A. Novelletto, A. Froment, J. M. Hombert, H. Rouba, and S. , Santachiara-Benerecetti, for kindly providing us with DNA samples. This work was supported by CNRS and Institut Pasteur research funding, E.P. was

E. Asprodini, E. Zifa, I. Papageorgiou, and A. Benakis, Determination of N-acetylation phenotyping in a greek population using caffeine as a metabolic probe, European Journal of Drug Metabolism and Pharmacokinetics, vol.369, issue.4, pp.501-506, 1998.
DOI : 10.1007/BF03190002

F. Austerlitz, L. Kalaydjieva, and E. Heyer, Detecting population growth, selection and inherited fertility from haplotypic data in humans, Genetics, vol.165, pp.1579-1586, 2003.
URL : https://hal.archives-ouvertes.fr/hal-00531063

L. Barreiro, E. Patin, O. Neyrolles, H. Cann, B. Gicquel et al., The Heritage of Pathogen Pressures and Ancient Demography in the Human Innate-Immunity CD209/CD209L Region, The American Journal of Human Genetics, vol.77, issue.5, pp.869-886, 2005.
DOI : 10.1086/497613

D. Behar, M. Hammer, D. Garrigan, R. Villems, B. Bonne-tamir et al., MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population, European Journal of Human Genetics, vol.12, issue.5, pp.355-364, 2004.
DOI : 10.1038/sj.ejhg.5201156

T. Bersaglieri, P. Sabeti, N. Patterson, T. Vanderploeg, S. Schaffner et al., Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene, The American Journal of Human Genetics, vol.74, issue.6, pp.1111-1120, 2004.
DOI : 10.1086/421051

M. Blum, D. Grant, W. Mcbride, M. Heim, and U. Meyer, -Acetyltransferase Genes: Isolation, Chromosomal Localization, and Functional Expression, DNA and Cell Biology, vol.9, issue.3, pp.193-203, 1990.
DOI : 10.1089/dna.1990.9.193
URL : https://hal.archives-ouvertes.fr/hal-00459362

A. Bozkurt, N. Basci, S. Kalan, M. Tuncer, and S. Kayaalp, N-acetylation phenotyping with sulphadimidine in a Turkish population, European Journal of Clinical Pharmacology, vol.23, issue.1, pp.53-56, 1990.
DOI : 10.1007/BF00314803

C. Bustamante, A. Fledel-alon, S. Williamson, R. Nielsen, M. Hubisz et al., Natural selection on protein-coding genes in the human genome, Nature, vol.437, issue.7062, pp.1153-1157, 2005.
DOI : 10.1038/nature04240

R. Cartwright, R. Glashan, H. Rogers, R. Ahmad, D. Barham-hall et al., ROLE OF N-ACETYLTRANSFERASE PHENOTYPES IN BLADDER CARCINOGENESIS: A PHARMACOGENETIC EPIDEMIOLOGICAL APPROACH TO BLADDER CANCER, The Lancet, vol.320, issue.8303, pp.842-846, 1982.
DOI : 10.1016/S0140-6736(82)90810-8

I. Cascorbi, N. Drakoulis, J. Brockmoller, A. Maurer, K. Sperling et al., Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity, Am J Hum Genet, vol.57, pp.581-592, 1995.

L. Cordain, S. Eaton, A. Sebastian, N. Mann, S. Lindeberg et al., Origins and evolution of the Western diet: health implications for the 21st century, Am J Clin Nutr, vol.81, pp.341-354, 2005.

J. Cornuet and G. Luikart, Description and power analysis of two tests for detecting recent population bottlenecks from allele frequency data, Genetics, vol.144, pp.2001-2014, 1996.

J. De-leon, K. Vatsis, and W. Weber, Characterization of naturally occurring and recombinant human N-acetyltransferase variants encoded by NAT1, Mol Pharmacol, vol.58, pp.288-299, 2000.

L. Eidus, M. Hodgkin, O. Schaefer, and A. Jessamine, Distribution of isoniazid inactivators determined in Eskimos and Canadian college students by a urine test, Rev Can Biol, vol.33, pp.117-123, 1974.

