© 2007 Nature Publishing Group http://www.nature.com/naturegenetics
Convergent adaptation of human lactase persistence in Africa and Europe Sarah A Tishkoff1,9, Floyd A Reed1,9, Alessia Ranciaro1,2, Benjamin F Voight3, Courtney C Babbitt4, Jesse S Silverman4, Kweli Powell1, Holly M Mortensen1, Jibril B Hirbo1, Maha Osman5, Muntaser Ibrahim5, Sabah A Omar6, Godfrey Lema7, Thomas B Nyambo7, Jilur Ghori8, Suzannah Bumpstead8, Jonathan K Pritchard3, Gregory A Wray4 & Panos Deloukas8 A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotypephenotype association study in 470 Tanzanians, Kenyans and Sudanese and identiﬁed three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that signiﬁcantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending 42.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past B7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption. lactase persistence trait: C/T-13910 and G/A-22018, located B14 kb and B22 kb upstream of LCT, respectively, within introns 9 and 13 of the adjacent minichromosome maintenance 6 (MCM6) gene4 (Fig. 1). The T-13910 and A-22018 alleles were 100% and 97% associated with lactase persistence, respectively, in the Finnish study4, and the T-13910 allele is B86%–98% associated with lactase persistence in other European populations6–8. Although these alleles could simply be in LD with an unknown regulatory mutation6, several additional lines of evidence, including mRNA transcription studies in intestinal biopsy samples9 and reporter gene assays driven by the LCT promoter in vitro10–12, suggest that the C/T-13910 SNP regulates LCT transcription in Europeans. It is hypothesized that natural selection has had a major role in determining the frequencies of lactase persistence in different human populations since the development of cattle domestication in the Middle East and North Africa B7,500–9,000 years ago2,3,6,13–18. A region of extensive LD spanning 41 Mb has been observed on European chromosomes with the T-13910 allele, consistent with recent positive selection6,14,16–18. Based on the breakdown of LD on chromosomes with the T-13910 allele, it is estimated14 that this allele arose within the past B2,000–20,000 years within Europeans, probably in response to strong selection for the ability to digest milk as adults.
In most humans, the ability to digest lactose, the main carbohydrate present in milk, declines rapidly after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase (LPH). LPH is predominantly expressed in the small intestine, where it hydrolyzes lactose into glucose and galactose, sugars that are easily absorbed into the bloodstream1. However, some individuals, particularly descendants from populations that have traditionally practiced cattle domestication, maintain the ability to digest milk and other dairy products into adulthood. These individuals have the ‘lactase persistence’ trait. The frequency of lactase persistence is high in northern European populations (490% in Swedes and Danes), decreases in frequency across southern Europe and the Middle East (B50% in Spanish, French and pastoralist Arab populations) and is low in non-pastoralist Asian and African populations (B1% in Chinese, B5%–20% in West African agriculturalists)1–3. Notably, lactase persistence is common in pastoralist populations from Africa (B90% in Tutsi,...
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