I am a geneticist focused on the application of computational and statistical methods to study genetic mechanisms of disease. My research interests include (i) genomic and precision medicine; (ii) detection and analysis of genetic variants using NGS data (WGS, WES, RNA-Seq); and (iii) transcriptome and allele-specific expression.

Professional Education

  • Master of Science, Unlisted School (2019)
  • Doctor of Philosophy, Universidade Federal Rio De Janeiro (2022)
  • Bachelor of Science, Unlisted School (2017)
  • PhD, Federal University of Rio de Janeiro, Genetics (2022)
  • MSc, National Laboratory of Scientific Computing, Computational Modeling (2019)
  • BSc, State University of Northern Rio de Janeiro, Biological Sciences (2017)

Stanford Advisors

All Publications

  • Multi-layered transcriptomic analysis reveals a pivotal role of FMR1 and other developmental genes in Alzheimer's disease-associated brain ceRNA network. Computers in biology and medicine Piergiorge, R. M., da Silva Francisco Junior, R., de Vasconcelos, A. T., Santos-Rebouças, C. B. 2023; 166: 107494


    Alzheimer's disease (AD) is an increasingly neurodegenerative disorder that causes progressive cognitive decline and memory impairment. Despite extensive research, the underlying causes of late-onset AD (LOAD) are still in progress. This study aimed to establish a network of competing regulatory interactions involving circular RNAs (circRNAs), microRNAs (miRNAs), RNA-binding proteins (RBPs), and messenger RNAs (mRNAs) connected to LOAD. A systematic analysis of publicly available expression data was conducted to identify integrated differentially expressed genes (DEGs) from the hippocampus of LOAD patients. Subsequently, gene co-expression analysis identified modules comprising highly expressed DEGs that act cooperatively. The competition between co-expressed DEGs and miRNAs/RBPs and the simultaneous interactions between circRNA and miRNA/RBP revealed a complex ceRNA network responsible for post-transcriptional regulation in LOAD. Hippocampal expression data for miRNAs, circRNAs, and RBPs were used to filter relevant relationships for AD. An integrated topological score was used to identify the highly connected hub gene, from which a brain core ceRNA subnetwork was generated. The Fragile X Messenger Ribonucleoprotein 1 (FMR1) coding for the RBP FMRP emerged as the prominent driver gene in this subnetwork. FMRP has been previously related to AD but not in a ceRNA network context. Also, the substantial number of neurodevelopmental genes in the ceRNA subnetwork and their related biological pathways strengthen that AD shares common pathological mechanisms with developmental conditions. Our results enhance the current knowledge about the convergent ceRNA regulatory pathways underlying AD and provide potential targets for identifying early biomarkers and developing novel therapeutic interventions.

    View details for DOI 10.1016/j.compbiomed.2023.107494

    View details for PubMedID 37769462

  • Genetic screening in a Brazilian cohort with inborn errors of immunity BMC GENOMIC DATA Ferreira, C., Francisco Jr, R., Gerber, A., de Campos Guimaraes, A., Anisio de Carvalho, F., Santos dos Reis, B., Pinto-Mariz, F., de Souza, M., Meira de Vasconcelos, Z., Goudouris, E., Vasconcelos, A. 2023; 24 (1): 47


    Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient's phenotype.Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction.A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes.Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.

    View details for DOI 10.1186/s12863-023-01148-z

    View details for Web of Science ID 001049466900001

    View details for PubMedID 37592284

    View details for PubMedCentralID PMC10433585

  • Assessing whole-exome sequencing data from undiagnosed Brazilian patients to improve the diagnostic yield of inborn errors of immunity. BMC genomic data Ferreira, C. S., da Silva Francisco Junior, R., Gerber, A. L., Guimaraes, A. P., Amendola, F. A., Pinto-Mariz, F., de Souza, M. S., Miranda, P. C., de Vasconcelos, Z. F., Goudouris, E. S., Vasconcelos, A. T. 2023; 24 (1): 36


    OBJECTIVES: Inborn error of immunity (IEI) comprises a broad group of inherited immunological disorders that usually display an overlap in many clinical manifestations challenging their diagnosis. The identification of disease-causing variants from whole-exome sequencing (WES) data comprises the gold-standard approach to ascertain IEI diagnosis. The efforts to increase the availability of clinically relevant genomic data for these disorders constitute an important improvement in the study of rare genetic disorders. This work aims to make available WES data of Brazilian patients' suspicion of IEI without a genetic diagnosis. We foresee a broad use of this dataset by the scientific community in order to provide a more accurate diagnosis of IEI disorders.DATA DESCRIPTION: Twenty singleton unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil were enrolled in our study. Half of the patients were male with mean ages of 9±3, while females were 12±10 years old. The WES was performed in the Illumina NextSeq platform with at least 90% of sequenced bases with a minimum of 30 reads depth. Each sample had an average of 20,274 variants, comprising 116 classified as rare pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics and the Association (ACMG) guidelines. The genotype-phenotype association was impaired by the lack of detailed clinical and laboratory information, besides the unavailability of molecular and functional studies which, comprise the limitations of this study. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Therefore, by making these data available, we aim to increase the number of WES data from Brazilian samples despite contributing to the study of monogenic IEI-disorders.

