Genetics and Molecular Biology, Volume: 44, Issue: 4, Published: 2021
  • FABP4 and omentin-1 gene expression in epicardial adipose tissue from coronary artery disease patients Human And Medical Genetics

    Miroshnikova, Valentina V.; Polyakova, Ekaterina A.; Pobozheva, Irina A.; Panteleeva, Aleksandra A.; Razgildina, Natalia D.; Kolodina, Diana A.; Belyaeva, Olga D.; Berkovich, Olga A.; Pchelina, Sofya N.; Baranova, Elena I.

    Abstract in English:

    Abstract Omentin-1 and fatty acid-binding protein 4 (FABP4) are adipose tissue adipokines linked to obesity-associated cardiovascular complications. The aim of this study was to investigate epicardial adipose tissue (EAT) omentin-1 and FABP4 gene expression in obese and non-obese patients with coronary artery disease (CAD). Omentin-1 and FABP4 mRNA levels in EAT and paired subcutaneous adipose tissue (SAT) as well as adipokine serum concentrations were assessed in 77 individuals (61 with CAD; 16 without CAD (NCAD)). EAT FABP4 mRNA level was decreased in obese CAD patients when compared to obese NCAD individuals (p=0.001). SAT FABP4 mRNA level was decreased in CAD patients compared to NCAD individuals without respect to their obesity status (p=0.001). Omentin-1 mRNA level in EAT and SAT did not differ between the CAD and NCAD groups. These findings suggest that omentin-1 gene expression in adipose tissue is not changed during CAD; downregulated FABP4 gene expression in SAT is associated with CAD while EAT FABP4 gene expression is decreased only in obesity-related CAD.
  • Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases Human And Medical Genetics

    Quaio, Caio Robledo D’Angioli Costa; Obando, María José Rivadeneira; Perazzio, Sandro Felix; Dutra, Aurelio Pimenta; Chung, Christine Hsiaoyun; Moreira, Caroline Monaco; Novo Filho, Gil Monteiro; Sacramento-Bobotis, Patricia Rossi; Penna, Michele Groenner; Souza, Rafaela Rogerio Floriano de; Cintra, Vivian Pedigone; Carnavalli, Juliana Emilia Prior; Silva, Rafael Alves da; Santos, Monize Nakamoto Provisor; Paixão, Daniele; Baratela, Wagner Antonio da Rosa; Olivati, Caroline; Spolador, Gustavo Marquezani; Pintao, Maria Carolina; Fornari, Alexandre Ricardo dos Santos; Burger, Matheus; Ramalho, Rodrigo Fernandes; Pereira, Otavio Jose Eulalio; Ferreira, Elisa Napolitano e; Mitne-Neto, Miguel; Kim, Chong Ae

    Abstract in English:

    Abstract Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.
  • Association between folate metabolism polymorphisms and breast cancer: a case-control study Human And Medical Genetics

    Gimenez-Martins, Ana Paula D’Alarme; Castanhole-Nunes, Márcia Maria Urbanin; Nascimento-Filho, Carlos Henrique Viesi do; Santos, Stéphanie Piacenti dos; Galbiatti-Dias, Ana Lívia Silva; Fernandes, Glaucia Maria de Mendonça; Cuzziol, Caroline Izak; Francisco, José Luis Esteves; Pavarino, Érika Cristina; Goloni-Bertollo, Eny Maria

    Abstract in English:

    Abstract We investigated the association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthetase (MTR A2756G), and methionine synthase reductase (MTRR A66G) polymorphisms involved in folate pathway and breast cancer risk, and the interaction between these polymorphisms and tobacco and alcohol consumption. Furthermore, we evaluated the association between these polymorphisms and clinicopathological variables. This case-control study included 606 Brazilian women, comprising 128 patients with breast cancer and 478 controls. MTHFR and MTR polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and MTRR polymorphisms using real-time PCR. Age ≥50 years (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.65-4.26; p<0.001) and alcohol consumption (OR: 1.76; 95% CI: 1.0-2.85; p=0.021) were associated with an increased risk of breast cancer. For MTHFR A1298C, we observed a reduced risk of developing breast cancer in the codominant model (genotype CC-OR: 0.22; 95% CI: 0.06-0.74; p=0.014), recessive model (OR: 0.22; 95% CI: 0.07-0.76 p=0.004), and log-additive model (OR: 0.70; 95% CI: 0.49-0.98; p=0.035). Women aged ≥50 years and those who are alcohol consumers had increased susceptibility to breast cancer, and MTHFR A1298C modulated the risk for this disease. This is the first study to evaluate the association between polymorphisms in folate metabolism and breast cancer in the northwest region of São Paulo State, Brazil.
  • NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms Human And Medical Genetics

