Abstract
The levels of haplotype diversity within the lineages defined by two single-nucleotide polymorphisms (SNPs) (−13910 C/T and −22018 G/A) associated with human lactase persistence were assessed with four fast-evolving microsatellite loci in 794 chromosomes from Portugal, Italy, Fulbe from Cameroon, São Tomé and Mozambique. Age estimates based on the intraallelic microsatellite variation indicate that the −13910*T allele, which is more tightly associated with lactase persistence, originated in Eurasia before the Neolithic and after the emergence of modern humans outside Africa. We detected significant departures from neutrality for the −13910*T variant in geographically and evolutionary distant populations from southern Europe (Portuguese and Italians) and Africa (Fulbe) by using a neutrality test based on the congruence between the frequency of the allele and the levels of intraallelic variability measured by the number of mutations in adjacent microsatellites. This result supports the role of selection in the evolution of lactase persistence, ruling out possible confounding effects from recombination suppression and population history. Reevaluation of the available evidence on variation of the −13910 and −22018 loci indicates that lactase persistence probably originated from different mutations in Europe and most of Africa, even if 13910*T is not the causal allele, suggesting that selective pressure could have promoted the convergent evolution of the trait. Our study shows that a limited number of microsatellite loci may provide sufficient resolution to reconstruct key aspects of the evolutionary history of lactase persistence, providing an alternative to approaches based on large numbers of SNPs.
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References
Aoki K (2001) Theoretical and empirical aspects of gene-culture coevolution. Theor Popul Biol 59:253–261
Bandelt H-J, Forster P, Röhl A (1999) Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16:37–48
Bayless TM (1971) Junior, why didn’t you drink your milk?. Gastroenterology 60:479–480
Behar DM, Thomas MG, Skorecki K, Hammer MF, Bulygina E, Rosengarten D, Jones AL, Held K, Moses V, Goldstein D, Bradman N, Weale ME (2003) Multiple origins of Ashkenazi Levites: Y chromosome evidence for both Near Eastern and European ancestries. Am J Hum Genet 73:768–779
Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE and Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111–1120
Enattah NS, Sahi T, Savilahti E, Terwilliger JS, Peltonen L, Järvelä I (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30:233–237
Flatz G (1987) Genetics of lactose digestion in humans. Adv Hum Genet 16:1–77
Goldstein DB, Reich DE, Bradman N, Usher S, Seligsohn U, Peretz H (1999) Age estimates of two common mutations causing factor XI deficiency: recent genetic drift is not necessary for elevated disease incidence among Ashkenazi Jews. Am J Hum Genet 64:1071–1075
Holden C, Mace R (1997) Phylogenetic analysis of the evolution of lactose digestion in adults. Hum Biol 69:605–628
Hollox E (2004) Genetics of lactase persistence-fresh lessons in the history of milk drinking. Eur J Hum Genet 13:267–269
Klein RG (2000) Archeology and the evolution of human behavior. Evol Anthropol 9:17–36
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247
Kretchmer N (1972) Lactose and lactase. Sci Am 227:70–78
Kruglyak L (1999) Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22:139–144
Marjoram P, Donnelly P (1994) Pairwise comparisons of mitochondrial DNA sequences in subdivided populations and implications for early human evolution. Genetics 136:673–683
McCracken RD (1971) Lactase deficiency: an example of dietary evolution. Curr Anthropol 12:479–517
Midgley MS (1992) TRB culture: the first farmers of the North European plain. Edinburgh University Press, Edinburgh
Mulcare CA, Weale ME, Jones AL, Connell B, Zeitlyn D, Tarekegn A, Swallow DM, Bradman N, Thomas MG (2004) The T allele of a single-nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C−13.9kbT) does not predict or cause the lactase-persistence phenotype in Africans. Am J Hum Genet 74:1102–1110
Nei M, Saitou N (1986) Genetic relationship of human populations and ethnic differences in relation to drugs and food. In: Kalow W, Goedde HW, Agarwal DP (eds) Ethnic differences in reactions to drugs and other xenobiotics. Alan L Riss, New York, pp 21–37