    View details for DOI 10.1186/s12863-023-01137-2

    View details for PubMedID 37391719

  • Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines FRONTIERS IN IMMUNOLOGY Francisco Junior, R., Temerozo, J. R., Ferreira, C., Martins, Y., Souza, T. L., Medina-Acosta, E., Vasconcelos, A. 2023; 13: 1101526


    Cell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with the disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs.We compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments.We identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes.Independent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

    View details for DOI 10.3389/fimmu.2022.1101526

    View details for Web of Science ID 000932655300001

    View details for PubMedID 36818472

    View details for PubMedCentralID PMC9929942

  • Phylodynamic analysis of SARS-CoV-2 spread in Rio de Janeiro, Brazil, highlights how metropolitan areas act as dispersal hubs for new variants MICROBIAL GENOMICS Lamarca, A., de Almeida, L. P., Francisco, R., Cavalcante, L., Brustolini, O., Gerber, A. L., Guimaraes, A. C., de Oliveira, T., Nascimento, e., Policarpo, C., de Souza, I., de Carvalho, E., Ribeiro, M., Carvalho, S., da Silva, F., Garcia, M., de Souza, L., Da Silva, C., Ribeiro, C., Cavalcanti, A., de Mello, C., Tanuri, A., de Vasconcelos, A. R. 2022; 8 (9)


    During the first semester of 2021, all of Brazil has suffered an intense wave of COVID-19 associated with the Gamma variant. In July, the first cases of Delta variant were detected in the state of Rio de Janeiro. In this work, we have employed phylodynamic methods to analyse more than 1 600 genomic sequences of Delta variant collected until September in Rio de Janeiro to reconstruct how this variant has surpassed Gamma and dispersed throughout the state. After the introduction of Delta, it has initially spread mostly in the homonymous city of Rio de Janeiro, the most populous of the state. In a second stage, dispersal occurred to mid- and long-range cities, which acted as new close-range hubs for spread. We observed that the substitution of Gamma by Delta was possibly caused by its higher viral load, a proxy for transmissibility. This variant turnover prompted a new surge in cases, but with lower lethality than was observed during the peak caused by Gamma. We reason that high vaccination rates in the state of Rio de Janeiro were possibly what prevented a higher number of deaths.

    View details for DOI 10.1099/mgen.0.000859

    View details for Web of Science ID 000861187700002

    View details for PubMedID 36106981

    View details for PubMedCentralID PMC9676039

  • Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report BMC PEDIATRICS Francisco Junior, R., de Morais, G., de Carvalho, J., Ferreira, C., Gerber, A., Guimaraes, A. C., Amendola, F., Pinto-Mariz, F., Meira de Vasconcelos, Z., Goudouris, E., Ribeiro de Vasconcelos, A. 2022; 22 (1): 181


    X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder.We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFβ1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFβ1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment.Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.

    View details for DOI 10.1186/s12887-022-03245-x

    View details for Web of Science ID 000778595300001

    View details for PubMedID 35382780

    View details for PubMedCentralID PMC8981605

  • Emergence of Within-Host SARS-CoV-2 Recombinant Genome After Coinfection by Gamma and Delta Variants: A Case Report FRONTIERS IN PUBLIC HEALTH Francisco Junior, R., Almeida, L., Lamarca, A. P., Cavalcante, L., Martins, Y., Gerber, A. L., Guimaraes, A. C., Salviano, R., dos Santos, F., de Oliveira, T., de Souza, I., de Carvalho, E., Ribeiro, M., Carvalho, S., da Silva, F., Garcia, M., de Souza, L., da Silva, C., Ribeiro, C., Cavalcanti, A., de Mello, C., Tanuri, A., Vasconcelos, A. R. 2022; 10: 849978


    In this study, we report the first case of intra-host SARS-CoV-2 recombination during a coinfection by the variants of concern (VOC) AY.33 (Delta) and P.1 (Gamma) supported by sequencing reads harboring a mosaic of lineage-defining mutations. By using next-generation sequencing reads intersecting regions that simultaneously overlap lineage-defining mutations from Gamma and Delta, we were able to identify a total of six recombinant regions across the SARS-CoV-2 genome within a sample. Four of them mapped in the spike gene and two in the nucleocapsid gene. We detected mosaic reads harboring a combination of lineage-defining mutations from each VOC. To our knowledge, this is the first report of intra-host RNA-RNA recombination between two lineages of SARS-CoV-2, which can represent a threat to public health management during the COVID-19 pandemic due to the possibility of the emergence of viruses with recombinant phenotypes.

