Biology subjects

Oliveira, G.

Publications and source records attributed to Oliveira, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Programmable antigen-presenting scaffolds expand rare tumor-antigen-specific T cells from peripheral blood

Adoptive cellular therapies can be effective against solid tumors but rely on the identification and expansion of rare tumor-reactive T cells (TRTs). Here, we utilize antigen-presenting cell-mimetic scaffolds (APC-ms), a modular biomaterial platform that presents defined peptide-HLA and co-stimulatory ligands on a fluid lipid bilayer to selectively recover rare antigen-specific T cells from peripheral blood. Independent variation of peptide-HLA, co-stimulatory ligands, and cytokine support defined a formulation that enriched MART-1-specific T cells to above 2% of CD8+ T cells in 35 of 50 HLA-A*02:01+ healthy donors from low or undetectable baseline frequencies. Compared with mo-DCs, APC-ms achieved greater fold expansion of MART-1-specific T cells with increased functional avidity and preservation of an early differentiation phenotype, and generated a higher number of MART-1-specific clonotypes. In five of eight patients with treatment-naive melanoma, APC-ms could enrich MART-1-specific T cells to a median of 13.7% of CD8+ cells (range 0.30 - 57.2%) Moreover, APC-ms could expand T cells specific for an HLA-A*24:01-restricted personal neoantigen that were previously undetectable in peripheral blood of a patient with melanoma. These findings establish APC-ms as a tunable platform for the recovery of rare TRTs from peripheral blood, supporting its further development for therapeutic TCR discovery and personalized adoptive cell therapy.

immunology↗

bioRxiv2026

Sustained GnRH Agonism Alters Endocrine Dynamics and Pubertal Progression in Juvenile Rats

PurposeGonadotropin releasing hormone (GnRH) agonists are clinically used to delay pubertal progression by suppressing the hypothalamic-pituitary-gonadal (HPG) axis. While GnRH agonists have long been used clinically, the developmental characterization of HPG axis suppression during puberty remains incompletely understood. Thus, we examined the effects of GnRH receptor agonism in juvenile rats. HypothesisSustained GnRH receptor agonism will result in lower gonadal mass, blunt peripheral pubertal landmarks, and alter hormonal signaling dynamics within the HPG axis. MethodsAnimals received a single injection of extended-release leuprolide acetate depot (LA) or vehicle control on postnatal day (PND) 23. Animals were assessed for body mass and peripheral markers of puberty. On PND 44, animals were euthanized and tissues were evaluated to assess additional markers of pubertal maturation, pituitary gene transcript levels, and hormone concentrations in serum and gonads. ResultsIn females, LA treatment resulted in a smaller gonad size, increased body mass, and less vaginal openings. In males, LA treatment resulted in smaller gonads but did not significantly alter body mass or preputial separation. In the pituitary, LA-treated rats had lower Gnrhr, Fshb, and Lhb transcript levels regardless of sex, while females exhibited higher Cga and Nr5a1. Serum FSH and ACTH were lower in LA-treated animals, and treated females also had lower progestins and androstenedione, and higher LH. ConclusionsLA treatment reduced aspects of pubertal maturation and HPG axis output, with sex specific outcomes. These findings highlight the need for integrated, multi-level approaches to understand how altered GnRH signaling impacts pubertal and long-term physiology.

Developmental Biology↗

bioRxiv2026

VDJdive and ECLIPSE enhance single-cell TCR sequencing analysis through the probabilistic resolution of ambiguous clonotypes

