Resumo em Inglês:

Abstract Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects – or teratogens – as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205), fetal deaths (annual average of 1,530), infant hospitalizations (annual average of 82,452), number of deaths of hospitalized infants (annual average of 2,175), and the average cost of hospitalizations (annual cost of $7,758). Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016). From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue.

Resumo em Inglês:

Abstract Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016.

Resumo em Inglês:

Abstract Butyrylcholinesterase (BChE) activity and polymorphisms in its encoding gene had previously been associated with metabolic traits of obesity. This study investigated the association of three single nucleotide polymorphisms (SNPs) in the BCHE gene: -116G > A (rs1126680), 1615GA (rs1803274), 1914A < G (rs3495), with obesity and lipid metabolism markers, body mass index (BMI), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride (TG) levels, and BChE enzymatic activity in obese (BMI≥30/n = 226) and non-obese women (BMI < 25/n = 81). BCHE SNPs genotyping was obtained by TaqMan allelic discrimination assay and by RFLP-PCR. Plasmatic BChE activity was measured using propionylthiocholine as substrate. Similar allele frequencies were found in obese and non-obese women for the three studied SNPs (p > 0.05). The dominant and recessive models were tested, and different effects were found. The -116A allele showed a dominant effect in BChE activity reduction in both non-obese and obese women (p = 0.045 and p < 0.001, respectively). The 1914A > G and 1615GA SNPs influenced the TG levels only in obese women. The 1914G and the 1615A alleles were associated with decreased plasma levels of TG. Thus, our results suggest that the obesity condition, characterized by loss of energy homeostasis, is modulated by BCHE polymorphisms.

Resumo em Inglês:

Abstract Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood.

Resumo em Inglês:

Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Resumo em Inglês:

Abstract Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A (p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships.

Resumo em Inglês:

ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

Resumo em Inglês:

Abstract Cluster of differentiation 40 (CD40), the receptor for CD154, is a member of the tumor necrosis factor (TNF) receptor superfamily. Several studies have been conducted to investigate the effect of the CD40 rs1883832 polymorphism on atherosclerotic disease in different population; however, inconsistent results were obtained. In this study, we investigated the association of four polymorphisms (rs1883832, rs13040307, rs752118 and rs3765459) of CD40 gene and their effect on CD40 expression with the risk of ischemic stroke (IS) in a Chinese population. Three hundred and eighty patients with IS and 450 control subjects were included in the study. The CD40 polymorphisms were discriminated by Snapshot SNP genotyping assay. Serum soluble CD40 (sCD40) levels were detected by ELISA. We found that the rs1883832CT and rs1883832TT genotypes were associated with an increased risk of IS compared with the rs1883832CC genotype (OR = 1.42, 95% CI: 1.03–1.95, p = 0.030 and OR = 1.91, 95% CI: 1.29–2.82, P = 0.001, respectively), and the rs1883832T allele was associated with a significantly increased risk of IS compared with rs1883832C allele (OR = 1.40, 95% CI: 1.15–1.70, P = 0.001). Elevated serum sCD40 levels were observed in patients with IS compared with the control gropu (P < 0.01). Individuals carrying the rs1883832TT or rs1883832CT genotypes showed significantly higher sCD40 levels compared with the rs1883832CC genotype in the IS group [(64.8 ± 25.4 pg/mL, TT = 94); (63.9 ± 24.3 pg/mL, CT = 185) vs (53.3 ± 22.5 pg/mL, CC = 101), P < 0.01]. The TCCA haplotype was associated with an increased risk of IS compared with the control group (OR = 2.10, 95% CI: 1.23–3.58, p = 0.005). However, we did not find a significant association between the other three polymorphisms and IS risk. In conclusion, after a comprehensive comparison with other studies, we confirmed that the rs1883832T allele but not the rs1883832C allele is associated with an increased risk of IS. The rs1883832 polymorphism may exert influences on abnormal CD40 expression in IS patients among the Chinese population.