    View details for DOI 10.3389/fpubh.2022.849978

    View details for Web of Science ID 000766335100001

    View details for PubMedID 35273945

    View details for PubMedCentralID PMC8902039

  • Genomic Surveillance Tracks the First Community Outbreak of the SARS-CoV-2 Delta (B.1.617.2) Variant in Brazil JOURNAL OF VIROLOGY Lamarca, A. P., de Almeida, L. P., Francisco, R., Cavalcante, L., Machado, D., Brustolini, O., Gerber, A. L., Guimaraes, A. C., Policarpo, C., de Oliveira, G., Boullosa, L., de Souza, I., de Carvalho, E., Ribeiro, M., Carvalho, S., da Silva, F., Garcia, M., de Souza, L., Da Silva, C., Ribeiro, C., Cavalcanti, A., de Mello, C., Tanuri, A., Vasconcelosa, A. R. 2022; 96 (2): e0122821

    View details for Web of Science ID 000767612200002

    View details for PubMedID 34730387

    View details for PubMedCentralID PMC8791247

  • Turnover of SARS-CoV-2 Lineages Shaped the Pandemic and Enabled the Emergence of New Variants in the State of Rio de Janeiro, Brazil VIRUSES-BASEL Francisco Junior, R., Lamarca, A. P., de Almeida, L. P., Cavalcante, L., Machado, D., Martins, Y., Brustolini, O., Gerber, A. L., Guimaraes, A. C., Goncalves, R., Alves, C., Mariani, D., Cruz, T., de Souza, I., de Carvalho, E., Ribeiro, M., Carvalho, S., da Silva, F., de Oliveira Garcia, M., de Souza, L., da Silva, C., Pereira Ribeiro, C., Cavalcanti, A., Braga de Mello, C., Struchiner, C. J., Tanuri, A., Vasconcelos, A. R. 2021; 13 (10)


    In the present study, we provide a retrospective genomic epidemiology analysis of the SARS-CoV-2 pandemic in the state of Rio de Janeiro, Brazil. We gathered publicly available data from GISAID and sequenced 1927 new genomes sampled periodically from March 2021 to June 2021 from 91 out of the 92 cities of the state. Our results showed that the pandemic was characterized by three different phases driven by a successive replacement of lineages. Interestingly, we noticed that viral supercarriers accounted for the overwhelming majority of the circulating virus (>90%) among symptomatic individuals in the state. Moreover, SARS-CoV-2 genomic surveillance also revealed the emergence and spread of two new variants (P.5 and P.1.2), firstly reported in this study. Our findings provided important lessons learned from the different epidemiological aspects of the SARS-CoV-2 dynamic in Rio de Janeiro. Altogether, this might have a strong potential to shape future decisions aiming to improve public health management and understanding mechanisms underlying virus dispersion.

    View details for DOI 10.3390/v13102013

    View details for Web of Science ID 000792951900010

    View details for PubMedID 34696443

    View details for PubMedCentralID PMC8537965

  • Genomic surveillance of SARS-CoV-2 tracks early interstate transmission of P.1 lineage and diversification within P.2 clade in Brazil PLOS NEGLECTED TROPICAL DISEASES Lamarca, A. P., de Almeida, L. P., Francisco Jr, R., Lima, L., Scortecci, K., Perez, V., Brustolini, O. J., Sousa, E., Secco, D., Santos, A., Albuquerque, G., Mariano, A., Maciel, B., Gerber, A. L., Guimaraes, A. C., Nascimento, P., Neto, F., Gadelha, S., Porto, L., Campana, E., Jeronimo, S., Vasconcelos, A. R. 2021; 15 (10): e0009835