Single-cell T cell receptor sequencing (scTCR-seq) has transformed our ability to track individual T cell clones and has been instrumental in advancing our understanding of human T cell differentiation. However, current computational pipelines for analysis, which require precise matching of CDR3 sequences from exactly 2 heterodimeric TCR chains to define the clonotype for each cell, are inherently limited because of the substantial proportion of cells possessing "ambiguous" clonotypes driven by missing (undetected from the technical issue of chain "dropout") or extra chains (present from either true biological expression or due to technical artifacts such as cellular doublets and ambient TCR contamination). As a result, clone sizes are artificially reduced, impeding the tracking of clones across conditions and differentiation states. Here we introduce VDJdive and ECLIPSE (Enhanced CLonotypic Inference via Prediction of Single-cell Expression), two computational methods that, together, resolve this clonal ambiguity by utilizing the expectation-maximization algorithm for the clonal prediction of ambiguous cells. These methods consider chain pairings across the sample, allowing for high-fidelity prediction of chains lost due to dropout and the discernment of biological expression of extra chains from technical artifacts. Consequently, clone sizes are augmented and cells without clonotype assignments are minimized. Our approach facilitates enhanced clonal tracking through these elevated clone sizes and is easily implementable, compatible with standard single-cell transcriptomic workflows, and broadly applicable across biological contexts and T cell subsets.

immunology↗

bioRxiv2025

Gene-based analysis identifies novel microRNA candidates for Autism Spectrum Disorder

BackgroundAutism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with unclear physiopathology. Biomarker-based diagnostic tools for early detection and targeted treatments have yet to be developed. MicroRNAs (miRNAs), which are critical regulators of genes involved in brain development and function, are emerging as promising candidates as molecular mechanisms, biomarkers, and therapeutic targets for ASD. This study aimed to identify miRNAs involved in ASD and evaluate their potential functions through in silico analysis. MethodsA comprehensive analysis was performed to find genomic variants with a predicted functional impact on miRNA activity. Using large datasets of Single Nucleotide Variants (SNVs, N = 4300) and Copy Number Variants (CNVs, N = 3570) from ASD cases, we identified miRNAs targeted by CNVs or containing SNVs predicted to disrupt their function in ASD subjects, and compared their frequencies with controls. Selected regulatory miRNA-mRNA networks and their associated biological functions were characterized. ResultsSeventy mature miRNAs were identified, including both previously reported and novel ASD candidates, predicted to regulate 2742 brain-expressed genes. Enrichment analysis revealed their involvement in cellular signaling, transcription regulation, protein metabolism, and chromatin organization - biological processes strongly related to ASD. Notably, 63% of these miRNAs are predicted to target 71 known ASD risk genes and the KCNB1, MECP2, NCKAP1 and ZBTB20 genes are each regulated by at least four miRNAs. ConclusionsThis gene-based analysis identified miRNAs regulating gene networks and biological pathways implicated in brain function and plasticity, frequently disrupted in ASD. These findings strengthen the evidence for miRNA involvement in ASD, paving the way for novel diagnostic and therapeutic strategies.

genetics↗

bioRxiv2023

Do you have enough space? Habitat selection of insectivorous cave-dwelling bats in fragmented landscapes of Eastern Amazon

Individual movements of bats result from a compromise between their recognition of the environment and their potential to fulfill bats life requirements, and to the potential threats associated with moving, all of this is mediated by habitat selection. Mining activities produce modifications to the environments that add heterogeneity and fragmentation to the landscapes used by bats, with overall poorly understood consequences to their movements and to the underground-related biodiversity. Cave dwelling bats spend a large part of their life cycle within their roosts, and they are of paramount importance to the subterranean biodiversity because of their constant movements between the external landscapes, which they selectively use, and the underground ecosystems, where they usually apport energy in form of organic matter. We investigated the variation of patterns of habitat use and selection by cave-dwelling bats in a mosaic of disturbed and conserved Eastern Amazonian forests and rupestrian iron-rich savannas (cangas) interspersed in an extensive iron-caves system. We studied the movements of two phylogenetically distant related insectivores, the aerial insect-catcher Furipterus horrens (Furipteridae) and the foliage gleaning bat Lonchorhina aurita (Phyllostomidae), both cave-dependent in the study area, one of them categorized as threatened to extinction in Brazil, and virtually unknown in terms of their movement behavior, and habitat use. We used radio telemetry to assess habitat use, under the prediction that these species prefer natural and conserved habitats for their foraging bouts, avoiding human-modified habitats. We also anticipated larger range-areas and commuting distances for both species when foraging in disturbed landscapes. Thirty-one bats were monitored in different landscapes (conserved Amazonian ombrophilous forests and cangas, mining sites and pasture) resulting in an average range of 346.9 {+/-} 762.5 ha and an average commuting distance of 1921.5 {+/-} 2269.7 m for F. horrens and of 716.8 {+/-} 1000.6 ha and 2582.2 {+/-} 1966.0 m for L. aurita. Our habitat selection analyses suggest that Furipterus horrens is an open space forager, with individuals frequently recorded foraging in cangas, and L. aurita is a forest forager, although using all habitats proportionally to their availability in the landscape. We did not detect landscape-related effects to the use of space by both species, whereas seasonal variation emerged as a relevant effect. This is the first time that movement data for F. horrens and L. aurita is presented. Our study delivers original baseline data on movement behavior and conservation of these threatened cave-dwelling bat species with virtually unknown biology and shed light into constraints related to the optimal and adjusted biological cycles of the bats and their range areas under scenarios of disturbance.

