Luis B Barreiro

Université de Montréal, Montréal, Quebec, Canada

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Publications (51)499.1 Total impact

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    ABSTRACT: Social relationships have profound effects on health in humans and other primates, but the mechanisms that explain this relationship are not well understood. Using shotgun metagenomic data from wild baboons, we found that social group membership and social network relationships predicted both the taxonomic structure of the gut microbiome and the structure of genes encoded by gut microbial species. Rates of interaction directly explained variation in the gut microbiome, even after controlling for diet, kinship, and shared environments. They therefore strongly implicate direct physical contact among social partners in the transmission of gut microbial species. We identified 51 socially structured taxa, which were significantly enriched for anaerobic and non-spore-forming lifestyles. Our results argue that social interactions are an important determinant of gut microbiome composition in natural animal populations-a relationship with important ramifications for understanding how social relationships influence health, as well as the evolution of group living.
    eLife Sciences 03/2015; 4. DOI:10.7554/eLife.05224 · 8.52 Impact Factor
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    ABSTRACT: The optimal coordination of the transcriptional response of host cells to infection is essential for establishing appropriate immunological outcomes. In this context, the role of microRNAs (miRNAs) - important epigenetic regulators of gene expression - in regulating mammalian immune systems is increasingly well recognised. However, the expression dynamics of miRNAs, and that of their isoforms, in response to infection remains largely unexplored. Here, we characterized the genome-wide miRNA transcriptional responses of human dendritic cells, over time, to various mycobacteria differing in their virulence as well as to other bacteria outside the genus Mycobacterium, using small RNA-sequencing. We detected the presence of a core temporal response to infection, shared across bacteria, comprising 49 miRNAs, highlighting a set of miRNAs that may play an essential role in the regulation of basic cellular responses to stress. Despite such broadly shared expression dynamics, we identified specific elements of variation in the miRNA response to infection across bacteria, including a virulence-dependent induction of the miR-132/212 family in response to mycobacterial infections. We also found that infection has a strong impact on both the relative abundance of the miRNA hairpin arms and the expression dynamics of miRNA isoforms. That we observed broadly consistent changes in relative arm expression and isomiR distribution across bacteria suggests that this additional, internal layer of variability in miRNA responses represents an additional source of subtle miRNA-mediated regulation upon infection. Collectively, this study increases our understanding of the dynamism and role of miRNAs in response to bacterial infection, revealing novel features of their internal variability and identifying candidate miRNAs that may contribute to differences in the pathogenicity of mycobacterial infections.
    PLoS Genetics 03/2015; 11(3):e1005064. DOI:10.1371/journal.pgen.1005064 · 8.17 Impact Factor
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    ABSTRACT: The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen-presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen-specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte-derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.
    Journal of Clinical Investigation 12/2014; 125(2). DOI:10.1172/JCI77014 · 13.77 Impact Factor
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    ABSTRACT: Zoonotic viruses, such as HIV, Ebola virus, coronaviruses, influenza A viruses, hantaviruses, or henipaviruses, can result in profound pathology in humans. In contrast, populations of the reservoir hosts of zoonotic pathogens often appear to tolerate these infections with little evidence of disease. Why are viruses more dangerous in one species than another? Immunological studies investigating quantitative and qualitative differences in the host-virus equilibrium in animal reservoirs will be key to answering this question, informing new approaches for treating and preventing zoonotic diseases. Integrating an understanding of host immune responses with epidemiological, ecological, and evolutionary insights into viral emergence will shed light on mechanisms that minimize fitness costs associated with viral infection, facilitate transmission to other hosts, and underlie the association of specific reservoir hosts with multiple emerging viruses. Reservoir host studies provide a rich opportunity for elucidating fundamental immunological processes and their underlying genetic basis, in the context of distinct physiological and metabolic constraints that contribute to host resistance and disease tolerance. Copyright © 2015 Elsevier Inc. All rights reserved.
