Lluis Quintana-Murci

French National Centre for Scientific Research, Lutetia Parisorum, Île-de-France, France

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Publications (143)1244.19 Total impact

  • Luis B Barreiro, Lluis Quintana-Murci
    Current opinion in immunology. 09/2014;
  • Laure Ségurel, Lluis Quintana-Murci
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    ABSTRACT: The progress of genomic technologies is allowing researchers to scan the genomes of different species for the occurrence of natural selection at an unprecedented level of resolution. These studies show that genes involved in immune processes are preferential targets of different forms of selection, some of which act to preserve immune diversity over time. Recent work in humans shows that this can be achieved either by inheriting advantageous immune variation from distant ancestral species, through long-term balancing selection, or by acquiring novel selected alleles through admixture with extinct hominins such as Neanderthals or Denisovans. These studies collectively increase our knowledge of immune genes for which maintaining the functional diversity has conferred a strong selective advantage for host survival.
    Current Opinion in Immunology 09/2014; 30C:79-84. · 8.77 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. · 9.81 Impact Factor
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    ABSTRACT: Identifying the genotypes underlying human disease phenotypes is a fundamental step in human genetics and medicine. High-throughput genomic technologies provide thousands of genetic variants per individual. The causal genes of a specific phenotype are usually expected to be functionally close to each other. According to this hypothesis, candidate genes are picked from high-throughput data on the basis of their biological proximity to core genes -- genes already known to be responsible for the phenotype. There is currently no effective gene-centric online interface for this purpose. We describe here the human gene connectome server (HGCS), a powerful, easy-to-use interactive online tool enabling researchers to prioritize any list of genes according to their biological proximity to core genes associated with the phenotype of interest. We also make available an updated and extended version for all human gene-specific connectomes. The HGCS is freely available to noncommercial users from: http://hgc.rockefeller.edu/. The HGCS should help investigators from diverse fields to identify new disease-causing candidate genes more effectively, via a user-friendly online interface.
    BMC Genomics 04/2014; 15(1):256. · 4.40 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; · 14.31 Impact Factor
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    ABSTRACT: Standardization of immunophenotyping procedures has become a high priority. We have developed a suite of whole-blood, syringe-based assay systems that can be used to reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errors associated with immune monitoring, we have defined the protein signatures induced by (1) medically relevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinically employed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines and we report the failure to release interleukin-1α as a common immunological phenotype. The observed naturally occurring variation of the immune response may help to explain differential susceptibility to disease or response to therapeutic intervention. The implementation of a general solution for assessment of functional immune responses will help support harmonization of clinical studies and data sharing.
    Immunity 03/2014; 40(3):436-50. · 19.80 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. · 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; · 14.40 Impact Factor
  • Katherine J Siddle, Lluis Quintana-Murci
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    ABSTRACT: Pathogens, and the infectious diseases they cause, have been paramount among the threats encountered by humans in their expansions throughout the globe. Numerous studies have identified immunity and host defence genes as being among the functions most strongly targeted by selection, most likely pathogen-driven. The dissection of the form and intensity of such selective pressures have increased our knowledge of the biological relevance of the underlying immunological mechanisms in host defence. Although the identities of the specific infectious agents imposing these selective pressures remain, in most cases, elusive, the impact of several pathogens, notably malaria and cholera, has been described. However, past selection against infectious diseases may have some fitness costs upon environmental changes, potentially leading to maladaptation and immunopathology.
    Current Opinion in Genetics & Development. 01/2014; 29:31–38.
  • Jean-Laurent Casanova, Laurent Abel, Lluis Quintana-Murci
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    ABSTRACT: Human genetic studies are rarely conducted for immunological purposes. Instead, they are typically driven by medical and evolutionary goals, such as understanding the predisposition or resistance to infectious or inflammatory diseases, the pathogenesis of such diseases, and human evolution in the context of the long-standing relationships between humans and their commensal and environmental microbes. However, the dissection of these experiments of Nature has also led to major immunological advances. In this review, we draw on some of the immunological lessons learned in the three branches of human molecular genetics most relevant to immunology: clinical genetics, epidemiological genetics, and evolutionary genetics. We argue that human genetics has become a new frontier not only for timely studies of specific features of human immunity, but also for defining general principles of immunity. These studies teach us about immunity as it occurs under "natural" conditions, through the transition from the almost complete wilderness that existed worldwide until about a century ago to the current unevenly distributed medically shaped environment. Hygiene, vaccines, antibiotics, and surgery have considerably decreased the burden of infection, but these interventions have been available only recently, so have yet to have a major impact on patterns of genomic diversity, making it possible to carry out unbiased evolutionary studies at the population level. Clinical genetic studies of childhood phenotypes have not been blurred by modern medicine either. Instead, medical advances have actually facilitated such studies, by making it possible for children with life-threatening infections to survive. In addition, the prevention and treatment of infectious diseases have increased life expectancy at birth from ∼20 yr to ∼80 yr, providing unique opportunities to study the genetic basis of immunological phenomena against which there is no natural counterselection, such as reactivation and secondary infectious diseases and breakdown of self-tolerance manifesting as autoimmunity, in populations of adult and aging patients. Recently developed deep sequencing and stem cell technologies are of unprecedented power, and their application to human genetics is opening up exciting and timely possibilities for young immunologists seeking uncharted waters to explore.
    Cold Spring Harbor Symposia on Quantitative Biology 10/2013;
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    ABSTRACT: Demographic changes are known to leave footprints on genetic polymorphism. Together with the increased availability of large polymorphism datasets, coalescent-based methods allow inferring the past demography of populations from their present-day patterns of genetic diversity. Here, we analyzed both nuclear (20 non-coding regions) and mitochondrial (HVS-I) re-sequencing data to infer the demographic history of 66 African and Eurasian human populations presenting contrasting life-styles (nomadic hunter-gatherers, nomadic herders and sedentary farmers). This allowed us to investigate the relationship between life-style and demography, and to address the long-standing debate about the chronology of demographic expansions and the Neolithic transition. In Africa, we inferred expansion events for farmers, but constant population sizes or contraction events for hunter-gatherers. In Eurasia, we inferred higher expansion rates for farmers than herders with HVS-I data, except in Central Asia and Korea. Although isolation and admixture processes could have impacted our demographic inferences, these processes alone seem unlikely to explain the contrasted demographic histories inferred in populations with different life-styles. The small expansion rates or constant population sizes inferred for herders and hunter-gatherers may thus result from constraints linked to nomadism. However, autosomal data revealed contraction events for two sedentary populations in Eurasia, which may be caused by founder effects. Finally, the inferred expansions likely predated the emergence of agriculture and herding. This suggests that human populations could have started to expand in Paleolithic times, and that strong Paleolithic expansions in some populations may have ultimately favored their shift towards agriculture during the Neolithic.