    Zanette, Vanessa; Valle, Daniel do; Telles, Bruno Augusto; Robinson, Alan J.; Monteiro, Vaneisse; Santos, Mara Lucia S. F.; Souza, Ricardo Lehtonen R.; Benincá, Cristiane

    Abstract in English:

    Abstract Mitochondrial complex I (CI) deficiency is the most common oxidative phosphorylation disorder described. It shows a wide range of phenotypes with poor correlation within genotypes. Herein we expand the clinics and genetics of CI deficiency in the brazilian population by reporting three patients with pathogenic (c.640G>A, c.1268C>T, c.1207dupG) and likely pathogenic (c.766C>T) variants in the NDUFV1 gene. We show the mutation c.766C>T associated with a childhood onset phenotype of hypotonia, muscle weakness, psychomotor regression, lethargy, dysphagia, and strabismus. Additionally, this mutation was found to be associated with headaches and exercise intolerance in adulthood. We also review reported pathogenic variants in NDUFV1 highlighting the wide phenotypic heterogeneity in CI deficiency.
  • Expression of Ubiquitin-specific protease 7 in oral squamous cell carcinoma promotes tumor cell proliferation and invasion Human And Medical Genetics

    Yang, Xiaojie; Jin, Jiamin; Yang, Jinfeng; Zhou, Lihua; Mi, Sisi; Qi, Guangying

    Abstract in English:

    Abstract Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting oral cavity. Recent studies have demonstrated that Ubiquitin-specific protease 7 (USP7) was upregulated in several types of cancers. USP7 expression was associated with various proto-oncogenes and tumor suppressor genes. However, USP7 expression level and its functional role in OSCC is unclear. In the current study, we showed that USP7 expression in OSCC tissues was generally upregulated compared to normal adjacent tissues by using IHC. Furthermore, statistical analysis uncovered that USP7 expression was positively correlated with Ki-67, MMP2, VEGF in OSCC tissues. Importantly, high USP7 expression was significantly correlated with lymph node metastasis and histological differentiation in OSCC patients. So, our hypothesis is that USP7 plays a tumor-promoting role in OSCC. Knocking down of USP7 in tumor cells not only suppressed HSC3 cells proliferation, migration and invasion, but also promoted cell apoptosis. Moreover, USP7 siRNA blocked the activation of Akt/ERK signaling pathway. In conclusion, data presented here suggests that USP7 promotes the progression of OSCC. USP7 may be used as a new therapeutic target for OSCC diagnosis and treatment.
  • Impact of maternal dietary counseling in the first year of life on DNA methylation in a cohort of children Human And Medical Genetics

    Castilhos, Janaína Kehl de; Campagnolo, Paula Dal Bó; Almeida, Silvana de; Vitolo, Márcia Regina; Mattevi, Vanessa Suñé

    Abstract in English:

    Abstract Epigenetic modifications established during prenatal and early life, including DNA methylation, have been suggested as potential mediators of the interaction between environmental exposures during the perinatal period and adult metabolic health adverse outcomes, especially cardiometabolic complications and overweight. The effect of a dietary intervention in the first year of life on global methylation levels in leukocyte samples from a cohort of children born between 2001 and 2002 in southern Brazil was examined. Overall methylation measurements were performed using enzyme-linked immunosorbent assays on DNA samples from 237 children at 4 years old. Mean methylation values were higher in the intervention group (mean: 2.20 ± 1.31%) than in the control group (mean: 1.65 ± 1.11%; P = 0.001). It was observed that nutritional counseling in the first year increased breastfeeding duration and stimulated the development of healthier eating habits. Therefore, these factors might have contributed to increase global DNA methylation. The findings of the present study reinforce the notion that performing nutritional interventions in the early stages of life is important and provide further evidence of the interaction between the environment and epigenetic traits.
  • Telomere length in healthy newborns is not affected by adverse intrauterine environments Human And Medical Genetics

    Hahn, Monique Cabral; Werlang, Isabel Cristina Ribas; Rechenmacher, Ciliana; Morais, Rahuany Velleda de; Barbé-Tuana, Florencia María; Grun, Lucas Kich; Guma, Fátima Theresinha Costa Rodrigues; Silva, Clécio Homrich da; Bernardi, Juliana Rombaldi; Michalowski, Mariana Bohns; Goldani, Marcelo Zubaran