  • Jessica F Brinkworth, Luis B Barreiro
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    ABSTRACT: Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Opinion in Immunology 12/2014; 31C:66-78. DOI:10.1016/j.coi.2014.09.008 · 7.87 Impact Factor
  • Jessica F. Brinkworth, Luis B. Barreiro
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    ABSTRACT: Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review.
    Current Opinion in Immunology 10/2014; 31:66:78. · 7.87 Impact Factor
  • Luis B Barreiro, Lluis Quintana-Murci
    Current Opinion in Immunology 09/2014; 30. DOI:10.1016/j.coi.2014.09.003 · 7.87 Impact Factor
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    ABSTRACT: The evolutionary history of the human pygmy phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (east central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses, we computed the haplotype-based integrated haplotype score (iHS) statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each genomic SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (west central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.
    Proceedings of the National Academy of Sciences 08/2014; 111(35):E3596-E3603. DOI:10.1073/pnas.1402875111 · 9.81 Impact Factor
  • Alain Pacis, Yohann Nédélec, Luis B Barreiro
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    ABSTRACT: The response of host immune cells to microbial stimuli is dependent on robust and coordinated gene expression programs involving the transcription of thousands of genes. The dysregulation of such regulatory programs is likely to significantly contribute to the marked differences in susceptibility to infectious diseases observed among individuals and between human populations. Although the specific factors leading to a dysfunctional immune response to infection remain largely unknown, we are increasingly appreciating the importance of genetic variants in altering the expression levels of immune-related genes, possibly via epigenetic changes. This review describes how recent technological advances have profoundly contributed to our current understanding of the genetic architecture and the epigenetic rules controlling immune responses to infectious agents and how genetic and epigenetic data can be combined to unravel the mechanisms associated with host variation in transcriptional responses to infection.
    Current Opinion in Immunology 06/2014; 29C:119-126. DOI:10.1016/j.coi.2014.06.002 · 7.87 Impact Factor
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    ABSTRACT: The NKG2 family of NK receptors includes activating and inhibitory members. With the exception of the homodimer-forming NKG2D, NKG2 receptors recognize the nonclassical MHC class I molecule HLA-E, and they can be subdivided into two groups: those that associate with and signal through DAP12 to activate cells, and those that contain an ITIM motif to promote inhibition. The function of NKG2 family member NKG2E is unclear in humans, and its surface expression has never been conclusively established, largely because there is no Ab that binds specifically to NKG2E. Seeking to determine a role for this molecule, we chose to investigate its expression and ability to form complexes with intracellular signaling molecules. We found that NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum instead of being expressed on cell surfaces, and that this localization was dependent on a sequence of hydrophobic amino acids in the extracellular domain of NKG2E. Because this particular sequence has emerged and been conserved selectively among higher order primates evolutionarily, this observation raises the intriguing possibility that NKG2E may function as an intracellular protein.
    The Journal of Immunology 06/2014; 193(2). DOI:10.4049/jimmunol.1400556 · 5.36 Impact Factor
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    ABSTRACT: Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.
    PLoS ONE 04/2014; 9(4):e89816. DOI:10.1371/journal.pone.0089816 · 3.53 Impact Factor
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    ABSTRACT: Genome-wide scans for selection have identified multiple regions of the human genome as being targeted by positive selection. However, only a small proportion has been replicated across studies, and the prevalence of positive selection as a mechanism of adaptive change in humans remains controversial. Here we explore the power of two haplotype-based statistics - the integrated haplotype score (iHS) and the Derived Intra-allelic Nucleotide Diversity (DIND) test - in the context of next-generation sequencing data, and evaluate their robustness to demography and other selection modes. We show that these statistics are both powerful for the detection of recent positive selection, regardless of population history, and robust to variation in coverage, with DIND being insensitive to very low coverage. We apply these statistics to whole-genome sequence datasets from the 1000 Genomes Project and Complete Genomics. We found that putative targets of selection were highly significantly enriched in genic and non-synonymous SNPs, and that DIND was more powerful than iHS in the context of small sample sizes, low-quality genotype calling or poor coverage. As we excluded genomic confounders and alternative selection models, such as background selection, the observed enrichment attests to the action of recent, strong positive selection. Further support to the adaptive significance of these genomic regions came from their enrichment in functional variants detected by genome-wide association studies, informing the relationship between past selection and current benign and disease-related phenotypic variation. Our results indicate that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution.