A. El-yazigi, K. Johansen, D. Raines, and M. Dossing, Dr. N-Acetylation Polymorphism and Diabetes Mellitus among Saudi Arabians, The Journal of Clinical Pharmacology, vol.7, issue.10, pp.905-910, 1992.
DOI : 10.1002/j.1552-4604.1992.tb04636.x

L. Excoffier, Human demographic history: refining the recent African origin model, Current Opinion in Genetics & Development, vol.12, issue.6, pp.675-682, 2002.
DOI : 10.1016/S0959-437X(02)00350-7

J. Fay and C. Wu, Hitchhiking under positive Darwinian selection, Genetics, vol.155, pp.1405-1413, 2000.

L. Ferguson, Natural and human-made mutagens and carcinogens in the human diet, Toxicology, vol.181, issue.182, pp.79-82, 2002.
DOI : 10.1016/S0300-483X(02)00258-5

Y. Fu and W. Li, Statistical tests of neutrality of mutations, Genetics, vol.133, pp.693-709, 1993.

S. Gabriel, S. Schaffner, H. Nguyen, J. Moore, J. Roy et al., The Structure of Haplotype Blocks in the Human Genome, Science, vol.296, issue.5576, pp.2225-2229, 2002.
DOI : 10.1126/science.1069424

M. Garcia-closas, N. Malats, D. Silverman, M. Dosemeci, M. Kogevinas et al., NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses, The Lancet, vol.366, issue.9486, pp.649-659, 2005.
DOI : 10.1016/S0140-6736(05)67137-1

D. Garrigan, Z. Mobasher, T. Severson, J. Wilder, and M. Hammer, Evidence for Archaic Asian Ancestry on the Human X Chromosome, Molecular Biology and Evolution, vol.22, issue.2, pp.189-192, 2005.
DOI : 10.1093/molbev/msi013

R. Griffiths and S. Tavaré, Sampling Theory for Neutral Alleles in a Varying Environment, Philosophical Transactions of the Royal Society B: Biological Sciences, vol.344, issue.1310, pp.403-410, 1994.
DOI : 10.1098/rstb.1994.0079

R. Harding and G. Mcvean, A structured ancestral population for the evolution of modern humans, Current Opinion in Genetics & Development, vol.14, issue.6, pp.667-674, 2004.
DOI : 10.1016/j.gde.2004.08.010

D. Harris, X chromosome evidence for ancient human histories, Proceedings of the National Academy of Sciences, vol.96, issue.6, pp.3320-3324, 1996.
DOI : 10.1073/pnas.96.6.3320
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC15940

M. Hashiguchi and A. Ebihara, Acetylation polymorphism of caffeine in a Japanese population, Clinical Pharmacology and Therapeutics, vol.52, issue.3, pp.274-276, 1992.
DOI : 10.1038/clpt.1992.141

T. Hayakawa, I. Aki, A. Varki, Y. Satta, and N. Takahata, Fixation of the Human-Specific CMP-N-Acetylneuraminic Acid Hydroxylase Pseudogene and Implications of Haplotype Diversity for Human Evolution, Genetics, vol.172, issue.2, 2005.
DOI : 10.1534/genetics.105.046995

D. Hein, Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis, Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol.506, issue.507, pp.65-77, 2002.
DOI : 10.1016/S0027-5107(02)00153-7

D. Hein, M. Doll, A. Fretland, M. Leff, S. Webb et al., Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms, Cancer Epidemiol Biomarkers Prev, vol.9, pp.29-42, 2000.

W. Hill and A. Robertson, The effects of inbreeding at loci with heterozygote advantage, Genetics, vol.60, pp.615-628, 1968.

M. Hodgkin, L. Eidus, and W. Bailey, Isoniazid phenotyping of black as well as white patients, Canadian Journal of Physiology and Pharmacology, vol.57, issue.7, pp.760-763, 1979.
DOI : 10.1139/y79-117

F. Hombhanje, An assessment of acetylator polymorphism and its relevance in Papua New Guinea, P N G Med J, vol.33, pp.107-110, 1990.

Y. Huang, H. Chern, W. Su, J. Wu, S. Lai et al., Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug???induced hepatitis, Hepatology, vol.4, issue.4, pp.883-889, 2002.
DOI : 10.1053/jhep.2002.32102

R. Hudson, Generating samples under a Wright-Fisher neutral model of genetic variation, Bioinformatics, vol.18, issue.2, pp.337-338, 2002.
DOI : 10.1093/bioinformatics/18.2.337

R. Hudson, M. Kreitman, and M. Aguade, A test of neutral molecular evolution based on nucleotide data, Genetics, vol.116, pp.153-159, 1987.

