|Human Evolutionary Genetics - CNRS URA3012|
|HEAD||Dr QUINTANA-MURCI Lluis / firstname.lastname@example.org|
|MEMBERS||Dr BEN ALI Meriem / Dr BONIOTTO Michele / Dr FORNARINO Simona / HARMANT Christine / Dr LAVAL Guillaume / MANRY Jérémy / MERLO Elise / QUACH Hélène / VASSEUR Estelle
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.
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. There is an intimate relationship between disease and selection that can be exploited for the identification of candidate disease loci. Specifically, we study the influence of natural selection on human genome variability at two different levels: (i) at the level of the entire human genome, and (iii) at the level of gene families involved in innate immunity (e.g. TLRs, NLRs, RLRs, etc. ). Two examples of our most recent studies are given here below.
Genomewide footprints of natural selection.The wide range of phenotypic variation in human populations may reflect distinctive processes of natural selection/adaptation to variable environmental conditions. To evaluate how natural selection has shaped, at the human genome scale, the current degree of population differentiation, we have recently analyzed the degree of population differentiation at 2.8 million Phase II HapMap single-nucleotide polymorphisms. We found thatnegative selection has globally reduced population differentiation at amino-acid altering mutations, particularly in disease-related genes. Conversely, positive selection ensured the regional adaptation of human populations by increasing population differentiation in gene regions, primarily at non-synonymous and 5’-UTR variants. Thus, our study has clearly indicated that natural selection has been a significant driving force in the processes of population differentiation in modern humans. Specifically, our analyses have identified a number of genes, which show strong signatures of population-specific positive selection, having participated in the processes of population adaptation to their specific environments. Interestingly, some of these genes are involved in host immunity against pathogens and in the metabolic syndrome (i.e. diabetes, obesity and hypertension). The next step will be to determine how genetic variation in loci found to be under selection, particularly in those genes of unknown function, modulates susceptibility to or the pathogenesis of human disease.
Natural selection and innate immunity: the human Toll-like receptor family.Toll-like receptors (TLRs) 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 a natural ecosystem governed by natural selection, we comprehensively re-sequenced the 10 TLRs in a panel of worldwide populations. In addition, we have empirically considered the confounding effects of demography on the patterns of genetic diversity by re-sequencing in the same individuals a set of non-coding regions dispersed throughout the genome. 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. 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. However, weak negative selection precludes increases in the frequency of these variants for some TLRs in the general population. Finally, we identified two haplotypic backgrounds in the region encompassing TLR10-TLR1-TLR6 showing clear signs of positive selection in Europeans and East-Asians, indicating the presence of variants conferring a selective advantage to host survival.
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
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
Quintana-Murci L, Quach H, Harmant C, Luca F, Massonnet B, Patin E, Sica L, Mouguiama-Daouda P, Comas D, Tzur S, Balanovsky O, Kidd KK, Kidd JR, van der Veen L, Hombert JM, Gessain A, Verdu P, Froment A, Bahuchet S, Heyer E, Dausset J, Salas A, Behar DM (2008) Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter-gatherers and Bantu-speaking farmers. Proc Natl Acad Sci U S A. 105(5):1596-601. PMID: 18216239
Quintana-Murci L, Alcaïs A, Abel L, Casanova JL (2007) Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat 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
Activity Reports 2009 - Institut Pasteur
If you have problems with this Web page, please write to email@example.com