Resumo em Inglês:

Abstract Lactase non-persistence (leading to primary lactose intolerance) is a genetically dependent inability to digest lactose in adulthood. As part of the human adaptation to dairying, the human lactase LCT-13910C/T mutation (which propagates adult expression of lactase) developed, spread and participated in the adaptation to dairying. This variant is associated with lactase activity persistence, and its carriers are able to digest lactose. We compared the frequencies of lactase 13910C/T (rs4988235) genotypes in Czechs/Slavs (N = 288) and Czech Gypsies/Roma (N = 300), two ethnically different groups where this polymorphism has not yet been analysed. Allelic frequencies significantly differed between the populations (p < 0.0001). In Czechs/Slavs, the lactase persistence T allele was present in 76% of the individuals, which is in agreement with frequencies among geographically neighbouring populations. In the Czech Gypsy/Roma population, only 27% of the adults were carriers of at least one lactase persistence allele, similar to the Indian population. In agreement with this result, dairy product consumption was reported by 70.5% of Czechs/Slavs and 39.0% of the Czech Gypsy/Roma population. Both in the Czech Gypsy/Roma and in the Czech/Slavs populations, the presence of carriers of the lactase persistence allele was similar in subjects self-reporting the consumption of unfermented/fresh milk, in comparison to the others.

Resumo em Inglês:

Abstract Genotypic and phenotypic data of 1,562 animals were analyzed to find genomic regions that potentially influence the birth weight (BW), weaning weight at seven months of age (WW) and yearling weight (YW) of Colombian Brahman cattle, with genotyping conducted using Illumina Bead chip array with 74,669 SNPs. A Single Step Genomic BLUP (ssGBLP), approach was used to estimate the proportion of variance explained by each marker. Multiple regions scattered across the genome were found to influence weights at different ages, also dependent on the trait component (direct or maternal). The most interesting regions were connected to previously identified QTLs and genes, such as ADAMTSL3, CAPN2, CAPN2, FABP6, ZEB2 influencing growth and weight traits. The identified regions will contribute to the development and refinement of genomic selection programs for Zebu Brahman cattle in Colombia.

Resumo em Inglês:

Abstract The process of karyotype evolution in Cervidae from a common ancestor (2n = 70, FN = 70) has been marked by complex chromosomal rearrangements. This ancestral karyotype has been retained by the current species Mazama gouazoubira (Fischer 1814), for which a chromosomal polymorphism (Robertsonian translocations and the presence of B chromosomes) has been described, presumably caused by a chromosome fragility. Thus, this study has identified doxorubicin-induced chromosome aberrations and mapped the regions involved in breaks, which may be related to the chromosome evolution process. G-banding pattern showed that 21 pairs of chromosomes presented chromosomal aberrations, 60% of the total chromosome number of the species M. gouazoubira. Among chromosomes that carry aberrations, the region where they were most frequently concentrated was distal relative to the centromere. These data suggest that certain chromosomal regions may be more susceptible to chromosome fragility and consequently could be involved in karyotype differentiation in species of the family Cervidae.

Resumo em Inglês:

Abstract Although manioc is well adapted to nutrient-poor Oxisols of Amazonia, ethnobotanical observations show that bitter manioc is also frequently cultivated in the highly fertile soils of the floodplains and Amazonian dark earths (ADE) along the middle Madeira River. Because different sets of varieties are grown in each soil type, and there are agronomic similarities between ADE and floodplain varieties, it was hypothesized that varieties grown in ADE and floodplain were more closely related to each other than either is to varieties grown in Oxisols. We tested this hypothesis evaluating the intra-varietal genetic diversity and the genetic relationships among manioc varieties commonly cultivated in Oxisols, ADE and floodplain soils. Genetic results did not agree with ethnobotanical expectation, since the relationships between varieties were variable and most individuals of varieties with the same vernacular name, but grown in ADE and floodplain, were distinct. Although the same vernacular name could not always be associated with genetic similarities, there is still a great amount of variation among the varieties. Many ecological and genetic processes may explain the high genetic diversity and differentiation found for bitter manioc varieties, but all contribute to the maintenance and amplification of genetic diversity within the manioc in Central Amazonia.