Pluzhnikov A, Di Rienzo A, Hudson R (2002) Inferences about human demography based on multilocus analyses of noncoding sequences. Genetics 161:1209–1218
Poulter M, Hollox E, Harvey CB, Mulcare C, Peuhkuri K, Kajander K, Sarner M, Korpela R, Swallow DM (2003) The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann Hum Genet 67:298–311
Pritchard JK, Seielstad MT, Pérez-Lezaun A, Feldman MW (1999) Population growth of human Y chromosomes: a study of Y chromosome microsatellites. Mol Biol Evol 16:1791–1798
Raymond M, Rousset F (1995) An exact test for population diferentiation. Evolution 49:1280–1281
Reich DE, Goldstein DB (1999) Estimating the age of mutations using the variation at linked markers. In: Goldstein DB, Schlötterer C (eds) Microsatellites: evolution and applications. Oxford Unviversity Press, Oxford, pp 129–138
Relethford JH (2001) Genetics and the search for modern human origins. Wiley, New York
Rogers AR, Harpending H (1992) Population growth makes waves in the distribution of pairwise genetic differences. Mol Biol Evol 9:552–569
Salas A, Richards M, De La Fe T, Lareu MV, Sobrino B, Sánchez-Diz P, Macaulay V, Carracedo A (2002) The making of the African mtDNA landscape. Am J Hum Genet 71:1082–1111
Schneider S, Roessli D, Excoffier L (2000) Arlequim, ver. 2.000: a software for population genetics data analysis. University of Geneva, Geneva
Seixas S, Garcia O, Trovoada MJ, Santos MT, Amorim A, Rocha J (2001) Patterns of haplotype diversity within the serpin gene cluster at 14q32.1: insights into the natural history of the alpha1-antitrypsin polymorphism. Hum Genet 108:20–30
Simoons FJ (1970) Primary adult lactose intolerance and the milking habit: a problem in biological and cultural interrelations. II. A culture historical hypothesis. Am J Dig Dis 15:695–710
Slatkin M (2002) The age of alleles. In: Slatkin M, Veuille M (eds) Modern developments in theoretical population genetics: the legacy of Gustave Malécot. Oxford University Press, New York, pp 233–260
Slatkin M, Bertorelle G (2001) The use of intraallelic variability for testing neutrality and estimating population growth rate. Genetics 158:865–874
Slatkin M, Rannala B (2000) Estimating allele age. Annu Rev Genomics Hum Genet 1:225–249
Spedini G, Destro-Bisol G, Mondovi S, Kaptué L, Taglioli L, Paoli G (1999) The peopling of sub-Saharian Africa: the case study of Cameroon. Am J Phys Anthropol 110:143–162
Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169
Stephens M, Smith N, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989
Stumpf MPH, Goldstein DB (2001) Genealogical and evolutionary inference with the human Y chromosome. Science 291:1738–1742
Swallow DM (2003) Genetics of lactase persistence and lactose intolerance. Annu Rev Genet 37:197–219
Takahata N (1993) Allelic genealogy and human evolution. Mol Biol Evol 10:2–22
Tomás G, Seco L, Seixas S, Faustino P, Lavinha J, Rocha J (2002) The peopling of São Tomé (Gulf of Guinea): origins of slave settlers and admixture with the Portuguese. Hum Biol 74:397–411
Wall JD, Przeworski M (2000) When did the human population size start increasing?. Genetics 155:1865–1874
Weber JL, Wong C (1993) Mutation of human short tandem repeats. Hum Mol Genet 2:1123–1128
Xu H, Fu Y (2004) Estimating effective population size or mutation rate with microsatellites. Genetics 166:555–563
Acknowledgements
We thank Luís Pedro Resende and Cinzia Battaggia for assistance in typing the Portuguese and Italian samples, respectively. We are also grateful to Gabriella Spedini for the Fulbe DNA samples and to António Prista and Sílvio Saranga for the Mozambique samples. We thank Eduardo Tarazona-Santos and Nuno Ferrand for comments on the manuscript. This research was supported by the Sociedade Portuguesa de Gastrenterologia and by the Fundação para a Ciência e a Tecnologia (grants POCTI/42510/ANT/2001 and POCTI/BIA-BDE/56654/2004). D.L. and G.D.B. were supported by the M.I.U.R. (grant numbers 2003054059 and 2005058414).
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Coelho, M., Luiselli, D., Bertorelle, G. et al. Microsatellite variation and evolution of human lactase persistence. Hum Genet 117, 329–339 (2005). https://doi.org/10.1007/s00439-005-1322-z
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DOI: https://doi.org/10.1007/s00439-005-1322-z