Insights into the evolutionary history of the most skilled tool-handling platyrrhini monkey: Sapajus libidinosus from the Serra da Capivara National Park.

Sapajus libidinosus members of the Pedra Furada group, living in the Serra da Capivara National Park, use stone tools in a wider variety of behaviors than any other living animal, except humans. To rescue the evolutionary history of the Caatinga S. libidinosus and identify factors that may have contributed to the emergence and maintenance of their tool-use culture, we conducted fieldwork seasons to obtain biological samples of these capuchin monkeys. UsingCYTBsequences, we show a discrete but constant population growth from the beginning of the Holocene to the present, overlapping the emergence of the Caatinga biome. Our habitat suitability reconstruction reports the presence of plants whose hard fruits, seeds, or roots are processed by capuchins using tools. TheS. libidinosusindividuals in the Caatinga were capable of dynamically developing and maintaining their autochthonous culture thanks to: a) cognitive capacity to generate and execute innovation under selective pressure; b) tolerance favoring learning and cultural inheritance; c) an unknown genetic repertoire that underpins the adaptive traits; d) a high degree of terrestriality; e) presence and abundance of natural resources, which makes some places "hot spots" for innovation, and cultural diversification within a relatively short time.

ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2.

The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to host-cell infection. We performed a comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses for analysis in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species, while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors.

AVPR1b variation and the emergence of adaptive phenotypes in Platyrrhini primates.

Platyrrhini (New World monkeys, NWm) are a group of primates characterized by behavioral and reproductive traits that are otherwise uncommon among primates, including social monogamy, direct paternal care, and twin births. As a consequence, the study of Platyrrhine primates is an invaluable tool for the discovery of the genetic repertoire underlying these taxon-specific traits. Recently, high conservation of vasopressin (AVP) sequence, in contrast with high variability of oxytocin (OXT), has been described in NWm. AVP and OXT functions are possible due to interaction with their receptors: AVPR1a, AVPR1b, AVPR2, and OXTR; and the variability in this system is associated with the traits mentioned above. Understanding the variability in the receptors is thus fundamental to understand the function and evolution of the system as a whole. Here we describe the variability of AVPR1b coding region in 20 NWm species, which is well-known to influence behavioral traits such as aggression, anxiety, and stress control in placental mammals. Our results indicate that 4% of AVPR1b sites may be under positive selection and a significant number of sites under relaxed selective constraint. Considering the known role of AVPR1b, we suggest that some of the changes described here for the Platyrrhini may be a part of the genetic repertoire connected with the complex network of neuroendocrine mechanisms of AVP-OXT system in the modulation of the HPA axis. Thus, these changes may have promoted the emergence of social behaviors such as direct paternal care in socially monogamous species that are also characterized by small body size and twin births.

Role of IL6, IL12B and VDR gene polymorphisms in Plasmodium vivax malaria severity, parasitemia and gametocytemia levels in an Amazonian Brazilian population.

OBJECTIVE: To investigate the influence of IL6, IL12B and VDR single nucleotide polymorphisms (SNPs) in uncomplicated Plasmodium vivax infection symptoms intensity, parasitemia and gametocytemia levels in a Brazilian Amazonian population. METHODS: A total of 167 malaria patients infected by P. vivax have parasitemia and gametocytemia levels estimated before treatment. Fourteen clinical symptoms were evaluated and included in a principal component analysis to derive a clinical symptom index. Patients were genotyped for IL6-174C>G, IL12B 735T>C, 458A>G, 159A>C, and VDR FokI, TaqI, BsmI SNPs by Taqman 5' nuclease assays. A General Linear Model analysis of covariance with age, gender, exposure period and infection history and genetic ancestry was performed to investigate the association of genotypes with parasitemia and gametocytemia levels and with a clinical symptom index. RESULTS: Higher parasitemia levels were observed in IL6-174C carriers (p=0.02) whereas IL12B CGT haplotype carriers presented lower parasitemia levels (p=0.008). VDR TaqIC/BsmIA haplotype carriers showed higher gametocyte levels than non-carriers (p=0.013). Based on the clinical index values the IL6-174C>G polymorphism was associated with malaria severity. The IL6-174C carriers presented a more severe clinical index when compared to GG homozygotes (p=0.001). CONCLUSION: The present study suggests that IL6, IL12 and VDR influence severity, parasitemia and gametocytemia clearance in P. vivax infections, and highlights their potential role in malaria immune response in an Amazonian population.

Impact of population diversity on the prediction of 7-SNP NAT2 phenotypes using the tagSNP rs1495741 or paired SNPs.