    The sharp increase of COVID-19 cases in late 2020 has made Brazil the new epicenter of the ongoing SARS-CoV-2 pandemic. The novel viral lineages P.1 (Variant of Concern Gamma) and P.2, respectively identified in the Brazilian states of Amazonas and Rio de Janeiro, have been associated with potentially higher transmission rates and antibody neutralization escape. In this study, we performed the whole-genome sequencing of 185 samples isolated from three out of the five Brazilian regions, including Amazonas (North region), Rio Grande do Norte, Paraíba and Bahia (Northeast region), and Rio de Janeiro (Southeast region) in order to monitor the spread of SARS-CoV-2 lineages in Brazil in the first months of 2021. Here, we showed a widespread dispersal of P.1 and P.2 across Brazilian regions and, except for Amazonas, P.2 was the predominant lineage identified in the sampled states. We estimated the origin of P.2 lineage to have happened in February, 2020 and identified that it has differentiated into new clades. Interstate transmission of P.2 was detected since March, but reached its peak in December, 2020 and January, 2021. Transmission of P.1 was also high in December and its origin was inferred to have happened in August 2020. We also confirmed the presence of lineage P.7, recently described in the southernmost region of Brazil, to have spread across the Northeastern states. P.1, P.2 and P.7 are descended from the ancient B.1.1.28 strain, which co-dominated the first phase of the pandemic in Brazil with the B.1.1.33 strain. We also identified the occurrence of a new lineage descending from B.1.1.33 that convergently carries the E484K mutation, N.9. Indeed, the recurrent report of many novel SARS-CoV-2 genetic variants in Brazil could be due to the absence of effective control measures resulting in high SARS-CoV2 transmission rates. Altogether, our findings provided a landscape of the critical state of SARS-CoV-2 across Brazil and confirm the need to sustain continuous sequencing of the SARS-CoV-2 isolates worldwide in order to identify novel variants of interest and monitor for vaccine effectiveness.

    View details for DOI 10.1371/journal.pntd.0009835

    View details for Web of Science ID 000708406900004

    View details for PubMedID 34644287

    View details for PubMedCentralID PMC8544873

  • Intra-host evolution during SARS-CoV-2 prolonged infection VIRUS EVOLUTION Voloch, C. M., Francisco Jr, R., de Almeida, L. P., Brustolini, O. J., Cardoso, C. C., Gerber, A. L., Guimaraes, A. C., Leitao, I., Mariani, D., Ota, V., Lima, C. X., Teixeira, M. M., Dias, A. F., Galliez, R., Faffe, D., Porto, L., Aguiar, R. S., Castineira, T. P., Ferreira, O. C., Tanuri, A., de Vasconcelos, A. R., Covidl9-UFRJ Workgrp, LNCC-Workgrp 2021; 7 (2): veab078


    Long-term infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a challenge to virus dispersion and the control of coronavirus disease 2019 (COVID-19) pandemic. The reason why some people have prolonged infection and how the virus persists for so long are still not fully understood. Recent studies suggested that the accumulation of intra-host single nucleotide variants (iSNVs) over the course of the infection might play an important role in persistence as well as emergence of mutations of concern. For this reason, we aimed to investigate the intra-host evolution of SARS-CoV-2 during prolonged infection. Thirty-three patients who remained reverse transcription polymerase chain reaction (RT-PCR) positive in the nasopharynx for on average 18 days from the symptoms onset were included in this study. Whole-genome sequences were obtained for each patient at two different time points. Phylogenetic, populational, and computational analyses of viral sequences were consistent with prolonged infection without evidence of coinfection in our cohort. We observed an elevated within-host genomic diversity at the second time point samples positively correlated with cycle threshold (Ct) values (lower viral load). Direct transmission was also confirmed in a small cluster of healthcare professionals that shared the same workplace by the presence of common iSNVs. A differential accumulation of missense variants between the time points was detected targeting crucial structural and non-structural proteins such as Spike and helicase. Interestingly, longitudinal acquisition of iSNVs in Spike protein coincided in many cases with SARS-CoV-2 reactive and predicted T cell epitopes. We observed a distinguishing pattern of mutations over the course of the infection mainly driven by increasing A→U and decreasing G→A signatures. G→A mutations may be associated with RNA-editing enzyme activities; therefore, the mutational profiles observed in our analysis were suggestive of innate immune mechanisms of the host cell defense. Therefore, we unveiled a dynamic and complex landscape of host and pathogen interaction during prolonged infection of SARS-CoV-2, suggesting that the host's innate immunity shapes the increase of intra-host diversity. Our findings may also shed light on possible mechanisms underlying the emergence and spread of new variants resistant to the host immune response as recently observed in COVID-19 pandemic.

