Human Evolutionary Genetics - CNRS URA3012  


  HEADDr QUINTANA-MURCI Lluis / quintana@pasteur.fr
  MEMBERSDr BEN ALI Meriem / Dr BONIOTTO Michele / Dr FORNARINO Simona / HARMANT Christine / Dr LAVAL Guillaume / MANRY Jérémy / MERLO Elise / QUACH Hélène / VASSEUR Estelle


  Annual Report

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 “neutral” genetic diversity (non-coding regions of the genome, mtDNA, etc.) 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.An outline of some aspects of our research is given here below.

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).

Population geneticsof 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 recently studied a family of innate immunity receptors, the Toll-like receptors (TLRs). The TLR members are thought to be essential for host defense by sensing and initiating innate and adaptive immune responses against microbes. To assess the relative biological importance of the individual TLRs in the natural setting, we comprehensively re-sequenced the 10 TLRs in a panel of worldwide populations. We found that the nucleic acid sensors TLR3, TLR7, TLR8 and TLR9, which are principally involved in viral recognition, have evolved under strong purifying selection indicating their essential role in host survival. Conversely, selective constraints on the remaining six TLRs, which detect non nucleic acid microbial products on the cell surface, have been much more relaxed, with higher rates of missense and nonsense mutations tolerated, suggesting higher levels of immunological redundancy. However, for this latter group of genes, we have also shown that mutations altering immune responses have been in some cases beneficial for host survival, as attested by the signature of positive selection favouring a reduced TLR1-mediated response in Europeans. Using the same evolutionary 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.

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, population genetics, human genetics, immunology, natural selection, populations

quintanamurci.jpg

FigureLegend:The “Evolutionary genetics” approach is complementary to those of “Clinical genetics” and “Epidemiological genetics” in the more general field of human genetics of infectious diseases. Evolutionary genetics evaluates the consequences of past infections (which may persist) in the genetic make-up of current human populations. The alleles identified as being under selection (either positive, balancing or negative) have a strong impact on population fitness (from Quintana-Murci, Alcaïs, Abel & Casanova, Nature Immunology, 2007).



  Publications

Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell J, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcaïs A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L (2009) Evolutionary Dynamics of Human Toll-Like Receptors and their Different Contributions to Host Defense. PLoS Genet 5(7), e1000562. PMID: 19609346

Louicharoen C, Patin E, Paul R, Nuchprayoon I, Witoonpanich B, Peerapittayamongkol C, Casademont I, Sura T, Laird NM, Singhasivanon P, Quintana-Murci L, Sakuntabhai A (2009) Positively Selected G6PD-Mahidol Mutation Reduces Plasmodium vivax Density in Southeast Asians. Science 326(5959):1546-1549. PMID: 20007901

Quach H, Barreiro LB, Laval G, Zidane N, Patin E, Kidd KK, Kidd JR, Bouchier C, Veuille M, Antoniewski C and Quintana-Murci L (2009) Signatures of purifying and local positive selection in human miRNAs. Am J Hum Genet 84, 316-327. PMID: 19232555

Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L (2008) Natural selection has driven population differentiation in modern humans. Nat Genet 40(3):340-345. PMID: 18246066

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



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Activity Reports 2009 - Institut Pasteur
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