ecology↗

bioRxiv2023

Yerba mate (Ilex paraguariensis) genome provides new insights into convergent evolution of caffeine biosynthesis

Yerba mate (Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large yerba mate genome size is partly due to a whole-genome duplication (Ip-) during the early evolutionary history of Ilex, in addition to the hexaploidization event ({gamma}) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of its relatives, coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in yerba mate and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the x-ray diffraction data suggests structural constraints are minimal for the convergent evolution of individual reactions.

plant biology↗

bioRxiv2023

STAPLER: Efficient learning of TCR-peptide specificity prediction from full-length TCR-peptide data

The prediction of peptide-MHC (pMHC) recognition by {beta} T-cell receptors (TCRs) remains a major biomedical challenge. Here, we develop STAPLER (Shared TCR And Peptide Language bidirectional Encoder Representations from transformers), a transformer language model that uses a joint TCR{beta}- peptide input to allow the learning of patterns within and between TCR{beta} and peptide sequences that encode recognition. First, we demonstrate how data leakage during negative data generation can confound performance estimates of neural network-based models in predicting TCR - pMHC specificity. We then demonstrate that, because of its pre-training and fine-tuning masked language modeling tasks, STAPLER outperforms both neural network-based and distance-based ML models in predicting the recognition of known antigens in an independent dataset, in particular for antigens for which little related data is available. Based on this ability to efficiently learn from limited labeled TCR- peptide data, STAPLER is well-suited to utilize growing TCR - pMHC datasets to achieve accurate prediction of TCR - pMHC specificity.

bioinformatics↗

bioRxiv2022

Overview of the SARS-CoV-2 genotypes circulating in Latin America during 2021

Latin America is one of the regions in which the COVID-19 pandemic has had a stronger impact, with more than 72 million reported infections and 1.6 million deaths until June 2022. Since this region is ecologically diverse and is affected by enormous social inequalities, efforts to identify genomic patterns of the circulating SARS-CoV-2 genotypes are necessary for the suitable management of the pandemic. To contribute to the genomic surveillance of the SARS-CoV-2 in Latin America, we extended the number of SARS-CoV-2 genomes available from the region by sequencing and analyzing the viral genome from COVID-19 patients from seven countries (Argentina, Brazil, Costa Rica, Colombia, Mexico, Bolivia and Peru). Subsequently, we analyzed the genomes circulating mainly during 2021 including records from GISAID database from Latin America. A total of 1534 genome sequences were generated from seven countries, demonstrating the laboratory and bioinformatics capabilities for genomic surveillance of pathogens that have been developed locally. For Latin America, patterns regarding several variants associated with multiple re-introductions, a relatively low percentage of sequenced samples, as well as an increment in the mutation frequency since the beginning of the pandemic, are in line with worldwide data. Besides, some variants of concern (VOC) and variants of interest (VOI) such as Gamma, Mu and Lambda, and at least 83 other lineages have predominated locally with a country-specific enrichments. This work has contributed to the understanding of the dynamics of the pandemic in Latin America as part of the local and international efforts to achieve timely genomic surveillance of SARS-CoV-2.