    View details for DOI 10.1093/ve/veab078

    View details for Web of Science ID 000765494700006

    View details for PubMedID 34642605

    View details for PubMedCentralID PMC8500031

  • Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome PLOS NEGLECTED TROPICAL DISEASES Borda, V., da Silva Francisco Junior, R., Carvalho, J. B., Morais, G. L., Rossi, A., Pezzuto, P., Azevedo, G. S., Schamber-Reis, B. L., Portari, E. A., Melo, A., Moreira, M. L., Guida, L. C., Cunha, D. P., Gomes, L., Vasconcelos, Z. M., Faucz, F. R., Tanuri, A., Stratakis, C. A., Aguiar, R. S., Cardoso, C., Ribeiro de Vasconcelos, A. 2021; 15 (6): e0009507


    Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn's genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10-5). The IL12RB2 gene (p-value: 2.18x10-11) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future.

    View details for DOI 10.1371/journal.pntd.0009507

    View details for Web of Science ID 000664533700002

    View details for PubMedID 34125832

    View details for PubMedCentralID PMC8224898

  • Genomic Characterization of a Novel SARS-CoV-2 Lineage from Rio de Janeiro, Brazil JOURNAL OF VIROLOGY Voloch, C. M., Francisco Jr, R., de Almeida, L. P., Cardoso, C. C., Brustolini, O. J., Gerber, A. L., Guimaraes, A. C., Mariani, D., da Costa, R., Ferreira Jr, O. C., Cavalcanti, A., Frauches, T., de Mello, C., Leitao, I., Galliez, R., Souza, D., Castineiras, T. P., Tanuri, A., de Vasconcelos, A. R., Covid-UFRJ Workgroup, LNCC Workgroup 2021; 95 (10)


    Almost simultaneously, several studies reported the emergence of novel SARS-CoV-2 lineages characterized by their phylogenetic and genetic distinction (1), (2), (3), (4).….

    View details for DOI 10.1128/JVI.00119-21

    View details for Web of Science ID 000644660800007

    View details for PubMedID 33649194

    View details for PubMedCentralID PMC8139668

  • Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg FRONTIERS IN GENETICS Alves-Leon, S., Ferreira, C., Herlinger, A., Fontes-Dantas, F., Rueda-Lopes, F., Francisco, R., Goncalves, J., de Araujo, A., Rego, C., Higa, L., Gerber, A., Guimaraes, A., de Menezes, M., de Paula Torres, M., Maia, R., Nogueira, B., Franca, L., da Silva, M., Naurath, C., Correia, A., Vasconcelos, C., Tanuri, A., Ferreira, O., Cardoso, C., Aguiar, R., de Vasconcelos, A. 2021; 12: 639364


    Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although <1% of cases develop severe neurological manifestations such as inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) like acute disseminated encephalomyelitis (ADEM) and extensive transverse myelitis. Genetic factors associated with host response and disease severity are still poorly understood. In this study, we performed whole-exome sequencing (WES) to identify HLA alleles, genes and cellular pathways associated with CNS IDD clinical phenotype outcomes following CHIKV infection. The cohort includes 345 patients of which 160 were confirmed for CHIKV. Six cases presented neurological manifestation mimetizing CNS IDD. WES data analysis was performed for 12 patients, including the CNS IDD cases and 6 CHIKV patients without any neurological manifestation. We identified 29 candidate genes harboring rare, pathogenic, or probably pathogenic variants in all exomes analyzed. HLA alleles were also determined and patients who developed CNS IDD shared a common signature with diseases such as Multiple sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD). When these genes were included in Gene Ontology analyses, pathways associated with CNS IDD syndromes were retrieved, suggesting that CHIKV-induced CNS outcomesmay share a genetic background with other neurological disorders. To our knowledge, this study was the first genome-wide investigation of genetic risk factors for CNS phenotypes in CHIKV infection. Our data suggest that HLA-DRB1 alleles associated with demyelinating diseases may also confer risk of CNS IDD outcomes in patients with CHIKV infection.

    View details for DOI 10.3389/fgene.2021.639364

    View details for Web of Science ID 000635099700001

    View details for PubMedID 33815474

    View details for PubMedCentralID PMC8010313

  • Pervasive transmission of E484K and emergence of VUI-NP13L with evidence of SARS-CoV-2 co-infection events by two different lineages in Rio Grande do Sul, Brazil VIRUS RESEARCH Jr, R., Benites, L., Lamarca, A. P., Almeida, L., Hansen, A., Gularte, J., Demoliner, M., Gerber, A. L., Guimara, A. C., Antunes, A., Heldt, F., Mallmann, L., Hermann, B., Ziulkoski, A., Goes, V., Schallenberger, K., Fillipi, M., Pereira, F., Weber, M., Almeida, P., Fleck, J., Vasconcelos, A. R., Spilki, F. 2021; 296: 198345


