loci and candidate genes for psoriasis and several cardiovascular diseases. The findings point toward immune-mediated pathways as potential links between these conditions and provide a prioritized list of targets warranting future functional study and therapeutic evaluation. Show less

The human genome is widely transcribed, with part of these transcribed regions producing stably expressed protein-coding or non-coding RNAs. Long intergenic non-coding RNAs (lincRNAs) are significantly differentially expressed in various cell lines and tissues. However, the influence of their transcription events remains unclear. In this study, we constructed a human genomic interaction network and found frequent interactions between lincRNA genes and protein-coding genes that are highly related to the occupancy of RNA polymerase II on the lincRNA gene. Interestingly, in the human genome interaction networks, the degree of lincRNA genes was significantly higher than that of protein-coding genes. The promoter regions of the protein-coding genes interacting with the lincRNA genes are enriched with R-loop structures, indicating that lincRNA may influence the target genes through R-loop structures. These promoters were enriched in more transcription factor binding sites. Furthermore, the whole network and sub-network could be utilized to explore potential biomarkers of leukemia. We found that zinc finger protein 668 (ZNF668), eosinophil granule ontogeny transcript (EGOT), and glutamate metabotropic receptor 7 (GRM7) could serve as novel biomarkers for acute myeloid leukemia (LMAL). Pasireotide acetate (CAS No. 396091-76-2) represents a potential drug for LMAL patients. These results suggested that potential biomarkers and corresponding drugs for cancer could be identified based on lincRNA-promoter network/sub-network topological parameters. Show less

Weining cattle is a Chinese indigenous breed influenced by complex breeding and geographical background. The multi-ethnic breeding culture makes Weining cattle require more attention as livestock resources for its genetic diversity. Here, we used 10 Weining cattle (five newly sequenced and five downloaded) and downloaded another 48 genome data to understand the aspects of Weining cattle: genetic diversity, population structure, and cold-adapted performance. In the current study, a high level of genetic diversity was found in Weining cattle, and its breed comprised two potential ancestries, which were Show less

The most common pathological subtype of renal carcinoma is RCC, and its development is closely related to immune infiltration. In our study, we investigated the relationship between zinc finger protein 668 and the prognostic risk, clinical characteristics, overall survival and related pathways. We analyzed the association between ZNF668 and immune cell infiltration through the TIMER database. The results showed that the expression of ZNF668 in RCC was higher than that in normal tissues (P < 0.001). The high expression of ZNF668 is clinically relevant, such as tumor stage (P = 0.001) and TNM classification (T: P = 7.37 e-04; N: P = 0.008; M: P < 0.001). Survival analysis showed that patients with high ZNF668 expression had a significantly poor prognosis (P = 0.023). Univariate analysis showed a significant decrease in overall survival in RCC patients with high ZNF668 expression (P = 0.023). Immuno-cell infiltration showed a significant decrease in CD4+ T cell and dendritic cell infiltration in RCC patients with high expression of ZNF668. GO/KEGG analysis showed that multiple pathways were differentially enriched in the high expression pathway of ZNF668, such as complement activation, and estrogen signaling pathway. In conclusion, high ZNF668 expression is a predictor in RCC. Show less

The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery. Show less

The number of tumor suppressor genes for which germline mutations have been linked to cancer risk is steadily increasing. However, while recent reports have linked constitutional normal tissue promoter methylation of BRCA1 and MLH1 to ovarian and colon cancer risk, the role of epigenetic alterations as cancer risk factors remains largely unknown, presenting an important area for future research. Currently, we lack fast and sensitive methods for assessment of promoter methylation status across known tumor suppressor genes. In this paper, we present a novel NGS-based approach assessing promoter methylation status across a large panel of defined tumor suppressor genes to base-pair resolution. The method omits the limitations related to commonly used array-approaches. Our panel includes 565 target regions covering the promoters of 283 defined tumor suppressors, selected by pre-specified criteria, and was applied for rapid targeted methylation-specific NGS. The feasibility of the method was assessed by analyzing normal tissue DNA (white blood cells, WBC) samples from 34 healthy postmenopausal women and by performing preliminary assessment of the methylation landscape of tumor suppressors in these individuals. The mean target coverage was 189.6x providing a sensitivity of 0.53%, sufficient for promoter methylation assessment of low-level methylated genes like BRCA1. Within this limited test-set, we detected 206 regions located in the promoters of 149 genes to be differentially methylated (hyper- or hypo-) at > 99% confidence level. Seven target regions in gene promoters (CIITA, RASSF1, CHN1, PDCD1LG2, GSTP1, XPA, and ZNF668) were found to be hyper-methylated in a minority of individuals, with a > 20 percent point difference in mean methylation across the region between individuals. In an exploratory hierarchical clustering analysis, we found that the individuals analyzed may be grouped into two main groups based on their WBC methylation profile across the 283 tumor suppressor gene promoters. Methylation-specific NGS of our tumor suppressor panel, with detailed assessment of differential methylation in healthy individuals, presents a feasible method for identification of novel epigenetic risk factors for cancer. Show less