microbiology↗

bioRxiv2022

Genomic and phenotypic analyses suggest moderate fitness differences among Zika virus lineages

RNA viruses have short generation times and high mutation rates, allowing them to undergo rapid molecular evolution during epidemics. However, the extent of RNA virus phenotypic evolution within epidemics and the resulting effects on fitness and virulence remain mostly unknown. Here, we screened the 2015-2016 Zika epidemic in the Americas for lineage-specific fitness differences. We engineered a library of recombinant viruses representing twelve major Zika virus lineages and used them to measure replicative fitness within disease-relevant human primary cells and live mosquitoes. We found that two of these lineages conferred significant in vitro replicative fitness changes among human primary cells, but we did not find fitness changes in Aedes aegypti mosquitoes. Additionally, we found evidence for elevated levels of positive selection among five amino acid sites that define major Zika virus lineages. While our work suggests that Zika virus may have acquired several phenotypic changes during a short time scale, these changes were relatively moderate and do not appear to have enhanced virulence or transmission during the epidemic.

evolutionary biology↗

bioRxiv2021

Genomic analysis of a parasite invasion: colonization of the Americas by the blood fluke, Schistosoma mansoni

Schistosoma mansoni, a snail-vectored, blood fluke that infects humans, was introduced into the Americas from Africa during the Trans-Atlantic slave trade. As this parasite shows strong specificity to the snail intermediate host, we expected that adaptation to S. American Biomphalaria spp. snails would result in population bottlenecks and strong signatures of selection. We scored 475,081 single nucleotide variants (SNVs) in 143 S. mansoni from the Americas (Brazil, Guadeloupe, and Puerto Rico) and Africa (Cameroon, Niger, Senegal, Tanzania, and Uganda), and used these data to ask: (i) Was there a population bottleneck during colonization? (ii) Can we identify signatures of selection associated with colonization? And (iii) what were the source populations for colonizing parasites? We found a 2.4-2.9-fold reduction in diversity and much slower decay in linkage disequilibrium (LD) in parasites from East to West Africa. However, we observed similar nuclear diversity and LD in West Africa and Brazil, suggesting no strong bottlenecks and limited barriers to colonization. We identified five genome regions showing selection in the Americas, compared with three in West Africa and none in East Africa, which we speculate may reflect adaptation during colonization. Finally, we infer that unsampled African populations from central African regions between Benin and Angola, with contributions from Niger, are likely the major source(s) for Brazilian S. mansoni. The absence of a bottleneck suggests that this is a rare case of a serendipitous invasion, where S. mansoni parasites were preadapted to the Americas and were able to establish with relative ease.

evolutionary biology↗

bioRxiv2021

Prime Editing Efficiency and Fidelity are Enhanced in the Absence of Mismatch Repair

Prime editing (PE) is a powerful genome engineering approach that enables the introduction of base substitutions, insertions and deletions into any given genomic locus. However, the efficiency of PE varies widely and depends not only on the genomic region targeted, but also on the genetic background of the edited cell. To determine which cellular factors affect PE efficiency, we carried out a focused genetic screen targeting 32 DNA repair factors, spanning all reported repair pathways. We show that, depending on cell line and type of edit, ablation of mismatch repair (MMR) affords a 2-17 fold increase in PE efficiency, across several human cell lines, types of edits and genomic loci. The accumulation of the key MMR factors MLH1 and MSH2 at PE sites argues for direct involvement of MMR in PE control. Our results shed new light on the mechanism of PE and suggest how its efficiency might be optimised.

molecular biology↗

bioRxiv2021

Optimized liquid and gas phase fractionation increase HLA-peptidome coverage for primary cell and tissue samples