    Abstract in English:

    Abstract Different intrauterine exposures are associated with different metabolic profiles leading to growth and development characteristics in children and also relate to health and disease patterns in adult life. The objective of this work was to evaluate the impact of four different intrauterine environments on the telomere length of newborns. This is a longitudinal observational study using a convenience sample of 222 mothers and their term newborns (>37 weeks of gestational age) from hospitals in Porto Alegre, Rio Grande do Sul (Brazil), from September 2011 to January 2016. Sample was divided into four groups: pregnant women with Gestational Diabetes Mellitus (DM) (n=38), smoking pregnant women (TOBACCO) (n=52), mothers with small-for-gestational age (SGA) children due to idiopathic intrauterine growth restriction (n=33), and a control group (n=99). Maternal and newborn genomic DNA were obtained from epithelial mucosal cells. Telomere length was assessed by qPCR, with the calculation of the telomere and single copy gene (T/S ratio). In this sample, there was no significant difference in telomere length between groups (p>0.05). There was also no association between childbirth weight and telomere length in children (p>0.05). For term newborns different intrauterine environments seems not to influence telomere length at birth.
  • A new view on the scenario of karyotypic stasis in Epinephelidae fish: Cytogenetic, historical, and biogeographic approaches Animal Genetics

    Amorim, Karlla Danielle Jorge; Costa, Gideão Wagner Werneck Félix da; Cioffi, Marcelo de Bello; Tanomtong, Alongklod; Bertollo, Luiz Antônio Carlos; Molina, Wagner Franco

    Abstract in English:

    Abstract Epinephelidae (groupers) is an astonishingly diverse group of carnivorous fish widely distributed in reef environments around the world, with growing economic importance. The first chromosomal inferences suggested a conservative scenario for the family. However, to date, this has not been validated using biogeographic and phylogenetic approaches. Thus, to estimate karyotype diversification among groupers, eight species from the Atlantic and Indian oceans were investigated using conventional cytogenetic protocols and fluorescence in situ hybridization of repetitive sequences (rDNA, microsatellites, transposable elements). Despite the remarkable persistence of some symplesiomorphic karyotype patterns, such as all species sharing 2n=48 and most preserve a basal karyotype (2n=48 acrocentrics), the chromosomal diversification in the family revealed an unsuspected evolutionary dynamic, where about 40% of the species escape from the ancestral karyotype pattern. These karyotype changes showed a relation with the historical biogeography, likely as a byproduct of the progressive occupancy of new areas (huge diversity of adaptive and speciation conditions). In this context, oceanic regions harboring more recent clades such as those of the Indo-Pacific, exhibited a higher karyotype diversity. Therefore, the karyotype evolution of Epinephelidae fits well with the expansion and geographic contingencies of its clades, providing a more complex and diverse scenario than previously assumed.
  • Influence of hypoxia on biochemical aspects and on expression of genes related to oxygen-homeostasis of the Amazonian cichlid Astronotus ocellatus (Agassiz, 1831) Animal Genetics

    Vasconcelos-Lima, José L.; Oikawa-Cardoso, Vanessa L.; Heinrichs-Caldas, Waldir; Almeida-Val, Vera M. F.

    Abstract in English:

    Abstract Variations in dissolved oxygen levels are common in the Amazonian aquatic environments and the aquatic organisms that inhabit these environments developed a variety of adaptive responses to deal with such conditions. Some Amazonian fish species are tolerant to low oxygen levels and the cichlid Astronotus ocellatus is one of the most hypoxia-tolerant species. Herein, we aimed to unveil the biochemical and molecular responses that A. ocellatus presents when submitted to hypoxia. Hypoxia indicators were measured, such as plasma glucose, plasma lactate, hepatic glycogen and relative transcript levels of prolyl hydroxylase 2 (phd2) and hypoxia-inducible factor-1α (hif-1α) in juveniles of approximately 50 g exposed to 1, 3, and 5 hours of hypoxia (0.7 mg O2.L-1), followed by 3 hours of recovery in normoxia (6 mg O2.L-1). Fish exposed to hypoxia reduced liver glycogen levels within 3 hours of hypoxia, when comparing with 1 hour, and increased plasma glucose and lactate. Under the same condition, phd2 transcripts levels increased in gills, but decreased in liver. In contrast, hypoxia did not affect relative gene expression of hif-1α in both tissues. Based on the transcription pattern of phd2, these results showed that liver and gills of A. ocellatus have different molecular strategies to cope with environmental hypoxia.
  • Reconstruction of the Doradinae (Siluriformes-Doradidae) ancestral diploid number and NOR pattern reveals new insights about the karyotypic diversification of the Neotropical thorny catfishes Animal Genetics