    Molecular Biology and Evolution 04/2014; DOI:10.1093/molbev/msu118 · 14.31 Impact Factor
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    ABSTRACT: The composition of the human gut microbiome is influenced by many environmental factors. Diet is thought to be one of the most important determinants, though we have limited understanding of the extent to which dietary fluctuations alter variation in the gut microbiome between individuals. In this study, we examined variation in gut microbiome composition between winter and summer over the course of one year in 60 members of a founder population, the Hutterites. Because of their communal lifestyle, Hutterite diets are similar across individuals and remarkably stable throughout the year, with the exception that fresh produce is primarily served during the summer and autumn months. Our data indicate that despite overall gut microbiome stability within individuals over time, there are consistent and significant population-wide shifts in microbiome composition across seasons. We found seasonal differences in both (i) the abundance of particular taxa (false discovery rate <0.05), including highly abundant phyla Bacteroidetes and Firmicutes, and (ii) overall gut microbiome diversity (by Shannon diversity; P = 0.001). It is likely that the dietary fluctuations between seasons with respect to produce availability explain, at least in part, these differences in microbiome composition. For example, high levels of produce containing complex carbohydrates consumed during the summer months might explain increased abundance of Bacteroidetes, which contain complex carbohydrate digesters, and decreased levels of Actinobacteria, which have been negatively correlated to fiber content in food questionnaires. Our observations demonstrate the plastic nature of the human gut microbiome in response to variation in diet.
    PLoS ONE 03/2014; 9(3):e90731. DOI:10.1371/journal.pone.0090731 · 3.53 Impact Factor
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    ABSTRACT: Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular ATP indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis, and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into AMP, and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage, but may also favor bacterial immune escape.
    The Journal of Infectious Diseases 03/2014; DOI:10.1093/infdis/jiu135 · 5.78 Impact Factor
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    ABSTRACT: The emergence of agriculture in West-Central Africa approximately 5,000 years ago, profoundly modified the cultural landscape and mode of subsistence of most sub-Saharan populations. How this major innovation has had an impact on the genetic history of rainforest hunter-gatherers-historically referred to as 'pygmies'-and agriculturalists, however, remains poorly understood. Here we report genome-wide SNP data from these populations located west-to-east of the equatorial rainforest. We find that hunter-gathering populations present up to 50% of farmer genomic ancestry, and that substantial admixture began only within the last 1,000 years. Furthermore, we show that the historical population sizes characterizing these communities already differed before the introduction of agriculture. Our results suggest that the first socio-economic interactions between rainforest hunter-gatherers and farmers introduced by the spread of farming were not accompanied by immediate, extensive genetic exchanges and occurred on a backdrop of two groups already differentiated by their specialization in two ecotopes with differing carrying capacities.
    Nature Communications 02/2014; 5:3163. DOI:10.1038/ncomms4163 · 10.74 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are critical regulators of gene expression and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context-dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ~40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell.
    Genome Research 01/2014; DOI:10.1101/gr.161471.113 · 13.85 Impact Factor
  • Alain Pacis, Yohann Nédélec, Luis B Barreiro
    [Show abstract] [Hide abstract]