Mass spectrometry is the most effective method to directly identify peptides presented on HLA molecules. However, current standard approaches often require many millions of cells for input material to achieve high coverage of the immunopeptidome and are therefore not compatible with the often limited amounts of tissue available from clinical tumor samples. Here, we evaluated microscaled basic reversed-phase fractionation to separate HLA peptide samples off-line followed by ion mobility coupled to LC-MS/MS for analysis. The combination of these two separation methods enabled identification of 20% to 50% more peptides compared to samples analyzed without either prior fractionation or use of ion mobility alone. We demonstrate coverage of HLA immunopeptidomes with up to 8,107 distinct peptides starting with as few as 100 million cells or 150 milligrams of wet weight tumor tissue. This increased sensitivity can improve HLA binding prediction algorithms and enable detection of clinically relevant epitopes such as neoantigens.

biochemistry↗

bioRxiv2021

PIMBA: a PIpeline for MetaBarcoding Analysis

SummaryDNA metabarcoding is an emerging monitoring method capable of assessing biodiversity from environmental samples (eDNA). Advances in computational tools have been required due to the increase of Next-Generation Sequencing data. Tools for DNA metabarcoding analysis, such as MOTHUR, QIIME, Obitools, and mBRAVE have been widely used in ecological studies. However, some difficulties are encountered when there is a need to use custom databases. Here we present PIMBA, a PIpeline for MetaBarcoding Analysis, which allows the use of customized databases, as well as other reference databases used by the softwares mentioned here. PIMBA is an open-source and user-friendly pipeline that consolidates all analyses in just three command lines. Availability and Implementationhttps://github.com/reinator/pimba Contactrenato.renison@gmail.com and guilherme.oliveira@pq.itv.org.

bioinformatics↗

bioRxiv2020

Two sides of a coin: a Zika virus mutation selected in pregnant rhesus macaques promotes fetal infection in mice but at a cost of reduced fitness in nonpregnant macaques and diminished transmissibility by vectors

Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intra-host mutation, M1404I, in the ZIKV polyprotein, located in NS2B. Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at sub-consensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I occurs rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases fitness in non-pregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to M1404, we observed that I1404 produced lower viremias in non-pregnant macaques and was a weaker competitor in tissues. In pregnant wildtype mice ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, contrasting with M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Ae. aegypti transmitted ZIKV I1404 more poorly than M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics, and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics. IMPORTANCEAlthough Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with it in non-pregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of non-pregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in non-pregnant hosts.

microbiology↗

bioRxiv2020

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

Tumor epitopes - peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.

cancer biology↗

bioRxiv2019

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ), and due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935. We synthesized a novel and potent LSD1 inhibitor, MC3935, which was used to treat schistosomula or adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors. Author SummarySchistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminth Schistosoma mansoni. The control and treatment of the disease rely almost exclusively on praziquantel (PZQ). Thus, there is an urgent need to search for promising protein targets to develop new drugs. Drugs that inhibit enzymes that modify the chromatin structure have been developed for a number of diseases. We and others have shown that S. mansoni epigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of the S. mansoni histone demethylase LSD1 (SmLSD1) as a drug target. We reported the synthesis of a novel and potent LSD1 inhibitor, MC3935, and show that it selectively inhibited the enzymatic activity of SmLSD1. Treatment of juvenile or adult worms with MC3935 caused severe damage to the tegument of the parasites and compromised egg production. Importantly, MC3935 proved to be highly toxic to S. mansoni, culminating in the death of juvenile or adult worms within 96 h. Transcriptomic analysis of MC3935-treated parasites revealed changes in the gene expression of hundreds of genes involved in key biological processes. Importantly, SmLSD1 contains unique sequences within its polypeptide chain that could be explored to develop a S. mansoni selective drug.