A novel NAT2 tagSNP (rs1495741) and a 2-SNP genotype (rs1041983 and rs1801280) have been recently shown to accurately predict the NAT2 acetylator phenotypes in populations of exclusive or predominant European/White ancestry. We confirmed the accuracy of the tagSNP approach in White Brazilians, but not in Brown or Black Brazilians, sub-Saharan Mozambicans, and Guarani Amerindians. The combined rs1041983 and rs1801280 genotypes provided considerably better prediction of the NAT2 phenotype in Guarani, but no consistent improvement in Brown or Black Brazilians and Mozambicans. Best predictions of the NAT2 phenotype in Mozambicans using NAT2 SNP pairs were obtained with rs1801280 and rs1799930, but the accuracy of the estimates remained inadequate for clinical use or for investigations in this sub-Saharan group or in Brazilians with considerable African ancestry. In conclusion, the rs1495741 tagSNP cannot be applied to predict the NAT2 acetylation phenotype in Guarani and African-derived populations, whereas 2-SNP genotypes may accurately predict NAT2 phenotypes in Guarani, but not in Africans.

IL1B, IL4R, IL12RB1 and TNF gene polymorphisms are associated with Plasmodium vivax malaria in Brazil.

BACKGROUND: Malaria is among the most prevalent parasitic diseases worldwide. In Brazil, malaria is concentrated in the northern region, where Plasmodium vivax accounts for 85% disease incidence. The role of genetic factors in host immune system conferring resistance/susceptibility against P. vivax infections is still poorly understood. METHODS: The present study investigates the influence of polymorphisms in 18 genes related to the immune system in patients with malaria caused by P. vivax. A total of 263 healthy individuals (control group) and 216 individuals infected by P. vivax (malaria group) were genotyped for 33 single nucleotide polymorphisms (SNPs) in IL1B, IL2, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, IL12RB1, SP110, TNF, TNFRSF1A, IFNG, IFNGR1, VDR, PTPN22 and P2X7 genes. All subjects were genotyped with 48 ancestry informative insertion-deletion polymorphisms to determine the proportion of African, European and Amerindian ancestry. Only 13 SNPs in 10 genes with differences lower than 20% between cases and controls in a Poisson Regression model with age as covariate were further investigated with a structured population association test. RESULTS: The IL1B gene -5839C > T and IL4R 1902A > G polymorphisms and IL12RB1 -1094A/-641C and TNF -1031 T/-863A/-857 T/-308 G/-238 G haplotypes were associated with malaria susceptibility after population structure correction (p = 0.04, p = 0.02, p = 0.01 and p = 0.01, respectively). CONCLUSION: Plasmodium vivax malaria pathophysiology is still poorly understood. The present findings reinforce and increase our understanding about the role of the immune system in malaria susceptibility.

SLCO1B1 gene variability influences lipid-lowering efficacy on simvastatin therapy in Southern Brazilians.

BACKGROUND: Variants in uptake and efflux transporters can influence diverse statin pharmacokinetics in different populations. This study aimed to investigate the influence of SLCO1B1 gene polymorphism on simvastatin treatment efficacy in a Brazilian population of European ancestry. METHODS: Two hundred and sixteen hypercholesterolemic patients were treated with 20 mg/day simvastatin for 6 months. Plasma lipid and lipoprotein levels were measured at baseline and after 2 and 6 months of treatment. The single nucleotide polymorphisms (SNPs) c.388A>G, c.463C>A and c.521T>C at SLCO1B1 gene were determined by allelic discrimination with TaqMan 5'-nuclease assays. The 388G allele was observed in 160 patients, the 521 C allele was observed in 64 individuals, whereas 61 subjects were 463 A allele carriers. RESULTS: Carriers of the SLCO1B1 388G allele had a greater reduction of total cholesterol and LDL cholesterol with simvastatin treatment, when compared with 56 388A homozygotes (-28.8% vs. -15.8%, p=0.005 and -39.0% vs. -30.6%, p=0.003; respectively). The c.463C>A and c.521T>C SNPs were not associated with simvastatin treatment. The SLCO1B1 haplotypes showed no statistically significant differences in mean percentage reductions in lipid and lipoprotein levels after simvastatin treatment. CONCLUSIONS: The present study suggests that the SLCO1B1 c.388A>G polymorphism could play a role in the inter-individual variation of clinical response to simvastatin in Brazilians. These results add to those that suggest that the effects of SLCO1B1 variants may be statin specific.

Y-STR analysis in Brazilian and South Amerindian populations.

A sample of 203 Brazilian males from Rio Grande do Sul (RS), the Brazilian southernmost state, was typed for 11 Y-STR markers (DYS19, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS385, DYS437, DYS438, and DYS439). We also typed 42 individuals from two South Amerindian tribes (Kaingang and Guarani) to use the data as parental Amerindian contribution to our analyses. Gene and haplotypic diversities were estimated, with the South Amerindian samples showing smaller values for these parameters than Brazilians. To obtain a more comprehensive picture of the genetic structure of the Brazilian population as a whole, the Y-STR data from the RS sample was compared with those already published. No genetic substructuring was observed in the comparisons performed. Multidimensional scaling confirmed the proposed European source of most Y-chromosome Brazilian patrilineages.