    Molecular Biology and Evolution 09/2013; · 14.31 Impact Factor
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    ABSTRACT: The Y chromosome and the mitochondrial genome have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y-chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y chromosome and the mitochondrial genome, we estimate the time to the most recent common ancestor (T(MRCA)) of the Y chromosome to be 120 to 156 thousand years and the mitochondrial genome T(MRCA) to be 99 to 148 thousand years. Our findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages.
    Science 08/2013; 341(6145):562-5. · 31.20 Impact Factor
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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; · 7.69 Impact Factor
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    Estelle Vasseur, Lluis Quintana-Murci
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    ABSTRACT: Investigations of the legacy of natural selection in the human genome have proved particularly informative, pinpointing functionally important regions that have participated in our genetic adaptation to the environment. Furthermore, genetic dissection of the intensity and type of selection acting on human genes can be used to predict involvement in different forms and severities of human diseases. We review here the progress made in population genetics studies toward understanding the effects of selection, in its different forms and intensities, on human genome diversity. We discuss some outstanding, robust examples of genes and biological functions subject to strong dietary, climatic and pathogen selection pressures. We also explore the possible relationship between cancer and natural selection, a topic that has been largely neglected because cancer is generally seen as a late-onset disease. Finally, we discuss how the present-day incidence of some diseases of modern societies may represent a by-product of past adaptation to other selective forces and changes in lifestyle. This perspective thus illustrates the value of adopting a population genetics approach in delineating the biological mechanisms that have played a major evolutionary role in the way humans have genetically adapted to different environments and lifestyles over time.
    Evolutionary Applications 06/2013; 6(4):596-607. · 4.15 Impact Factor
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    ABSTRACT: Most approaches aiming at finding genes involved in adaptive events have focused on the detection of outlier loci, which resulted in the discovery of individually 'significant' genes with strong effects. However, a collection of small effect mutations could have a large effect on a given biological pathway that includes many genes, and such a polygenic mode of adaptation has not been systematically investigated in humans. We propose here to evidence polygenic selection by detecting signals of adaptation at the pathway or gene set level instead of analyzing single independent genes. Using a gene-set enrichment test to identify genome-wide signals of adaptation among human populations, we find that most pathways globally enriched for signals of positive selection are either directly or indirectly involved in immune response. We also find evidence for long-distance genotypic linkage disequilibrium, suggesting functional epistatic interactions between members of the same pathway. Our results show that past interactions with pathogens have elicited widespread and coordinated genomic responses, and suggest that adaptation to pathogens can be considered as a primary example of polygenic selection.
    Molecular Biology and Evolution 04/2013; · 14.31 Impact Factor
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    ABSTRACT: Haplogroup H dominates present-day Western European mitochondrial DNA variability (>40%), yet was less common (~19%) among Early Neolithic farmers (~5450 BC) and virtually absent in Mesolithic hunter-gatherers. Here we investigate this major component of the maternal population history of modern Europeans and sequence 39 complete haplogroup H mitochondrial genomes from ancient human remains. We then compare this ‘real-time’ genetic data with cultural changes taking place between the Early Neolithic (~5450 BC) and Bronze Age (~2200 BC) in Central Europe. Our results reveal that the current diversity and distribution of haplogroup H were largely established by the Mid Neolithic (~4000 BC), but with substantial genetic contributions from subsequent pan-European cultures such as the Bell Beakers expanding out of Iberia in the Late Neolithic (~2800 BC). Dated haplogroup H genomes allow us to reconstruct the recent evolutionary history of haplogroup H and reveal a mutation rate 45% higher than current estimates for human mitochondria.
    Nature Communications 04/2013; 4(1764). · 10.74 Impact Factor
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    ABSTRACT: Homogeneous Proto-Slavic genetic substrate and/or extensive mixing after World War II were suggested to explain homogeneity of contemporary Polish paternal lineages. Alternatively, Polish local populations might have displayed pre-war genetic heterogeneity owing to genetic drift and/or gene flow with neighbouring populations. Although sharp genetic discontinuity along the political border between Poland and Germany indisputably results from war-mediated resettlements and homogenisation, it remained unknown whether Y-chromosomal diversity in ethnically/linguistically defined populations was clinal or discontinuous before the war. In order to answer these questions and elucidate early Slavic migrations, 1156 individuals from several Slavic and German populations were analysed, including Polish pre-war regional populations and an autochthonous Slavic population from Germany. Y chromosomes were assigned to 39 haplogroups and genotyped for 19 STRs. Genetic distances revealed similar degree of differentiation of Slavic-speaking pre-war populations from German populations irrespective of duration and intensity of contacts with German speakers. Admixture estimates showed minor Slavic paternal ancestry (∼20%) in modern eastern Germans and hardly detectable German paternal ancestry in Slavs neighbouring German populations for centuries. BATWING analysis of isolated Slavic populations revealed that their divergence was preceded by rapid demographic growth, undermining theory that Slavic expansion was primarily linguistic rather than population spread. Polish pre-war regional populations showed within-group heterogeneity and lower STR variation within R-M17 subclades compared with modern populations, which might have been homogenised by war resettlements. Our results suggest that genetic studies on early human history in the Vistula and Oder basins should rely on reconstructed pre-war rather than modern populations.European Journal of Human Genetics advance online publication, 12 September 2012; doi:10.1038/ejhg.2012.190.
    European journal of human genetics: EJHG 04/2013; 21:415-422. · 3.56 Impact Factor
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    ABSTRACT: Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients-a nonsense, a frameshift duplication, and five different missense-cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.
    Science 04/2013; · 31.20 Impact Factor
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    ABSTRACT: High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.
    Proceedings of the National Academy of Sciences 03/2013; · 9.81 Impact Factor
  • Lluís Quintana-Murci, Andrew G Clark
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    ABSTRACT: Innate immunity involves direct interactions between the host and microorganisms, both pathogenic and symbiotic, so natural selection is expected to strongly influence genes involved in these processes. Population genetics investigates the impact of past natural selection events on the genome of present-day human populations, and it complements immunological as well as clinical and epidemiological genetic studies. Recent data show that the impact of selection on the different families of innate immune receptors and their downstream signalling molecules varies considerably. This Review discusses these findings and highlights how they help to delineate the relative functional importance of innate immune pathways, which can range from being essential to being redundant.
    Nature Reviews Immunology 03/2013; · 32.25 Impact Factor

