|Human Evolutionary Genetics - CNRS URA3012|
|HEAD||Dr QUINTANA-MURCI Lluis / firstname.lastname@example.org|
|MEMBERS||BARREIRO Luis / Dr BEN ALI Meriem / Dr FORNARINO Simona / HARMANT Christine / Dr LAVAL Guillaume / MANRY Jérémy / MERLO Elise / PATIN Etienne / QUACH Hélène
Our laboratory focuses on the different factors (selective, demographic, genomic) shaping the variability of the human genome. Our research activities cover two highly inter-related areas: the study of human genetic diversity at the population level, from which we can infer human origins and population structure, and the study of diversity in genomic regions involved in immune response or host-pathogen interactions, with which we can unmask the footprints of natural selection.Using an evolutionary approach, our goals are (i) to explore the extent to which infectious agents have exerted selective pressures on human genes, (ii) to identify the genes having played a major biological role in host survival, and (iii) to delineate the redundant and non-redundant role of immunity-related genes in the natural setting.For this, our laboratory combines molecular and population genetics approaches, with computational modelling and development of new statistical frameworks.
Demographic inference: human origins and population structure
Demographic inference from our population genetic studies has led to the identification of two genes with unusual gene tree topologies (NAT1 and DC-SIGN). The estimated time depth of these two genes (from 2 to 2.8 MYA) places the most recent common ancestor of modern humans back in the Pliocene. Excluding other factors that might have led to such patterns (balancing selection, gene conversion), our observations, and those of other studies reporting similar patterns, are consistent with the hypothesis that some of the diversity in the genome of modern humans may have persisted from a structured ancestral population. However, such inferences require additional analyses of independent non-coding loci. To this end, we have now sequenced 25 unlinked autosomal non-coding regions in a large panel of populations. Statistical analyses are ongoing. Non-coding regions distant from genes are probably not subject to natural selection and may therefore more accurately reflect human demographic history than data from coding regions. In addition, these data will provide a more realistic empirical framework for the null model of evolutionary neutrality, improving our inferences about natural selection
Evolutionary Immunology: Population Genetics of human immune response
Inferences concerning the action of natural selection in host defense genes provide a powerful tool for identifying regions of the genome having played a major biological role in human survival and therefore, potentially associated with disease. The identification of selected loci or variants of immunity-related genes may provide insight into immunological defense mechanisms and highlight host pathways playing an important role in pathogen resistance. In this context, we identified distinctive patterns of selection in two closely related innate immunity genes (DC-SIGNand L-SIGN). By studying their population genetic diversity, we showed that (i) DC-SIGN diversity is compatible with strong selective constraints preventing the accumulation of amino-acid changes over time, and (ii) L-SIGN exhibits an excess of diversity in Eurasians, a pattern that is compatible with the action of balancing selection. We also addressed the long-debated issue of the role of the mannose-binding lectin (MBL) in host defences against pathogens. Using an evolutionary approach, we showed that the pattern of MBL2 variation is consistent with neutral evolution, suggesting a largely redundant role for this lectin in the context of human defences. More recently, we have investigated whether and how natural selection has acted upon the human TLR family and assessed the relative biological importance of the individual TLRs. We have thus characterized the level of genetic variation of the 10 TLRs in a natural ecosystem governed by natural selection: a panel of healthy individuals representative of the general population worldwide. Our data show that human TLRs have evolved into two distinct groups, differing in biological importance. The nucleic acid sensors TLR3, TLR7, TLR8 and TLR9 are under strong purifying selection, highlighting their essential and non redundant role in host anti-viral defenses. The remaining TLRs, subject to more relaxed evolutionary constraints, would correspond instead to those sharing overlapping functions among them or with other non-TLR sensors. Further population genetics and functional studies are now ongoing to confirm these preliminary observations.
Our studies, based on a multi-locus approach and considering the different forces shaping the patterns of human genome variability, will both shed light onto the complex demographic history of our species (migration, demographic expansions, admixture) as well as deepen our understanding of the extent to which pathogens have exerted selective pressures on the variability of the human genome.
Keywords: evolution, genetics, immunology, natural selection, human populations
Quintana-Murci L, Alcaïs A, Abel L, Casanova JL (2007) Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nature Immunol 8(11):1165-1171. PMID: 17952041
Verdu P, Barreiro LB, Patin E, Gessain A, Cassar O, Kidd JR, Kidd KK, Behar DM, Froment A, Heyer E, Sica L, Casanova JL, Abel L, Quintana-Murci L (2006) Evolutionary Insights into the High Worldwide Prevalence of MBL2 Deficiency Alleles. Hum Mol Genet 15:2650-2658. PMID: 16885193
Barreiro LB, Neyrolles O, Babb C, Tailleux L, Quach H, McElreavey K, van Helden P, Hoal E, Gicquel B, Quintana-Murci L (2006) Promoter variation in the DC-SIGN encoding gene CD209 is associated with tuberculosis. PloS Med 3(2):e20. PMID: 16379498
Patin E, Barreiro LB, Sabeti PC, Austerlitz F, Luca F, Sajantila A, Behar DM, Semino O, Sakuntabhai A, Guiso N, Gicquel B, McElreavey K, Harding RM, Heyer E, Quintana-Murci L (2006) Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. Am J Hum Genet 78(3):423-436. PMID: 16416399
Barreiro LB, Patin E, Neyrolles O, Cann HM, Gicquel B, Quintana-Murci L (2005) The heritage of pathogen pressures and ancient demography in the human innate immunity CD209/CD209L region. Am J Hum Genet 77:869-886. PMID: 16252244
Activity Reports 2007 - Institut Pasteur
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