Physicians observe very often that their patients can react differently to the same medical treatment: for some of them, the drug will prove inefficient, whereas for others it might provoke side-effects, sometimes rather serious.
Such differences in response to drug intake are due to several factors, of which molecular variations in specific genes, named « ADME ». This acronym stems from the fact that, after ingestion of a chemical compound, these genes are involved in its Absorption in the circulatory system, its Distribution to given tissues, its Metabolism in the liver and/or its Excretion from the organism. This project aims at investigating the evolutionary mechanisms responsible for the diversity of ADME genes in human populations. Thanks to local and international collaborations, the project will document, through the use of bioinformatics and biostatistics tools, the variability of ADME genotypes and phenotypes in targeted populations.
- Do we find the same ADME variants in different populations ? If so, do we find them at similar frequencies?
- Do we find similar genotype-phenotype associations in all populations?
This information will be integrated in analyses aimed at evidencing the relative influence of demographic history, on one hand, and of natural selection on the other, on the genetic and genomic structure of populations in ADME regions.
- Does the history of human migrations explain the diversity observed in ADME genes?
- Should we rather invoke an effect of the chemical environment, which would have exerted population-specific selective pressures?
Because of their role at the interface between the organism and its chemical environment, ADMEgenes are likely targets of recent selective pressures linked to changes in the environments in which humans evolved, such as changes in dietary habits for instance. We will couple a « top-down » approach to identify genomic ADME regions that are different between populations, with a « bottom-up » approach to detect « gene-response » associations common to several populations, so as to determine which ADME genes or sets of genes might have undergone recent selective pressures, and of what type. This project is thus intended to evidence the evolutionary mechanisms that shaped genomic regions that are functionally important from the clinical and epidemiological point of view. It will allow us to extend the knowledge of human molecular diversity and its evolution to a key-region of the peopling history of our species.
- Kickoff meeting with international collaborators, 15-16 October 2015, University of Geneva, Switzerland
- Conference of 26 November 2015 at the Faculty of Science, Charles University in Prague, Czech Republic
- Conference of 26 December 2015 at the College of Health Sciences, Addis Ababa University, Ethiopia
- Conference of 9 November 2016 at the College of Medicine and Health Sciences, Sultan Qaboos University, Oman
- Conference of 3 March 2017 at the Health Sciences School, Department of Molecular Biology and Genetics, Democritus University of Thrace, Greece
- End of Project workshop with international collaborators, 7-8 November 2019, University of Geneva, Switzerland
- Dr Jules Desmeules, co-Applicant (HUG Geneva)
- Dr Youssef Daali, co-Applicant (HUG Geneva)
- Dr Mylène Docquier (iGE3 Genomics platform)
- Dr Viktor Cerny (Charles University)
- Dr Getnet Yimer (Addis Ababa University)
- Dr Said Al-Yahyaee (Sultan Qaboos University)
- Dr Sotiria Boukouvala (Democritus University of Thrace)
Selected publications related to the project
- Gloor Y, Matthey A, Sobo K, Mouterde M, Kosek E, Pickering G, Poloni ES, Cedraschi C, Ehret G, Desmeules JA (2022) Uncovering a genetic polymorphism located in Huntingtin Associated Protein 1 in modulation of central pain sensitization signaling pathways. Front Neurosci 16:807773.
- Kulichová I, Mouterde M, Mokhtar MG, Diallo I, Tříska P, Diallo YM, Hofmanová Z, Poloni ES, Černý V (2021) Demographic history was a formative mechanism of the genetic structure for the taste receptor (TAS2R16) in human populations inhabiting Africa's Sahel/Savannah Belt. Am J Biol Anthropol 177(3):540-555..
- Vicente M, Priehodová E, Diallo I, Podgorná E, Poloni ES, Černý V, Schlebusch CM (2019) Population history and genetic adaptation of the Fulani nomads: inferences from genome-wide data and the lactase persistence trait. BMC Genomics 20:915.
- Vangenot C, Gagneux P, de Groot NG, Baumeyer A, Mouterde M, Crouau-Roy B, Darlu P, Sanchez-Mazas A, Sabbagh A, Poloni ES (2019) Humans and chimpanzees display opposite patterns of diversity in arylamine N-acetyltranferase genes. G3: Genes, Genomes, Genetics 9(7):2199-2224.
Publications of the project
- Mouterde M, Daali Y, Rollason V, Čížková M, Mulugeta A, Al-Balushi KK, Fakis G, Konstantinidis T, Al-Thihli K, Cerná M, Makonnen E, Boukouvala S, Al-Yahyaee S, Yimer G, Černý V, Desmeules J, Poloni ES (2022) Joint analysis of phenotypic and genomic diversity sheds light on the evolution of xenobiotic metabolism in humans. Genome Biol Evol evac167.
- Rollason V, Mouterde M, Daali Y, Čížková M, Priehodová E, Kulichová I, Posová H, Petanová J, Mulugeta A, Makonnen E, Al-Habsi A, Davidson R, Al-Balushi K, Al-Thihli K, Cerná M, Al-Yahyaee S, Černý V, Yimer G, Poloni ES, Desmeules J (2020) Safety of the Geneva cocktail, a cytochrome P450 and P-glycoprotein phenotyping cocktail, in healthy volunteers from three different geographic origins. Drug Saf 43:1181–1189.