    Emergence of novel SARS-CoV-2 lineages are under the spotlight of the media, scientific community and governments. Recent reports of novel variants in the United Kingdom, South Africa and Brazil (B.1.1.28-E484K) have raised intense interest because of a possible higher transmission rate or resistance to the novel vaccines. Nevertheless, the spread of B.1.1.28 (E484K) and other variants in Brazil is still unknown. In this work, we investigated the population structure and genomic complexity of SARS-CoV-2 in Rio Grande do Sul, the southernmost state in Brazil. Most samples sequenced belonged to the B.1.1.28 (E484K) lineage, demonstrating its widespread dispersion. We were the first to identify two independent events of co-infection caused by the occurrence of B.1.1.28 (E484K) with either B.1.1.248 or B.1.91 lineages. Also, clustering analysis revealed the occurrence of a novel cluster of samples circulating in the state (named VUI-NP13L) characterized by 12 lineage-defining mutations. In light of the evidence for E484K dispersion, co-infection and emergence of VUI-NP13 L in Rio Grande do Sul, we reaffirm the importance of establishing strict and effective social distancing measures to counter the spread of potentially more hazardous SARS-CoV-2 strains.

    View details for DOI 10.1016/j.virusres.2021.198345

    View details for Web of Science ID 000632514200006

    View details for PubMedID 33631222

    View details for PubMedCentralID PMC7898980

  • Evolution and epidemic spread of SARS-CoV-2 in Brazil SCIENCE Candido, D. S., Claro, I. M., de Jesus, J. G., Souza, W. M., Moreira, F. R., Dellicour, S., Mellan, T. A., du Plessis, L., Pereira, R. M., Sales, F. S., Manuli, E. R., Theze, J., Almeida, L., Menezes, M. T., Voloch, C. M., Fumagalli, M. J., Coletti, T. M., Silva, C. M., Ramundo, M. S., Amorim, M. R., Hoeltgebaum, H. H., Mishra, S., Gill, M. S., Carvalho, L. M., Buss, L. F., Prete Jr, C. A., Ashworth, J., Nakaya, H., Peixoto, P. S., Brady, O. J., Nicholls, S. M., Tanuri, A., Rossi, A. D., Braga, C. K., Gerber, A. L., Guimaraes, A. C., Gaburo Jr, N., Alencar, C., Ferreira, A. S., Lima, C. X., Levi, J., Granato, C., Ferreira, G. M., Francisco Jr, R. S., Granja, F., Garcia, M. T., Moretti, M., Perroud Jr, M. W., Castineiras, T. P., Lazari, C. S., Hill, S. C., de Souza Santos, A., Simeoni, C. L., Forato, J., Sposito, A. C., Schreiber, A. Z., Santos, M. N., de Sa, C., Souza, R. P., Resende-Moreira, L. C., Teixeira, M. M., Hubner, J., Leme, P. F., Moreira, R. G., Nogueira, M. L., Ferguson, N. M., Costa, S. F., Proenca-Modena, J., Vasconcelos, A. R., Bhatt, S., Lemey, P., Wu, C., Rambaut, A., Loman, N. J., Aguiar, R. S., Pybus, O. G., Sabino, E. C., Faria, N., Brazil-UK Ctr Arbovirus Discovery 2020; 369 (6508): 1255-+


    Brazil currently has one of the fastest-growing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemics in the world. Because of limited available data, assessments of the impact of nonpharmaceutical interventions (NPIs) on this virus spread remain challenging. Using a mobility-driven transmission model, we show that NPIs reduced the reproduction number from >3 to 1 to 1.6 in São Paulo and Rio de Janeiro. Sequencing of 427 new genomes and analysis of a geographically representative genomic dataset identified >100 international virus introductions in Brazil. We estimate that most (76%) of the Brazilian strains fell in three clades that were introduced from Europe between 22 February and 11 March 2020. During the early epidemic phase, we found that SARS-CoV-2 spread mostly locally and within state borders. After this period, despite sharp decreases in air travel, we estimated multiple exportations from large urban centers that coincided with a 25% increase in average traveled distances in national flights. This study sheds new light on the epidemic transmission and evolutionary trajectories of SARS-CoV-2 lineages in Brazil and provides evidence that current interventions remain insufficient to keep virus transmission under control in this country.