molecular biology↗

bioRxiv2019

Habitat loss does not always entail negative genetic consequences

Although habitat loss has large, consistently negative effects on biodiversity, its genetic consequences are not yet fully understood. In this paper, we assess the genetic consequences of extreme habitat loss driven by mining in two endemic plants from Amazonian Savannas. Our analyses are the first to overcome major methodological limitations like the confounding effect of habitat fragmentation, historical processes underpinning genetic differentiation, time-lags between the onset of disturbances and genetic outcomes, and the need for large numbers of samples, genetic markers and replicated landscapes to ensure sufficient statistical power. We found that both species are remarkably resilient, as genetic diversity and gene flow patterns were unaffected by habitat loss. Our study unambiguously demonstrates that it is not possible to generalize about the genetic consequences of habitat loss, and imply that future conservation efforts need to consider species-specific genetic information.

ecology↗

bioRxiv2019

A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

IntroductionAutism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder defined by deficits in social communication and interaction and repetitive and stereotyped interests and behaviors. ASD heritability estimates of 50-83% support a strong role of genetics in its onset, with large sequencing studies reporting a high burden of rare potentially pathogenic copy number variants (CNVs) and single nucleotide variants (SNVs) in affected subjects. Recent data strongly suggests that prenatal to postnatal exposure to ubiquitous environmental factors (e.g. environmental toxins, medications and nutritional factors) contribute to ASD risk. Detoxification processes and physiological permeability barriers (i.e. blood-brain barrier, placenta and respiratory cilia) are crucial in regulating exposure and response to external agents during early development. Thus, the objectives of this study were: 1) to find genes involved in detoxification and regulation of barriers permeability with a high load of relevant CNVs and SNVs in ASD subjects; 2) to explore interactions between the identified genes and environmental factors relevant for the disorder.\n\nMaterial and MethodsThrough literature and databases review we searched for genes involved in detoxification and regulation of barriers permeability processes. Genetic data collected from large datasets of subjects with ASD (Autism Genome Project (AGP), Simmons Simplex Collection (SSC), and Autism Sequencing Consortium (ASC)) was used to identify potentially pathogenic variants targeting detoxification and barrier genes. Data from control subjects without neuropsychiatric disorder history was used for comparison purposes. The Comparative Toxicogenomics Database (CTD) was interrogated to identify putatively relevant gene-environment interactions reported in humans throughout the literature.\n\nResultsWe compiled a list of 519 genes involved in detoxification and regulation of permeability barriers. The analysis of AGP and SSC data resulted in the identification of 7 genes more-frequently targeted by CNVs in ASD-subjects from both datasets, after Bonferroni correction for multiple testing (AGP: P<3.5211x10-4; SSC: P< 4.587x10-4). Moreover, 8 genes were exclusively targeted by CNVs from ASD subjects. Regarding SNVs analyses using the ASC dataset, we found 40 genes targeted by potentially pathogenic loss-of-function and/or missense SNVs exclusive to 6 or more cases. The CTD was interrogated for interactions between 55 identified genes and 54 terms for unique chemicals associated with the disorder. A total of 212 gene-environment interaction pairs, between 51/55 (92.7%) genes and 38/54 (70.4%) chemicals, putatively relevant for ASD, were discovered. ABCB1, ABCG2, CYP2C19, GSTM1, CYP2D6, and SLC3A2 were the genes that interacted with more chemicals, while valproic acid, benzo(a)pyrene (b(a)p), bisphenol A, particulate matter and perfluorooctane sulfonic acid (PFOS) were the top chemicals.\n\nDiscussionThe identified genes code for functionally diverse proteins, ranging from enzymes that increase the degradability of xenobiotics (CYP450s, UGTs and GSTs), to transporters (ABCs and SLCs), proteins that regulate the correct function of barriers (claudins and dyneins) and placental hormones. The identified gene-environment interactions may reflect the fact that some genes and chemicals are understudied and that the potential neurotoxicity of many substances is unreported. We suggest that environmental factors can have pathogenic effects when individuals carry variants targeting these genes and discuss the potential mechanisms by which these genes can influence ASD risk.\n\nConclusionWe reinforce the hypothesis that gene-environment interactions are relevant, at least, for a subset of ASD cases. Given that no treatment exists for the pathology, the identification of relevant modifiable exposures can contribute to the development of preventive strategies for health management policies in ASD.

genetics↗