Publication Stats

5k Citations
1,244.19 Total Impact Points

Institutions

  • 2004–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2002–2014
    • Institut Pasteur
      • Department of Genomes and Genetics
      Lutetia Parisorum, Île-de-France, France
    • Cyprus Institute of Neurology and Genetics
      Lefkoşa, Lefkosia, Cyprus
  • 2013
    • University of Bologna
      • Department of Biological, Geological and Environmental Sciences BiGeA
      Bolonia, Emilia-Romagna, Italy
  • 2010–2013
    • The Rockefeller University
      • St. Giles Laboratory of Human Genetics of Infectious Diseases
      New York City, NY, United States
    • University Pompeu Fabra
      • • Institute of Evolutionary Biology (CSIC-UPF)
      • • Department of Experimental and Health Sciences
      Barcino, Catalonia, Spain
  • 2012
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Fudan University
      • State Key Laboratory of Genetic Engineering
      Shanghai, Shanghai Shi, China
  • 2008–2011
    • Muséum National d'Histoire Naturelle
      • UMR 7206 Éco-anthropologie et ethnobiologie
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Spanish National Research Council
      Madrid, Madrid, Spain
  • 2007
    • Institut de Génétique Humaine
      Montpelhièr, Languedoc-Roussillon, France
  • 2001–2007
    • French Institute of Health and Medical Research
      • Unité de Génétique Humaine des Maladies Infectieuses U980
      Paris, Ile-de-France, France
  • 2000
    • University of Florence
      • Dipartimento di Scienze Biomediche, Sperimentali e Cliniche
      Florence, Tuscany, Italy
  • 1998–1999
    • University of Pavia
      • Department of Biology and Biotechnology "Lazzaro Spallanzani"
      Pavia, Lombardy, Italy
    • Université René Descartes - Paris 5
      • Faculté des Sciences Pharmaceutiques et Biologiques de Paris
      Paris, Ile-de-France, France