The Pasteur Museum is housed in the apartment where Louis Pasteur spent his final seven years and offers a rare behind-the-scenes look at the living and working environment of the world-renowned scientist. Visitors can gain a unique insight into his everyday life alongside his wife and can admire his rich and diverse scientific work.
The Institut Pasteur’s scientific strategy focuses on developing original and innovative topics and promoting interdisciplinary and multidisciplinary cooperation and approaches. The Institut Pasteur teams have access to the technological resources needed to speed up and further improve the quality of their outstanding research.
Ever since the introduction of the world’s first "Technical Microbiology" course in 1889, teaching has been a priority for the Institut Pasteur. The Institut Pasteur has an international reputation for quality teaching that attracts students from all over the world who come to further their training or top up their degree programs.
With international courses, PhD and postdoctoral traineeship, each institute of the Institut Pasteur International Network (RIIP) contributes to the transmission of knowledge with the training of young researchers all around the world. In this context, doctoral and postdoctoral programmes, study and traineeship fellowships are available to scientists. Alongside training, dynamism and attractiveness of RIIP will result in the creation of 4-year group for the young researchers.
Understanding the different forces driving human genome variability is a central issue in population genetics and evolutionary biology.
Currently, the main questions we address in the laboratory are: How natural selection and human demography have driven the variability of the human genome? How, and to which extent, natural selection has shaped immunity and host defence genes in humans? How differences in human lifestyle and modes of subsistence between populations have influenced their demographic regimes and adaptation to pathogen pressures? A detailed description of the relative weight and influence of these different processes will provide important insights into human evolutionary history, which might, in turn, also facilitate identification of complex infectious disease genes.
Selected examples of our research interests can be found here below. For information about other ongoing projects, please contact us.
The footprints of natural selection in the human genome
The wide range of phenotypic variation in human populations may reflect distinctive processes of natural selection/adaptation to variable environmental conditions (e.g. climate, pathogens, nutritional resources). The recent advent of massive genome-wide polymorphism datasets (HapMap, Perlegen, HGDP-CEPH) allows us to test different hypotheses concerning how natural selection, in its different forms and intensities, has influenced the variability of the human genome. For example, we recently found that negative selection has globally reduced population differentiation at amino-acid altering mutations at the genome-wide scale, particularly in disease-related genes. Conversely, positive selection appears to have increased population differentiation in gene regions, primarily at non-synonymous and 5’-UTR variants. Our analyses have also identified a group of genes, which show strong signatures of population-specific positive selection, having most likely participated in the processes of population adaptation to their specific environments. Interestingly, some of these genes are involved in immunity-related processes and in the metabolic syndrome (i.e. diabetes, obesity and hypertension). In the same line, we are now evaluating how other types of natural selection (e.g. balancing selection) have influenced the patterns of variability of the human genome. We are also interested in the evolutionary processes behind the patterns of variability of genomic regions involved in the regulation of gene expression (e.g. microRNAs) or in xenobiotic metabolism (e.g. NAT genes).
Barreiro et al. (2008)
Selected relevant papers:
Quach et al. (2009) Am J Hum Genet 84, 316-327.
Barreiro et al. (2008) Nat Genet 40, 340-345.
Patin et al. (2006) Am J Hum Genet 78, 423-436.
Evolutionary Genomics of Innate Immunity in Humans
Inferences concerning the action of natural selection in the human genome provide a powerful tool for predicting regions of the genome potentially associated with disease. As infectious diseases have exerted, and exert, strong selection pressures, the identification of selected loci or variants of immunity-related genes may provide insight into immunological defence mechanisms and highlight host pathways playing an important role in pathogen resistance.