N. Hughes, S. Janezic, K. Mcqueen, M. Jewett, T. Castranio et al., Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe, Pharmacogenetics, vol.8, issue.1, pp.55-66, 1998.
DOI : 10.1097/00008571-199802000-00008

K. Ilett, G. Chiswell, R. Spargo, E. Platt, and R. Minchin, Acetylation phenotype and genotype in Aboriginal leprosy patients from the north-west region of Western Australia, Pharmacogenetics, vol.3, issue.5, pp.264-269, 1993.
DOI : 10.1097/00008571-199310000-00006

H. Innan, A two-locus gene conversion model with selection and its application to the human RHCE and RHD genes, Proceedings of the National Academy of Sciences, vol.100, issue.15, pp.8793-8798, 2003.
DOI : 10.1073/pnas.1031592100

Y. Irshaid, H. Hadidi, M. Abuirjeie, A. Latif, O. Sartawi et al., Acetylator phenotypes of Jordanian diabetics, European Journal of Clinical Pharmacology, vol.22, issue.1, pp.621-623, 1992.
DOI : 10.1007/BF02284960

A. Jeffreys and C. May, Intense and highly localized gene conversion activity in human meiotic crossover hot spots, Nature Genetics, vol.36, issue.2, pp.151-156, 2004.
DOI : 10.1038/ng1287

L. Jeyakumar and M. French, Polymorphic acetylation of sulphamethazine in a Nigerian (Yoruba) population, Xenobiotica, vol.9, issue.5, pp.319-321, 1981.
DOI : 10.3109/00498258109045310

L. Jorge-nebert, M. Eichelbaum, E. Griese, T. Inaba, and T. Arias, Analysis of six SNPs of NAT2 in Ngawbe and Embera Amerindians of Panama and determination of the Embera acetylation phenotype using caffeine, Pharmacogenetics, vol.12, issue.1, pp.39-48, 2002.
DOI : 10.1097/00008571-200201000-00006

A. Karim, M. Elfellah, and D. Evans, Human acetylator polymorphism: estimate of allele frequency in Libya and details of global distribution., Journal of Medical Genetics, vol.18, issue.5, pp.325-330, 1981.
DOI : 10.1136/jmg.18.5.325

M. Kimura, Evolutionary Rate at the Molecular Level, Nature, vol.16, issue.5129, pp.624-626, 1968.
DOI : 10.1038/217624a0

V. Kukongviriyapan, V. Lulitanond, C. Areejitranusorn, B. Kongyingyose, and P. Laupattarakasem, N-Acetyltransferase Polymorphism in Thailand, Human Heredity, vol.34, issue.4, pp.246-249, 1984.
DOI : 10.1159/000153471

D. Labuda, E. Zietkiewicz, and M. Labuda, The Genetic Clock and the Age of the Founder Effect in Growing Populations: A Lesson from French Canadians and Ashkenazim, The American Journal of Human Genetics, vol.61, issue.3, pp.768-771, 1997.
DOI : 10.1016/S0002-9297(07)64341-9

S. Lee, K. Lee, C. Ki, O. Kwon, H. Kim et al., Complete sequencing of a genetic polymorphism in NAT2 in the Korean population, Clin Chem, vol.48, pp.775-777, 2002.

R. Lewin, Africa: cradle of modern humans, Science, vol.237, issue.4820, pp.1292-1295, 1987.
DOI : 10.1126/science.3114877

R. Lewontin, The interaction of selection and linkage. II. Optimum models, Genetics, vol.50, pp.757-782, 1964.

E. Lil-'in, M. Korsunskaia, V. Meksin, E. Drozdov, and V. Nazarov, Distribution of acetylator phenotypes in the normal Moscow city population and in chronic alcoholism, Genetika, vol.20, pp.1557-1559, 1984.

G. Marth, G. Schuler, R. Yeh, R. Davenport, R. Agarwala et al., Sequence variations in the public human genome data reflect a bottlenecked population history, Proceedings of the National Academy of Sciences, vol.100, issue.1, pp.376-831, 2003.
DOI : 10.1073/pnas.222673099

J. Mcdonald and M. Kreitman, Adaptive protein evolution at the Adh locus in Drosophila, Nature, vol.351, issue.6328, pp.652-654, 1991.
DOI : 10.1038/351652a0

J. Neel, Diabetes mellitus: a " thrifty " genotype rendered detrimental by " progress " ?, Am J Hum Genet, vol.14, pp.353-362, 1962.