    View details for DOI 10.1126/science.abd2161

    View details for Web of Science ID 000567525400055

    View details for PubMedID 32703910

    View details for PubMedCentralID PMC7402630

  • Pervasive Inter-Individual Variation in Allele-Specific Expression in Monozygotic Twins FRONTIERS IN GENETICS Francisco Junior, R., Ferreira, C., Santos e Silva, J., Machado, D., Martins, Y., Ramos, V., Carnivali, G., Garcia, A., Medina-Acosta, E. 2019; 10: 1178


    Despite being developed from one zygote, heterokaryotypic monozygotic (MZ) co-twins exhibit discordant karyotypes. Epigenomic studies in biological samples from heterokaryotypic MZ co-twins are of the most significant value for assessing the effects on gene- and allele-specific expression of an extranumerary chromosomal copy or structural chromosomal disparities in otherwise nearly identical germline genetic contributions. Here, we use RNA-Seq data from existing repositories to establish within-pair correlations for the breadth and magnitude of allele-specific expression (ASE) in heterokaryotypic MZ co-twins discordant for trisomy 21 and maternal 21q inheritance, as well as homokaryotypic co-twins. We show that there is a genome-wide disparity at ASE sites between the heterokaryotypic MZ co-twins. Although most of the disparity corresponds to changes in the magnitude of biallelic imbalance, ASE sites switching from either strictly monoallelic to biallelic imbalance or the reverse occur in few genes that are known or predicted to be imprinted, subject to X-chromosome inactivation or A-to-I(G) RNA edited. We also uncovered comparable ASE differences between homokaryotypic MZ twins. The extent of ASE discordance in MZ twins (2.7%) was about 10-fold lower than the expected between pairs of unrelated, non-twin males or females. The results indicate that the observed within-pair dissimilarities in breadth and magnitude of ASE sites in the heterokaryotypic MZ co-twins could not solely be attributable to the aneuploidy and the missing allelic heritability at 21q.

    View details for DOI 10.3389/fgene.2019.01178

    View details for Web of Science ID 000558115100001

    View details for PubMedID 31850058

    View details for PubMedCentralID PMC6887657

  • Evidence for Clonally Associated Increasing Rates of Azithromycin Resistant Neisseria gonorrhoeae in Rio de Janeiro, Brazil BIOMED RESEARCH INTERNATIONAL Barros dos Santos, K. T., Skaf, L. B., Justo-da-Silva, L. H., Medeiros, R. C., Francisco Junior, R. S., Canine, M. A., Fracalanzza, S. L., Bonelli, R. R. 2019; 2019: 3180580


    Azithromycin is one of the drugs used in the combined therapy for syndromic treatment of gonorrhoea in many countries, including Brazil. Our research group, which receives isolates from clinical laboratories since 2006, has detected, after 2016, a tendency of rising rates of azithromycin resistance, with isolates showing higher minimal inhibitory concentrations (MICs) than those previously reported in this country. In this study, we report the susceptibility to azithromycin of 93 N. gonorrhoeae isolates obtained between 2014 and 2017. Strains with MIC ≥2 μg/mL were characterized according to azithromycin resistance mechanisms and strain typing. Results indicate that azithromycin resistance has emerged in all these years in unrelated MLST-STs, but after 2016 a clonal complex connected with ST1901 has been more frequently detected, grouping isolates with MIC varying from 2 to 64 μg/mL, with DelA mutations at the mtrR promoter region associated or not with mutations at rrl alleles. High rates of azithromycin resistance may compromise the use of this drug in the combined therapy with ceftriaxone. Inclusion of Rio de Janeiro in the Brazilian gonococcal surveillance program is important to evaluate if this data indicates an epidemiological phenomenon in the country.

    View details for DOI 10.1155/2019/3180580

    View details for Web of Science ID 000458000900001

    View details for PubMedID 30800666

    View details for PubMedCentralID PMC6360546

  • Maternal 5(m)CpG Imprints at the PARD6G-AS1 and GCSAML Differentially Methylated Regions Are Decoupled From Parent-of-Origin Expression Effects in Multiple Human Tissues FRONTIERS IN GENETICS Machado Araujo, G., da Silva Francisco Junior, R., Ferreira, C., Mozer Rodrigues, P., Machado, D., de Souza, T., de Souza, J., Osorio da Silva, C., Alves da Silva, A., Franco Andrade, C., da Silva, A., Ramos, V., Garcia, A., Machado, F., Medina-Acosta, E. 2018; 9: 36