In this context, we have provided a striking example of selection acting on the innate immunity C-type lectins DC-SIGN and L-SIGN, which act as cell adhesion receptors and pathogen recognition receptors. We have shown that negative selection has prevented the accumulation of aminoacid changes on DC-SIGN, whereas L-SIGN variability has been shaped by the action of balancing selection in non-Africans. In addition, the evolutionary genetic approach can be very useful in supporting the redundant role of certain genes in host defences. For example, mannose-binding lectin (MBL) deficiency has been associated with an increase in susceptibility to several infectious diseases; however, alleles conferring MBL deficiency are very common worldwide (up to 30%), suggesting that they may also protect against some other infectious agent(s). Yet we have shown that the pattern of variation at MBL2, encoding MBL, is consistent with strictly neutral evolution, indicating that the high worldwide prevalence of deleterious MBL2 alleles is the result of genetic drift and that MBL is largely redundant in immunity. More recently, we have studied the ten members of the human Toll-like receptor (TLR) family in humans. Our data have revealed a surprising split of TLRs into two evolutionary distinct groups: the intracellular nucleic-acid sensors TLR3, TLR7, TLR8 and TLR9 are subject to strong purifying selection, highlighting their essential non-redundant role in human survival. Conversely, the remaining six TLRs, which detect non nucleic acid microbial products on the cell surface, display greater biological redundancy, with higher rates of missense and nonsense mutation being tolerated at the population level. Using the same rationale, we are now extending our studies to other major families of innate immunity microbial sensors, such as Nod-Like receptors (NLRs), RIG-I-like receptors (RLRs) and C-type lectin receptors (CLRs). These studies will provide important insights into microbial sensors playing a major biological role for past and present human survival in the natural setting.
Barreiro et al. (2009)
Selected relevant papers:
Barreiro et al. (2009) PLoS Genet 5(7), e1000562.
Quintana-Murci et al. (2007) Nat Immunol 8, 1165-1171.
Verdu et al. (2006) Hum Mol Genet 15, 2650-2658.
Barreiro et al. (2006) PLoS Med 3, e20.
Barreiro et al. (2005) Am J Hum Genet 77, 869-886.
Lifestyle, demography and infectious disease
The most important cultural innovation witnessed by modern humans has probably been the transition from a hunter-gatherer nomadic mode of subsistence to an agricultural sedentary lifestyle. This transition occurred in many parts of the world on a massive scale starting 13-10,000 years ago. In addition, farming involved, at least initially, inadequate sanitary practices, dramatic increases in human population sizes and zoonosis following the domestication of animals, allowing the establishment of a substantial reservoir of infection and most likely contributing to the rise in death and sickness caused by infectious diseases in Neolithic times. We are interested in understanding how the transition from a hunter-gatherer and nomadic lifestyle towards an agricultural and sedentary lifestyle has influenced the diversity of both neutral genetic loci and of genes involved in immune response. We focus our studies in Central Africa where both hunter-gatherers and agriculturalists share the same environment. Sequence diversity of both “neutral” (i.e. multiple dispersed non-coding regions of the genome as well as mtDNA and Y-chromosome) and coding regions involved in immune response are studied in different agricultural Bantu-speaking and Pygmy hunter-gatherer populations from the Cameroon/Gabon region. The study of “neutral” diversity will set the baseline to establish the demographic history of these populations to subsequently infer the extent to which natural selection has differently targeted immunity genes between farmers and hunter-gatherers. These studies will help to understand how a major transition in human lifestyle (i.e. the emergence of agriculture) may have influenced our relation with pathogens.
Phylogeographic inference of past demographic events from genetic data
The use of uniparentally inherited markers, such as the paternally-inherited Y-chromosome and maternally-inherited mitochondrial DNA (mtDNA), has proved a useful means of obtaining insight into human origins and migration processes. Assuming that there is no selection at these loci, studies of the mutations accumulated by these molecules during their evolution are highly informative for deducing the patrilinear and matrilinear histories of human populations, as well as for assessing how cultural factors and modes of subsistence has influenced the patterns of genetic diversity at the population level. In this context, we are interested in the demographic history of some specific populations of Europe (e.g. Basques), Africa (e.g. South African admixed populations) and the Pacific (e.g. Vanuatu Islands).
We are also part of the GENOGRAPHIC project (https://genographic.nationalgeographic.com), in which our main task is the study of the mtDNA diversity in different European populations.
Quintana-Murci et al. (2008)
Selected relevant papers:
Quintana-Murci et al. (2008). Proc Natl Acad Sci U S A 105, 1596-1601.
Behar et al. (2008). Am J Hum Genet 82, 1130-1140.
Behar et al. (2007). PLoS Genet 3, e104.
Quintana-Murci et al. (2004). Am J Hum Genet 74, 827-845.
Chaix et al. (2004). Am J Hum Genet 75, 1113-1116.
Updated on 08/04/2014
Unit Human Evolutionary Genetics
25, rue du Dr. Roux
75724 Paris Cedex 15, France