The knowledge about the effects of environmental temperature on human epigenome is a potential key to understand the health impacts of temperature and to guide acclimation under climate change. We performed a systematic review on the epidemiological studies that have evaluated the association between environmental temperature and human epigenetic modifications. We identified seven original articles on this topic published between 2009 and 2019, including six cohort studies and one cross-sectional study. They focused on DNA methylation in elderly people (blood sample) or infants (placenta sample), with sample size ranging from 306 to 1798. These studies were conducted in relatively low temperature setting (median/mean temperature: 0.8-13 °C), and linear models were used to evaluate temperature-DNA methylation association over short period (≤28 days). It has been reported that short-term ambient temperature could affect global human DNA methylation. A total of 15 candidate genes (ICAM-1, CRAT, F3, TLR-2, iNOS, ZKSCAN4, ZNF227, ZNF595, ZNF597, ZNF668, CACNA1H, AIRE, MYEOV2, NKX1-2 and CCDC15) with methylation status associated with ambient temperature have been identified. DNA methylation on ZKSCAN4, ICAM-1 partly mediated the effect of short-term cold temperature on high blood pressure and ICAM-1 protein (related to cardiovascular events), respectively. In summary, epidemiological evidence about the impacts of environment temperature on human epigenetics remains scarce and limited to short-term linear effect of cold temperature on DNA methylation in elderly people and infants. More studies are needed to broaden our understanding of temperature related epigenetic changes, especially under a changing climate. Show less

Zinc finger protein 668 (ZNF668) is a recently discovered protein and its expression levels, as well as its involvement in the invasion and metastasis of non-small cell lung cancer (NSCLC), are largely unknown. In the present study, immunohistochemical analysis demonstrated that ZNF668 protein expression was decreased in lung tumors (51/167, 30.5%) compared with adjacent normal lung tissues (43/62, 69.4%; P<0.001). Subsequent statistical analysis revealed that ZNF668 expression was negatively associated with increased tumor-node-metastasis stage (P=0.019) and lymph node metastasis (P=0.002). Following ZNF668 downregulation by transfection of a Show less

Blood pressure rises with a drop in external temperature, but the role of DNA methylation in such blood pressure modulation has not been studied in detail. We evaluated blood pressure and DNA methylation of vascular disease-related genes in association with low temperature. To examine changes in blood pressure and DNA methylation associated with low temperature, we conducted repeated measures analysis among 50 participants over 3 repeated visits, and validated the association among another 52 participants. In addition, the mean of methylation changes in the identified CpG sites was evaluated with changes in blood pressure. Mediation analyses were also conducted to model the indirect association between low ambient temperature and blood pressure through changes in DNA methylation. With a 1°C decrease in temperature, increases of 0.6mmHg (standard error (SE), 0.2) in SBP and 0.3mmHg (SE, 0.1) in DBP occurred (P<0.05). Of 24,490 CpG sites in vascular genes, 2 CpG sites of zinc finger (ZNF) genes were significantly associated with temperature after Bonferroni's correction in discovery and replication data. A 10% increase in methylation expression in 2 CpG sites in ZNF genes was associated with a 4-mmHg elevation in DBP (SE, 1.8; P=0.0236). The hypermethylation was attributable to the association of ambient temperature with DBP (proportion of mediation=11.8-20.4%). Methylation changes in ZNF genes might be involved in the elevation of blood pressure when the body is exposed to cold temperature. Show less

Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695. Show less

Many tumor suppressors play an important role in the DNA damage pathway. Zinc finger protein 668 (ZNF668) has recently been identified as one of the potential tumor suppressors in breast cancer, but its function in DNA damage response is unknown. Herein, we report that ZNF668 is a regulator of DNA repair. ZNF668 knockdown impairs cell survival after DNA damage without affecting the ATM/ATR DNA-damage signaling cascade. However, recruitment of repair proteins to DNA lesions is decreased. In response to IR, ZNF668 knockdown reduces Tip60-H2AX interaction and impairs IR-induced histone H2AX hyperacetylation, thus impairing chromatin relaxation. Impaired chromatin relaxation causes decreased recruitment of repair proteins to DNA lesions, defective homologous recombination (HR) repair and impaired cell survival after IR. In addition, ZNF668 knockdown decreased RPA phosphorylation and its recruitment to DNA damage foci in response to UV. In both IR and UV damage responses, chromatin relaxation counteracted the impaired loading of repair proteins and DNA repair defects in ZNF668-deficient U2OS cells, indicating that impeded chromatin accessibility at sites of DNA breaks caused the DNA repair defects observed in the absence of ZNF668. Our findings suggest that ZNF668 is a key molecule that links chromatin relaxation with DNA damage response in DNA repair control. Show less

Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability. Show less

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. Show less