C. Nhachi, Polymorphic acetylation of sulphamethazine in a Zimbabwe population., Journal of Medical Genetics, vol.25, issue.1, pp.29-31, 1988.
DOI : 10.1136/jmg.25.1.29

M. Ong, T. Mant, K. Veerapen, D. Fitzgerald, F. Wang et al., THE LACK OF RELATIONSHIP BETWEEN ACETYLATOR PHENOTYPE AND IDIOPATHIC SYSTEMIC LUPUS ERYTHEMATOSUS IN A SOUTH-EAST ASIAN POPULATION: A STUDY OF INDIANS, MALAYS AND MALAYSIAN CHINESE, Rheumatology, vol.29, issue.6, pp.462-464, 1990.
DOI : 10.1093/rheumatology/29.6.462

¨. Pä-a and S. , The mosaic that is our genome, Nature, vol.421, pp.409-412, 2003.

M. Przeworski, R. Hudson, D. Rienzo, and A. , Adjusting the focus on human variation, Trends in Genetics, vol.16, issue.7, pp.296-302, 2000.
DOI : 10.1016/S0168-9525(00)02030-8

J. Reeve and B. Rannala, DMLE+: Bayesian linkage disequilibrium gene mapping, Bioinformatics, vol.18, issue.6, pp.894-895, 2002.
DOI : 10.1093/bioinformatics/18.6.894
URL : http://bioinformatics.oxfordjournals.org/cgi/content/short/18/6/894

J. Rozas, J. Sanchez-delbarrio, X. Messeguer, and R. Rozas, DnaSP, DNA polymorphism analyses by the coalescent and other methods, Bioinformatics, vol.19, issue.18, pp.2496-2497, 2003.
DOI : 10.1093/bioinformatics/btg359

P. Sabeti, D. Reich, J. Higgins, H. Levine, D. Richter et al., Detecting recent positive selection in the human genome from haplotype structure, Nature, vol.5, issue.6909, pp.832-837, 2002.
DOI : 10.1038/35075590

M. Saleem, S. Malik, M. Ahmed, and N. Saleem, Isoniazid acetylation and polymorphism in humans, J Pak Med Assoc, vol.39, pp.285-286, 1989.

S. Sardas, B. Lahijany, I. Cok, and A. Karakaya, N-acetylation phenotyping with sulfamethazine in an Iranian population, Pharmacogenetics, vol.3, pp.131-134, 1993.

M. Saunders, M. Slatkin, C. Garner, M. Hammer, and M. Nachman, The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans, Genetics, vol.171, issue.3, pp.1219-1229, 2005.
DOI : 10.1534/genetics.105.048140

S. Schaffner, C. Foo, S. Gabriel, D. Reich, M. Daly et al., Calibrating a coalescent simulation of human genome sequence variation, Genome Research, vol.15, issue.11, pp.1576-1583, 2005.
DOI : 10.1101/gr.3709305

S. Schneider, D. Roessli, L. Excoffier, P. Sebastiani, L. R. Weiss et al., Arlequin version 2.000: a software for population genetic data analysis Minimal haplotype tagging, Genetics and Biometry Laboratory Proc Natl Acad Sci, vol.100, pp.9900-9905, 2000.

E. Sim, M. Payton, M. Noble, and R. Minchin, An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes, Human Molecular Genetics, vol.9, issue.16, pp.2435-2441, 2000.
DOI : 10.1093/hmg/9.16.2435

M. Slatkin and G. Bertorelle, The use of intraallelic variability for testing neutrality and estimating population growth rate, Genetics, vol.158, pp.865-874, 2001.

M. Slatkin and B. Rannala, Estimating the age of alleles by use of intraallelic variability, Am J Hum Genet, vol.60, pp.447-458, 1997.

N. Soranzo, B. Bufe, P. Sabeti, J. Wilson, M. Weale et al., Positive Selection on a High-Sensitivity Allele of the Human Bitter-Taste Receptor TAS2R16, Current Biology, vol.15, issue.14, pp.1257-1265, 2005.
DOI : 10.1016/j.cub.2005.06.042

M. Stephens and P. Donnelly, A Comparison of Bayesian Methods for Haplotype Reconstruction from Population Genotype Data, The American Journal of Human Genetics, vol.73, issue.5, pp.1162-1169, 2003.
DOI : 10.1086/379378

F. Tajima, Statistical method for testing the neutral mutation hypothesis by DNA polymorphism, Genetics, vol.123, pp.585-595, 1989.

