Research

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 have natural selection and human demography driven the variability of the human genome? How, and to what extent, has natural selection shaped immunity and host defence genes? How have differences in lifestyles and modes of subsistence influenced the genetic history and epigenetic landscape of human populations? To what extent is variation in immune responses to infection under genetic control, and how does such variation contribute to human adaptation?

 

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 selection/adaptation to variable environmental conditions (e.g. climate, pathogens, nutritional resources). The advent of genome-wide datasets allows testing different hypotheses concerning how natural selection, in its different forms and intensities, has influenced the variability of the human genome. For example, we found that negative selection has globally reduced population differentiation at non-synonymous variants 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. We are also interested in the evolutionary processes behind the patterns of variability of genomic regions involved in the regulation of gene expression, such as microRNAs. We are currently developing new statistical approaches to identify the effects of natural selection from next-generation sequencing datasets.

figure1.png

 

Selected relevant papers: Fagny et al. (2014) Mol Biol Evol; Barreiro and Quintana-Murci. (2010) Nat Rev Genet; Quach et al. (2009) Am J Hum Genet; Barreiro et al. (2008) Nat Genet

 

 

EVOLUTIONARY GENOMICS OF INNATE IMMUNITY IN HUMANS

 

Inferences concerning the action of selection provide a powerful tool for predicting regions of the genome associated with disease. As infectious diseases exert strong selection pressures, the identification of immunity-related genes targeted by selection may provide insight into immunological defence mechanisms and highlight pathways playing an important role in pathogen resistance. Over the past years, we have focused on the dissection of how pathogen-driven selection has impacted the diversity of genes involved in innate immunity, including families of microbial sensors - such as the TLRs, NLRs and RLRs - as well as effector molecules - such as interferons. Our population genetic analyses have shown that innate immunity microbial sensors and other molecules involved in immunity to infection differ widely in their biological relevance, and highlighted evolutionarily important determinants of host immune responsiveness in the natural setting. Our work has also demonstrated that a G6PD-deficiency mutation is under strong positive selection in Southeast Asian populations, and provided a direct link between this mutation and protection against Plasmodium vivax rather than P. falciparum. This selection event coincides with the time at which rice started to be extensively cultured in the region — generating breeding grounds for mosquitoes — providing a link between environmental changes, natural selection and human health.

 

figure2.png

 

Selected relevant papers: Quintana-Murci & Clark (2013) Nat Rev Immunol; Vasseur et al. (2012) Am J Hum Genet; Manry et al. (2011). J Exp Med; Barreiro & Quintana-Murci (2010) Nat Rev Genet; Barreiro et al. (2009) PLoS Genet; Louicharoen et al. (2009) Science; Quintana-Murci et al. (2007) Nat Immunol; Barreiro et al. (2006) PLoS Med

 

 

GENETICS OF GENE EXPRESSION IN IMMUNITY TO INFECTION

 

By integrating cutting-edge knowledge and technology in the fields of genomics, population genetics, immunology and bioinformatics, our aim is to establish a thorough understanding of how variable the human immune response is in the natural setting and how this phenotypic variation is under genetic control. To do so, we define population-level variation in immune responses, by studying levels of transcript abundance (of both mRNA and miRNA) before and after activation with various immune/infectious stimuli. We then map expression quantitative trait loci (eQTLs), with a particular emphasis on response/interaction eQTLs, in order to identify immune-related molecular phenotypes that have conferred a selective advantage in human adaptation. For example, we have recently assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped eQTL in dendritic cells. We found 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 identified two infection-specific response eQTLs, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. We have also found that infection has a strong impact on both the relative abundance of the miRNA hairpin arms and the expression dynamics of miRNA isoforms.

 

In this context, our laboratory leads the EVOIMMUNOPOP project (funded by the ERC), which aims to understand how genetic variation controls transcriptional responses to TLR stimuli in populations of European and African descent. We also co-lead the MILIEU INTERIEUR Consortium (www.milieuinterieur.fr), which aims to establish the determinants of a “healthy” immune response by identifying factors (genetic, epigenetic and environmental) that contribute to the heterogeneity of immune responses in the population.  

figure3.png

 

Selected relevant papers: Siddle et al. (2015) PLoS Genet; Siddle et al. (2014) Genome Res; Duffy et al. (2014) Immunity

 

 

HUMAN LIFESTYLE & GENETIC AND EPIGENETIC VARIATION

 

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 inadequate sanitary practices and zoonosis following the domestication of animals, allowing the establishment of a substantial reservoir of infection and most likely contributing to the rise of infectious diseases. We are interested in understanding how this major transition has affected the demographic and adaptive history of human populations, as well as their epigenomic landscape. To do so, we focus our studies on populations of Bantu-speaking farmers and rainforest hunter-gatherers from central Africa. For example, we have shown that the ancestors of these two population groups diverged ~60,000 years ago, and that the two main groups of rainforest hunter-gatherers separated ~20,000 years ago following a period of major climatic change, the Last Glacial Maximum. We have also shown, based on genome-wide data, that hunter-gatherer and farmer populations have strongly differed in their population sizes over time, and that these differences precede the introduction of agriculture in sub-Saharan Africa. We are now evaluating how demography and lifestyle have affected the efficiency of purifying selection in these populations, as well as developing methods to investigate the occurrence of adaptation through various evolutionary mechanisms (i.e., classic sweep model, selection on standing variation, polygenic adaptation and adaptive introgression).

 

figure-4.png

 

 

Selected relevant papers: Patin et al. (2014) Nat Commun; Patin et al. (2009) PLoS Genet; Berniell-Lee et al. (2009) Mol Biol Evol; Verdu et al. (2009) Curr Biol; Quintana-Murci et al. (2008) Proc Natl Acad Sci U S A; Patin & Quintana-Murci (2008) Trends Ecol Evol

Updated on 09/06/2015

logo_heg.jpg

logo_cnrs.jpg

Contact

Unit Human Evolutionary Genetics

CNRS URA3012

 

Institut Pasteur
25, rue du Dr. Roux
75724 Paris Cedex 15, France
 

Tel: +33 1 40 61 34 43
Fax: +33 1 45 68 87 27


Contact us

Organizer

Access to all events