    A hallmark of imprinted genes in mammals is the occurrence of parent-of-origin-dependent asymmetry of DNA cytosine methylation (5mC) of alleles at CpG islands (CGIs) in their promoter regions. This 5mCpG asymmetry between the parental alleles creates allele-specific imprinted differentially methylated regions (iDMRs). iDMRs are often coupled to the transcriptional repression of the methylated allele and the activation of the unmethylated allele in a tissue-specific, developmental-stage-specific and/or isoform-specific fashion. iDMRs function as regulatory platforms, built through the recruitment of chemical modifications to histones to achieve differential, parent-of-origin-dependent chromatin segmentation states. Here, we used a comparative computational data mining approach to identify 125 novel constitutive candidate iDMRs that integrate the maximal number of allele-specific methylation region records overlapping CGIs in human methylomes. Twenty-nine candidate iDMRs display gametic 5mCpG asymmetry, and another 96 are candidate secondary iDMRs. We established the maternal origin of the 5mCpG imprints of one gametic (PARD6G-AS1) and one secondary (GCSAML) iDMRs. We also found a constitutively hemimethylated, nonimprinted domain at the PWWP2AP1 promoter CGI with oocyte-derived methylation asymmetry. Given that the 5mCpG level at the iDMRs is not a sufficient criterion to predict active or silent locus states and that iDMRs can regulate genes from a distance of more than 1 Mb, we used RNA-Seq experiments from the Genotype-Tissue Expression project and public archives to assess the transcriptional expression profiles of SNPs across 4.6 Mb spans around the novel maternal iDMRs. We showed that PARD6G-AS1 and GCSAML are expressed biallelically in multiple tissues. We found evidence of tissue-specific monoallelic expression of ZNF124 and OR2L13, located 363 kb upstream and 419 kb downstream, respectively, of the GCSAML iDMR. We hypothesize that the GCSAML iDMR regulates the tissue-specific, monoallelic expression of ZNF124 but not of OR2L13. We annotated the non-coding epigenomic marks in the two maternal iDMRs using data from the Roadmap Epigenomics project and showed that the PARD6G-AS1 and GCSAML iDMRs achieve contrasting activation and repression chromatin segmentations. Lastly, we found that the maternal 5mCpG imprints are perturbed in several hematopoietic cancers. We conclude that the maternal 5mCpG imprints at PARD6G-AS1 and GCSAML iDMRs are decoupled from parent-of-origin transcriptional expression effects in multiple tissues.

    View details for DOI 10.3389/fgene.2018.00036

    View details for Web of Science ID 000426393600001

    View details for PubMedID 29545821

    View details for PubMedCentralID PMC5838017

  • Trisomy 21 Alters DNA Methylation in Parent-of-Origin-Dependent and -Independent Manners PLOS ONE Alves da Silva, A., Machado, F., Pavarino, E., Biselli-Perico, J., Zampieri, B., Francisco Junior, R., Mozer Rodrigues, P., Machado, D., Santos-Reboucas, C., Fernandes, M., Chuva de Sousa Lopes, S., Lopes Rios, A., Medina-Acosta, E. 2016; 11 (4): e0154108


    The supernumerary chromosome 21 in Down syndrome differentially affects the methylation statuses at CpG dinucleotide sites and creates genome-wide transcriptional dysregulation of parental alleles, ultimately causing diverse pathologies. At present, it is unknown whether those effects are dependent or independent of the parental origin of the nondisjoined chromosome 21. Linkage analysis is a standard method for the determination of the parental origin of this aneuploidy, although it is inadequate in cases with deficiency of samples from the progenitors. Here, we assessed the reliability of the epigenetic 5mCpG imprints resulting in the maternally (oocyte)-derived allele methylation at a differentially methylated region (DMR) of the candidate imprinted WRB gene for asserting the parental origin of chromosome 21. We developed a methylation-sensitive restriction enzyme-specific PCR assay, based on the WRB DMR, across single nucleotide polymorphisms (SNPs) to examine the methylation statuses in the parental alleles. In genomic DNA from blood cells of either disomic or trisomic subjects, the maternal alleles were consistently methylated, while the paternal alleles were unmethylated. However, the supernumerary chromosome 21 did alter the methylation patterns at the RUNX1 (chromosome 21) and TMEM131 (chromosome 2) CpG sites in a parent-of-origin-independent manner. To evaluate the 5mCpG imprints, we conducted a computational comparative epigenomic analysis of transcriptome RNA sequencing (RNA-Seq) and histone modification expression patterns. We found allele fractions consistent with the transcriptional biallelic expression of WRB and ten neighboring genes, despite the similarities in the confluence of both a 17-histone modification activation backbone module and a 5-histone modification repressive module between the WRB DMR and the DMRs of six imprinted genes. We concluded that the maternally inherited 5mCpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in several tissues and that trisomy 21 alters DNA methylation in parent-of-origin-dependent and -independent manners.

    View details for DOI 10.1371/journal.pone.0154108

    View details for Web of Science ID 000374898500146

    View details for PubMedID 27100087

    View details for PubMedCentralID PMC4839675