    ABSTRACT: The response of host immune cells to microbial stimuli is dependent on robust and coordinated gene expression programs involving the transcription of thousands of genes. The dysregulation of such regulatory programs is likely to significantly contribute to the marked differences in susceptibility to infectious diseases observed among individuals and between human populations. Although the specific factors leading to a dysfunctional immune response to infection remain largely unknown, we are increasingly appreciating the importance of genetic variants in altering the expression levels of immune-related genes, possibly via epigenetic changes. This review describes how recent technological advances have profoundly contributed to our current understanding of the genetic architecture and the epigenetic rules controlling immune responses to infectious agents and how genetic and epigenetic data can be combined to unravel the mechanisms associated with host variation in transcriptional responses to infection.
  • Jessica F Brinkworth, Luis B Barreiro
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review.
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    ABSTRACT: The study of the genetic and selective landscape of immunity genes across primates can provide insight into the existing differences in susceptibility to infection observed between human and non-human primates. Here, we explored how selection has driven the evolution of a key family of innate immunity receptors, the Toll-like receptors (TLRs), in African great ape species. We sequenced the ten TLRs in various populations of chimpanzees and gorillas, and analysed these data jointly with a human dataset. We found that purifying selection has been more pervasive in great apes than in humans. Furthermore, in chimpanzees and gorillas, purifying selection has targeted TLRs irrespectively of whether they are endosomal or cell-surface, in contrast with humans where strong selective constraints are restricted to endosomal TLRs. These observations suggest important differences in the relative importance of TLR-mediated pathogen sensing, such as that of recognition of flagellated bacteria by TLR5, between human and great apes. Lastly, we used a population genetics-phylogenetics method that jointly analyse polymorphism and divergence data to detect fine-scale variation in selection pressures at specific codons within TLR genes. We identified different codons at different TLRs as being under positive selection in each species, highlighting that functional variation at these genes has conferred a selective advantage in immunity to infection to specific primate species. Overall, this study showed that the degree of selection driving the evolution of TLRs has largely differed between human and non-human primates, increasing our knowledge on their respective biological contribution to host defence in the natural setting.
    Human Molecular Genetics 07/2013; DOI:10.1093/hmg/ddt335 · 6.68 Impact Factor
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    ABSTRACT: Leprosy reversal reactions type 1 (T1R) are acute immune episodes that affect a subset of leprosy patients and remain a major cause of nerve damage. Little is known about the relative importance of innate versus environmental factors in the pathogenesis of T1R. In a retrospective design, we evaluated innate differences in response to Mycobacterium leprae between healthy individuals and former leprosy patients affected or free of T1R by analyzing the transcriptome response of whole blood to M. leprae sonicate. Validation of results was conducted in a subsequent prospective study. We observed the differential expression of 581 genes upon exposure of whole blood to M. leprae sonicate in the retrospective study. We defined a 44 T1R gene set signature of differentially regulated genes. The majority of the T1R set genes were represented by three functional groups: i) pro-inflammatory regulators; ii) arachidonic acid metabolism mediators; and iii) regulators of anti-inflammation. The validity of the T1R gene set signature was replicated in the prospective arm of the study. The T1R genetic signature encompasses genes encoding pro- and anti-inflammatory mediators of innate immunity. This suggests an innate defect in the regulation of the inflammatory response to M. leprae antigens. The identified T1R gene set represents a critical first step towards a genetic profile of leprosy patients who are at increased risk of T1R and concomitant nerve damage.
    PLoS Genetics 07/2013; 9(7):e1003624. DOI:10.1371/journal.pgen.1003624 · 8.17 Impact Factor

Publication Stats

2k Citations
499.10 Total Impact Points

Institutions

  • 2011–2015
    • Université de Montréal
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 2014
    • CHU Sainte-Justine
      Montréal, Quebec, Canada
  • 2009–2014
    • University of Chicago
      • Department of Human Genetics
      Chicago, Illinois, United States
  • 2006–2011
    • Institut Pasteur
      • Department of Genomes and Genetics
      Paris, Ile-de-France, France
  • 2010
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2007–2009
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Institut de Génétique Humaine
      Montpelhièr, Languedoc-Roussillon, France
    • Imperial College London
      • Centre for Molecular Microbiology and Infection
      London, ENG, United Kingdom