SLCO1A2, SLCO1B1 and SLCO2B1 polymorphisms influences chloroquine and primaquine treatment in Plasmodium vivax malaria.

AIM: The association of transporters gene polymorphisms with chloroquine/primaquine malaria treatment response was investigated in a Brazilian population. PATIENTS & METHODS: Totally, 164 Plasmodium vivax malaria infected patients were included. Generalized estimating equations were performed to determine gene influences on parasitemia and/or gametocytemia clearance over treatment time. RESULTS: Significant interaction between SLCO2B1 genotypes and treatment over time for parasitemia clearance rate on day 2 were observed (p FDR = 0.002). SLCO1A2 and SLCO1B1 gene treatment over time interactions were associated with gametocytemia clearance rate (p FDR = 0.018 and p FDR = 0.024). ABCB1, ABCC4 and SLCO1B3 were not associated with treatment response. CONCLUSION: The present work presents the first pharmacogenetic report of an association between chloroquine/primaquine responses with OATP transporters.

The effect of SNPs in CYP450 in chloroquine/primaquine Plasmodium vivax malaria treatment.

BACKGROUND: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region. AIMS: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment. PATIENTS & METHODS: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients. RESULTS: An effect of CYP2C8 low-activity alleles on treatment was observed (p = 0.01). From baseline to first day of treatment, wild-type individuals achieved greater reduction of gametocytes than low-activity allele carriers. CYP2C9 and CYP3A5 genes showed a trend for gametocytemia and parasitemia clearance rates. CONCLUSION: Future studies should be performed to access the extent of CYP2C8, CYP2C9 and CYP3A5 gene polymorphisms influence on cloroquine/primaquine treatment.

Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.

The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions.

Haplotypes of the IL10 gene as potential protection factors in leprosy patients.

Leprosy is an infectious disease caused by Mycobacterium leprae characterized by dermatoneurological signs and symptoms that has a large number of new cases worldwide. Several studies have associated interleukin 10 with susceptibility/resistance to several diseases. We investigated haplotypes formed by three single nucleotide polymorphisms (SNPs) located in the IL10 gene (A-1082G, C-819T, and C-592A) in order to better understand the susceptibility to and severity of leprosy in an admixed northern Brazil population, taking into account estimates of interethnic admixture. We observed the genotypes ACC/ACC (P = 0.021, odds ratio [OR] [95% confidence interval (CI)] = 0.290 [0.085 to 0823]) and ACC/GCC (P = 0.003, OR [95% CI] = 0.220 [0.504 to 0.040]) presenting significant results for protection against leprosy development, framed in the profiles of low and medium interleukin production, respectively. Therefore, we suggest that genotypes A-1082G, C-819T, and C-592A formed by interleukin-10 polymorphisms are closely related to protection of the leprosy development in an admixed northern Brazil population, in particular ACC/ACC and ACC/GCC genotypes.

The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected.

Based on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a "total ancestry" estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19th and 20th centuries--a phenomenon described and intended as the "whitening of Brazil"--is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations.

Caracterização antigênica e molecular de oito amostras do vírus da doença de Aujeszky isoladas no estado do Rio Grande do Sul em 2003 / Antigenic and molecular characterization of eight samples of Aujeszky's disease virus isolated in the state of Rio Grande do Sul, Brazil, in 2003

A doença de Aujeszky ou pseudoraiva (DA), causada pelo vírus da pseudoraiva (PRV) é a maior preocupação na produção de suínos. No estado do Rio Grande do Sul, Brasil, a DA foi somente detectada em 1954, em bovino. Em 2003, ocorreram dois surtos de encefalite em granjas na região norte do estado, fronteira com o estado de Santa Catarina. O vírus da doença de Aujeszky (VDA) foi isolado a partir de animais coletados em oito granjas distintas da região e submetido a análises antigênicas e moleculares. As amostras de VDA isoladas foram comparadas com as amostras padrão NIA-3 e NP. A caracterização antigênica dos mesmos foi realizada com testes de imunoperoxidase frente a um painel de anticorpos mono-clonais (Mabs) preparado contra epitopos de glicoproteinas virais (gB, gC, gD e gE). A caracterização genômica foi realizada através da análise restrição enzimática (REA) sobre o genoma total das amostras, com a enzima de restrição (REA) Bam HI. O perfil antigênico das oito amostras isoladas no Rio Grande do Sul, bem como os apresentados pelas amostras padrão NIA-3 e NP, foram similares. A REA revelou que todos as oito amostras do Rio Grande do Sul apresentaram um arranjo genômico do tipo II, genótipo frequentemente encontrado em surtos prévios de DA em outros estados do Brasil. Os resultados aqui obtidos indicam que as oito amostras isoladas no Rio Grande do Sul são similares.