M. Takahashi, F. Matsuda, N. Margetic, and M. Lathrop, Automated Identification of Single Nucleotide Polymorphisms from Sequencing Data, Journal of Bioinformatics and Computational Biology, vol.01, issue.02, pp.253-265, 2003.
DOI : 10.1142/S021972000300006X

N. Takahata, Allelic genealogy and human evolution, Mol Biol Evol, vol.10, pp.2-22, 1993.

N. Takahata, S. Lee, and Y. Satta, Testing Multiregionality of Modern Human Origins, Molecular Biology and Evolution, vol.18, issue.2, pp.172-183, 2001.
DOI : 10.1093/oxfordjournals.molbev.a003791

K. Tang, L. Wong, E. Lee, S. Chong, and C. Lee, Genomic evidence for recent positive selection at the human MDR1 gene locus, Human Molecular Genetics, vol.13, issue.8, pp.783-797, 2004.
DOI : 10.1093/hmg/ddh099

E. Thompson, H. Kuttab-boulos, D. Witonsky, L. Yang, B. Roe et al., CYP3A Variation and the Evolution of Salt-Sensitivity Variants, The American Journal of Human Genetics, vol.75, issue.6, pp.1059-1069, 2004.
DOI : 10.1086/426406

C. Toomajian, R. Ajioka, L. Jorde, J. Kushner, and M. Kreitman, A method for detecting recent selection in the human genome from allele age estimates, Genetics, vol.165, pp.287-297, 2003.

C. Toomajian and M. Kreitman, Sequence variation and haplotype structure at the human HFE locus, Genetics, vol.161, pp.1609-1623, 2002.

A. Upton, N. Johnson, J. Sandy, and E. Sim, Arylamine N-acetyltransferases ??? of mice, men and microorganisms, Trends in Pharmacological Sciences, vol.22, issue.3, pp.140-146, 2001.
DOI : 10.1016/S0165-6147(00)01639-4

Z. Wang, B. Wang, K. Tang, E. Lee, S. Chong et al., A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection, Human Molecular Genetics, vol.14, issue.14, pp.2075-2087, 2005.
DOI : 10.1093/hmg/ddi212

G. Watterson, On the number of segregating sites in genetical models without recombination, Theoretical Population Biology, vol.7, issue.2, pp.256-276, 1975.
DOI : 10.1016/0040-5809(75)90020-9

W. Weber, . Jb, and R. Harding, The acetylator genes and drug response Common 5 b-globin RFLP haplotypes harbour a surprising level of ancestral sequence mosaicism, Hum Genet, vol.113, pp.123-139, 1987.

S. Williamson and M. Orive, The Genealogy of a Sequence Subject to Purifying Selection at Multiple Sites, Molecular Biology and Evolution, vol.19, issue.8, pp.1376-1384, 2002.
DOI : 10.1093/oxfordjournals.molbev.a004199

S. Wooding, U. Kim, M. Bamshad, J. Larsen, L. Jorde et al., Natural Selection and Molecular Evolution in PTC, a Bitter-Taste Receptor Gene, The American Journal of Human Genetics, vol.74, issue.4, pp.637-646, 2004.
DOI : 10.1086/383092
URL : http://doi.org/10.1086/383092

S. Wooding, W. Watkins, M. Bamshad, D. Dunn, R. Weiss et al., DNA Sequence Variation in a 3.7-kb Noncoding Sequence 5??? of the CYP1A2 Gene: Implications for Human Population History and Natural Selection, The American Journal of Human Genetics, vol.71, issue.3, pp.528-542, 2002.
DOI : 10.1086/342260

N. Woolhouse, M. Qureshi, S. Bastaki, M. Patel, Y. Abdulrazzaq et al., Polymorphic N-acetyltransferase (NAT2) genotyping of Emiratis, Pharmacogenetics, vol.7, issue.1, pp.73-82, 1997.
DOI : 10.1097/00008571-199702000-00010

R. Zaid, M. Nargis, S. Neelotpol, J. Hannan, S. Islam et al., Acetylation phenotype status in a Bangladeshi population and its comparison with that of other Asian population data, Biopharmaceutics & Drug Disposition, vol.25, issue.6, pp.237-241, 2004.
DOI : 10.1002/bdd.403

Y. Zang, S. Zhao, M. Doll, J. States, and D. Hein, The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation, Pharmacogenetics, vol.14, issue.11, pp.717-723, 2004.
DOI : 10.1097/00008571-200411000-00002

B. Zhao, A. Seow, E. Lee, and H. Lee, Correlation between acetylation phenotype and genotype in Chinese women, European Journal of Clinical Pharmacology, vol.56, issue.9-10, pp.689-692, 2000.
DOI : 10.1007/s002280000203