Resumo em Inglês:

Abstract The barley HvAACT1 gene codes for a citrate transporter associated with tolerance to acidic soil. In this report, we describe a single nucleotide polymorphism (SNP) in the HvAACT1 coding region that was detected as T-1,198 (in genotypes with lower root growth on acidic soil) or G-1,198 (greater root growth) and resulted in a single amino acid change (L/V-172). Molecular dynamic analysis predicted that HvAACT1 proteins with L or V-172 were stable, although the substitution led to structural changes within the protein. To evaluate the effect of the SNP on tolerance to acidic soil, barley accessions were separated into haplotypes based on the presence of a 1 kb insertion in the HvAACT1 promoter and a 21 bp insertion/deletion. These markers and the SNP-1,198 allowed the identification of five haplotypes. Short-term soil experiments showed no difference in root growth for most of the accessions containing the 21 bp insertion and T or G-1,198. In contrast, genotypes showing both the 21 bp deletion and G-1,198, with one of them having the 1 kb insertion, showed greater root growth. These results indicate that the SNP was not advantageous or deleterious when genotypes from the same haplotype were compared. The occurrence of the SNP was highly correlated with the 21 bp insertion/deletion that, together with the 1 kb insertion, explained most of the barley tolerance to acidic soil.

Resumo em Inglês:

Abstract Benzo[a]pyrene (B[a]P) is a petroleum derivative capable of inducing cancer in human and animals. In this work, under laboratory conditions, we analyzed the responses of Colossoma macropomum to B[a]P acute exposure through intraperitoneal injection of four different B[a]P concentrations (4, 8, 16 and 32 μmol/kg) or corn oil (control group). We analyzed expression of the ras oncogene and the Hypoxia-inducible factor-1 alpha (hif-1α) gene using quantitative real-time PCR. Additionally, liver histopathological changes and genotoxic effects were evaluated through the comet assay. Ras oncogene was overexpressed in fish exposed to 4, 8 of 16 μmol/kg B[a]P, showing 4.96, 7.10 and 6.78-fold increases, respectively. Overexpression also occurred in hif-1α in fish injected with 4 and 8 μmol/kg B[a]P, showing 8.82 and 4.64-fold increases, respectively. Histopathological damage in fish liver was classified as irreparable in fish exposed to 8, 16 and 32 μmol/kg μM B[a]P. The genotoxic damage increased in fish injected with 8 and 16 μmol/kg in comparison with the control group. Acute exposure of B[a]P was capable to interrupt the expression of ras oncogene and hif-1α, and increase DNA breaks due to tissue damage.

Resumo em Inglês:

Abstract The Morato's Digger Toad, Proceratophrys moratoi, is a critically endangered toad species with a marked population decline in southern Brazilian Cerrado. Despite this, new populations are being discovered, primarily in the northern part of the distribution range, which raises a number of questions with regard to the conservation status of the species. The present study analyzed the genetic diversity of the species based on microsatellite markers. Our findings permitted the identification of two distinct management units. We found profound genetic structuring between the southern populations, on the left margin of the Tietê River, and all other populations. A marked reduction was observed in the contemporary gene flow among the central populations that are most affected by anthropogenic impacts, such as extensive sugar cane plantations, which presumably decreases habitat connectivity. The results indicated reduced diversity in the southern populations which, combined with a smaller effective population size, may make these populations more susceptible to extinction. We recommend the reclassification of P. moratoi as vulnerable and the establishment of a special protection program for the southern populations. Our results provide important insights about the local extinction of southern populations of this toad.