    Takagui, Fábio H.; Viana, Patrik; Baumgärtner, Lucas; Bitencourt, Jamille A.; Margarido, Vladimir Pavan; Lui, Roberto Laridondo; Feldberg, Eliana; Birindelli, Jose Luis Olivan; Almeida, Fernanda Simões; Giuliano-Caetano, Lucia

    Abstract in English:

    Abstract Doradinae (Siluriformes: Doradidae) is the most species-rich subfamily among thorny catfishes, encompassing over 77 valid species, found mainly in Amazon and Platina hydrographic basins. Here, we analyzed seven Doradinae species using combined methods (e.g., cytogenetic tools and Mesquite ancestral reconstruction software) in order to scrutinize the processes that mediated the karyotype diversification in this subfamily. Our ancestral reconstruction recovered that 2n=58 chromosomes and simple nucleolar organizer regions (NOR) are ancestral features only for Wertheimerinae and the most clades of Doradinae. Some exceptions were found in Trachydoras paraguayensis (2n=56), Trachydoras steindachneri (2n=60), Ossancora punctata (2n=66) and Platydoras hancockii whose karyotypes showed a multiple NOR system. The large thorny catfishes, such as Pterodoras granulosus, Oxydoras niger and Centrodoras brachiatus share several karyotype features, with subtle variations only regarding their heterochromatin distribution. On the other hand, a remarkable karyotypic variability has been reported in the fimbriate barbells thorny catfishes. These two contrasting karyoevolution trajectories emerged from a complex interaction between chromosome rearrangements (e.g., inversions and Robertsonian translocations) and mechanisms of heterochromatin dispersion. Moreover, we believe that biological features, such as microhabitats preferences, populational size, low vagility and migratory behavior played a key role during the origin and maintenance of chromosome diversity in Doradinae subfamily.
  • Chloroplast genome characteristics and phylogenetic analysis of the medicinal plant Blumea balsamifera (L.) DC Plant Genetics

    Zhao, Chao; Xu, Wenfen; Huang, Yuan; Sun, Qingwen; Wang, Bo; Chen, Chunlin; Chen, Qiyu

    Abstract in English:

    Abstract Blumea balsamifera (L.) DC., a medicinal plant with high economic value in the Asteraceae family, is widely distributed in China and Southeast Asia. However, studies on the population structure or phylogenetic relationships with other related species are rare owing to the lack of genome information. In this study, through high-throughput sequencing, we found that the chloroplast genome of B. balsamifera was 151,170 bp in length, with a pair of inverted repeat regions (IRa and IRb) comprising 24,982 bp, a large single-copy (LSC) region comprising 82,740 bp, and a small single-copy (SSC) region comprising 18,466 bp. A total of 130 genes were identified in the chloroplast genome of B. balsamifera, including 85 protein-coding, 37 transfer RNA, and 8 ribosomal RNA genes; furthermore, sequence analysis identified 53 simple sequence repeats. Whole chloroplast genome comparison indicated that the inverted regions (IR) were more conserved than large single-copy and SSC regions. Phylogenetic analysis showed that B. balsamifera is closely related to Pluchea indica. Conclusively, the chloroplast genome of B. balsamifera was helpful for species identification and analysis of the genetic diversity and evolution in the genus Blumea and family Asteraceae.
  • Integrated analysis of gene expression and DNA methylation datasets identified key genes and a 6-gene prognostic signature for primary lung adenocarcinoma Human And Medical Genetics

    Meng, Jing; Cao, Lei; Song, Huifang; Chen, Lichun; Qu, Zhiguo

    Abstract in English:

    Abstract Lung adenocarcinoma (LUAD) is the main subtype of non-small cell lung cancer with a poor survival prognosis. In our study, gene expression, DNA methylation, and clinicopathological data of primary LUAD were utilized to identify potential prognostic markers for LUAD, which were recruited from The Cancer Genome Atlas (TCGA) database. Univariate regression analysis showed that there were 21 methylation-associated DEGs related to overall survival (OS), including 9 down- and 12 up-regulated genes. The 12 up-regulated genes with hypomethylation may be risky genes, whereas the other 9 down-regulated genes with hypermethylation might be protective genes. By using the Step-wise multivariate Cox analysis, a methylation-associated 6-gene (consisting of CCL20, F2, GNPNAT1, NT5E, B3GALT2, and VSIG2) prognostic signature was constructed and the risk score based on this gene signature classified patients into high- or low-risk groups. Patients of the high-risk group had shorter OS than those of the low-risk group in both the training and validation cohort. Multivariate Cox analysis and the stratified analysis revealed that the risk score was an independent prognostic factor for LUAD patients. The methylation-associated gene signature may serve as a prognostic factor for LUAD patients and the represent hypermethylated or hypomethylated genes might be potential targets for LUAD therapy.
  • Primary cells derived from Tuberous Sclerosis Complex patients show autophagy alteration in the haploinsufficiency state Cellular, Molecular And Developmental Genetics

    Rosset, Clévia; Jaeger, Mariane da Cunha; Filippi-Chiela, Eduardo; Reis, Larissa Brussa; Sartor, Ivaine Taís Sauthier; Oliveira Netto, Cristina Brinckmann; Farias, Caroline Brunetto de; Roesler, Rafael; Ashton-Prolla, Patricia

    Abstract in English:

    Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant cancer predisposition disorder caused by heterozygous mutations in TSC1 or TSC2 genes and characterized by mTORC1 hyperactivation. TSC-associated tumors develop after loss of heterozygosity mutations and their treatment involves the use of mTORC1 inhibitors. We aimed to evaluate cellular processes regulated by mTORC1 in TSC cells with different mutations before tumor development. Flow cytometry analyses were performed to evaluate cell viability, cell cycle and autophagy in non-tumor primary TSC cells with different heterozygous mutations and in control cells without TSC mutations, before and after treatment with rapamycin (mTORC1 inhibitor). We did not observe differences in cell viability and cell cycle between the cell groups. However, autophagy was reduced in mutated cells. After rapamycin treatment, mutated cells showed a significant increase in the autophagy process (p=0.039). We did not observe differences between cells with distinct TSC mutations. Our main finding is the alteration of autophagy in non-tumor TSC cells. Previous studies in literature found autophagy alterations in tumor TSC cells or knock-out animal models. We showed that autophagy could be an important mechanism that leads to TSC tumor formation in the haploinsufficiency state. This result could guide future studies in this field.
  • Overexpression of RAPGEF3 enhances the therapeutic effect of dezocine in treatment of neuropathic pain Cellular, Molecular And Developmental Genetics

    Liu, Xue; Song, Li; Ma, Xiaojun; Liu, Yong; Huang, Hui; Xu, Yongsheng; Yan, Wei

    Abstract in English:

    Abstract Pain is a significant problem worldwide that affects the quality of life of patients. Dezocine is a non-addictive analgesic drug with kappa-opioid antagonist activity and has been successfully used to alleviate of postoperative pain. In addition, dezocine has an analgesic effect similar to that of morphine, alleviating moderate to severe pain. Rap guanine nucleotide exchange factor 3 (RAPGEF3) is a guanine nucleotide exchange factor for GTPases Rap1 and Rap2, which could enhance the activity of Rap1 to promote cell adhesion and axon regeneration, as well as promote neurite extension by interacting with nerve growth factors. Here, we first observed that overexpression of RAPGEF3 increased cell viability, as shown by a CCK-8 assay, and recovered brain function in rats. The expression of inflammation-related factors at the mRNA level was detected using qPCR, and the concentration of these factors in a cultured cell medium and rat serum samples were decreased as shown by ELISA after RAPGEF3 overexpression. Through western blotting, we further found that pro-inflammatory proteins were decreased, and these effects might be mediated by inhibition of the Ras/p-38 MAPK signaling pathway. Taken together, we speculated that RAPGEF3overexpression enhances the therapeutic effect of dezocine on neuropathic pain by inhibiting the inflammatory response through inhibition of the Ras/p-38 MAPK signaling pathway.
  • In silico comparisons of lipid-related genes between Mycobacterium tuberculosis and BCG vaccine strains Genomics And Bioinformatics

    Sarno, Alice; Bitencourt, Julia; Queiroz, Adriano; Arruda, Sergio

    Abstract in English:

    Abstract Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine’s impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine’s inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.
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