Biology subjects

Passos-Bueno, M. R.

Publications and source records attributed to Passos-Bueno, M. R..

6 recordsLinked to original sources

bioRxiv2025

Maternal-fetal inflammation affects Cdh1/E-cadherin epigenetic regulation and craniofacial development

Cleft lip with or without palate (CLP) is a multifactorial trait associated with environmental exposures such as smoking, alcohol consumption, and pro-inflammatory conditions during early pregnancy, as well as with both common and rare genetic variants. Our group identified CDH1 loss-of-function variants segregating in families with CLP, with incomplete penetrance linked to promoter hypermethylation. Previously, we demonstrated that gene-environment interactions driven by pro-inflammatory factors can induce this methylation, downregulate E-cadherin expression, and impair neural crest migration, thereby contributing to the etiology of CLP. However, the embryonic consequences of the two-hit CLP model (CDH1 haploinsufficiency combined with pro-inflammatory insult) have not yet been explored in mammals. Here, under single dose of floxed-Cdh1, we investigated the pro-inflammatory response at the maternal-fetal interface, its impact on cytokine and Cdh1 expression along the anteroposterior axis, the associated epigenetic landscape in the embryonic head, and the effect on cranial structures. We found that pro-inflammatory activation differentially signals to the embryo between anterior and posterior regions, impairing Cdh1/E-cadherin expression in NC cells of the head, accompanied by Cdh1 promoter hypermethylation and other differentially methylated genes involved in cell-junction maintenance. Our findings support a model in which maternal pro-inflammatory responses act as environmental factors that repress NC CDH1 expression through epigenetic mechanisms, contributing to CLP development by downregulating E-cadherin and potentially compromising overall epithelial integrity. Animal Ethics Committee (CEUA IB/USP) number approval: 394/2022

developmental biology↗

bioRxiv2023

Optimal HLA imputation of admixed population with dimension reduction

Human genomics has quickly evolved, powering genome-wide association studies (GWASs). SNP-based GWASs cannot capture the intense polymorphism of HLA genes, highly associated with disease susceptibility. There are methods to statistically impute HLA genotypes from SNP-genotypes data, but lack of diversity in reference panels hinders their performance. We evaluated the accuracy of the 1,000 Genomes data as a reference panel for imputing HLA from admixed individuals of African and European ancestries, focusing on (a) the full dataset, (b) 10 replications from 6 populations, (c) 19 conditions for the custom reference panels. The full dataset outperformed smaller models, with a good F1-score of 0.66 for HLA-B. However, custom models outperformed the multiethnic or population models of similar size (F1-scores up to 0.53, against up to 0.42). We demonstrated the importance of using genetically specific models for imputing admixed populations, which are currently underrepresented in public datasets, opening the door to HLA imputation for every genetic population.

genomics↗

bioRxiv2020

Whole-genome sequencing of 1,171 elderly admixed individuals from the largest Latin American metropolis (Sao Paulo, Brazil)

As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enabled identifying ~2,000 novel mobile element insertions, nearly 5Mb of genomic segments absent from human genome reference, and over 140 novel alleles from HLA genes. We reclassified and curated nearly four hundred variant's pathogenicity assertions in genes associated with dominantly inherited Mendelian disorders and calculated the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observed that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS.

genomics↗

bioRxiv2019

"mir152 hypomethylation, potentially triggered by embryonic hypoxia, as a mechanism for non-syndromic cleft lip/palate"

Non-syndromic cleft lip/palate (NSCLP), the most common human craniofacial malformations, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological and epigenetic findings. Association of epigenetic variations with NSCLP has been made, however still of little functional investigation. Here we combined a reanalysis of NSCLP methylome data with genetic analysis and used both in vitro and in vivo approaches to dissect the functional effects of epigenetic changes. We found a frequent differentially methylated region in mir152, hypomethylated in NSCLP cohorts (21-26%), leading to mir152 overexpression. In vivo analysis using zebrafish embryos revealed that mir152 upregulation leads to craniofacial impairment analogue to palatal defects. Also, we demonstrated that zebrafish embryonic hypoxia leads to mir152 upregulation combined with mir152 hypomethylation and also analogue palatal alterations. We therefore suggest mir152 hypomethylation, potentially induced by hypoxia in early development, as a novel and frequent predisposing factor to NSCLP.

developmental biology↗

bioRxiv2019

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass- and fat mass-indexes

Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely under-represented in genomic studies. Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of Body Mass Index (BMI) in three population-based cohorts from Northeast (Salvador), Southeast (Bambui) and South (Pelotas) of the country. We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p= 2.76 e-06). This variant is very rare in Europeans but with frequencies of ~3% in West Africa, and has a strong female-specific effect (95%CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat-mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from Sao Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among morbidly obese women from Pelotas, Sao Paulo, and Bambui. The effect size of rs114066381 is at least five-times the effect size of the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects, and for which we replicated associations in Pelotas. We demonstrate how, after a decade of GWAS mostly performed in European-ancestry populations, non-European and admixed populations are a source of new relevant phenotype-associated genetic variants.

genetics↗

bioRxiv2019

Structural variation of the malaria-associated human glycophorin A-B-E region

Approximately 5% of the human genome consists of structural variants, which are enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120kb in length, carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A and glycophorin B are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They act as receptors for invasion of a causative agent of malaria, Plasmodium falciparum. A particular complex structural variant (DUP4) that creates a GYPB/GYPA fusion gene is known to confer resistance to malaria. Many other structural variants exist, and remain poorly characterised. Here, we analyse sequences from 6466 genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection using fibre-FISH and breakpoint mapping. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by unequal cross over events (non-allelic homologous recombination, NAHR) and. by comparing the structural variant breakpoints with recombination hotspot maps, show the importance of a particular meiotic recombination hotspot on structural variant formation in this region.

genetics↗