Resumo em Inglês:

Abstract Pathway activity assessment-based approaches are becoming highly influential in various fields of biology and medicine. However, these approaches mostly rely on analysis of mRNA expression, and total mRNA from a given locus is measured in the majority of cases. Notably, a significant portion of protein-coding genes produces more than one transcript. This biological fact is responsible for significant noise when changes in total mRNA transcription of a single gene are analyzed. The NFE2L2/AP-1 pathway is an attractive target for biomedical applications. To date, there is a lack of data regarding the agreement in expression of even classical target genes of this pathway. In the present paper we analyzed whether transcript variants of GPX2, NQO1 and SQSTM1 were characterized by individual features of expression when HeLa cells were exposed to pro-oxidative stimulation with hydrogen peroxide. We found that all the transcripts (10 in total) appeared to be significantly individually regulated under the conditions tested. We conclude that individual transcripts, rather than total mRNA, are best markers of pathway activation. We also discuss here some biological roles of individual transcript regulation.

Resumo em Inglês:

Abstract Studies have demonstrated that miRNA-378 is expressed in various malignant tumors. In the present study, we aimed to explore the expression of serum miRNA-378 and its clinical significance in renal cell carcinoma (RCC) patients. A total of 75 RCC patients, 63 renal cysts (RC) patients and 75 healthy controls were selected. The miRNA-378 level in RCC and RC groups was significantly higher than in healthy control group, with RCC group having the highest level. The miRNA-378 levels were significantly decreased within the same group after surgery. When compared with healthy controls, RC group had higher levels but not significantly (p > 0.05) while levels in RCC group were significantly higher (p < 0.05). miRNA-378 expression was correlated with clinical stage and differentiation degree, but not correlated with patient's age, gender, surgical strategy and tumor diameter. The AUC of miRNA-378 was 0.896, 95% confidence interval was 0.847 to 0.945, and AUC hypothesis testing was statistically significant (p < 0.001, RCC vs healthy control). miRNA-378 shows potential in the diagnosis and prediction of postoperative curative effect of renal cell carcinoma, but further studies with lager samples are needed.

Resumo em Inglês:

Abstract The advent of next-generation sequencing allows simultaneous processing of several genomic regions/individuals, increasing the availability and accuracy of whole-genome data. However, these new approaches may present some errors and bias due to alignment, genotype calling, and imputation methods. Despite these flaws, data obtained by next-generation sequencing can be valuable for population and evolutionary studies of specific genes, such as genes related to how pigmentation evolved among populations, one of the main topics in human evolutionary biology. Melanocortin-1 receptor (MC1R) is one of the most studied genes involved in pigmentation variation. As MC1R has already been suggested to affect melanogenesis and increase risk of developing melanoma, it constitutes one of the best models to understand how natural selection acts on pigmentation. Here we employed a locally developed pipeline to obtain genotype and haplotype data for MC1R from the raw sequencing data provided by the 1000 Genomes FTP site. We also compared such genotype data to Phase 3 VCF to evaluate its quality and discover any polymorphic sites that may have been overlooked. In conclusion, either the VCF file or one of the presently described pipelines could be used to obtain reliable and accurate genotype calling from the 1000 Genomes Phase 3 data.

Resumo em Inglês:

Abstract The mechanisms involved in the fast growth of Angiostrongylus cantonensis from fifth-stage larvae (L5) to female adults and how L5 breaks through the blood-brain barrier in a permissive host remain unclear. In this work, we compared the transcriptomes of these two life stages to identify the main factors involved in the rapid growth and transition to adulthood. RNA samples from the two stages were sequenced and assembled de novo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of 1,346 differentially expressed genes between L5 and female adults was then undertaken. Based on a combination of analytical results and developmental characteristics, we suggest that A. cantonensis synthesizes a large amount of cuticle in L5 to allow body dilatation in the rapid growth period. Products that are degraded via the lysosomal pathway may provide sufficient raw materials for cuticle production. In addition, metallopeptidases may play a key role in parasite penetration of the blood-brain barrier during migration from the brain. Overall, these results indicate that the profiles of each transcriptome are tailored to the need for survival in each developmental stage.