Convergent Adaptation of Human Lactase Persistence in Africa and Europe

Abstract

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 genotype-phenotype 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 >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past ~7,000 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. 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 (>90% in Swedes and Danes), decreases in frequency across southern Europe and the Middle East (~50% in Spanish, French and pastoralist Arab populations) and is low in non-pastoralist Asian and African populations (~1% in Chinese, ~5%-20% in West African agriculturalists)1-3. Notably, lactase persistence is common in pastoralist populations from Africa (~90% in Tutsi, ~50% in Fulani)1,3. Lactase persistence is inherited as a dominant mendelian trait in Europeans1,2,4. Adult expression of the gene encoding LPH ( LCT), located on 2q21, is thought to be regulated by cis-acting elements5 (Fig. 1). A linkage disequilibrium (LD) and haplotype analysis of Finnish pedigrees identified two single SNPs associated with the lactase persistence trait: C/ T-13910 and G/A-22018, located ~14 kb and ~22 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 ~86%-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 ~7,500-9,000 years ago2,3,6,13-18. A region of extensive LD spanning >1 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 ~2,000-20,000 years within Europeans, probably in response to strong selection for the ability to digest milk as adults. Although the T-13910 variant is likely to be the causal variant for the lactase persistence trait in Europeans, analyses of this SNP in culturally and geographically diverse African populations indicated that it is present (and at low frequency (<14%)) in only a few West African pastoralist populations, such as the Fulani (or Fulbe) and Hausa from Cameroon15,19,20. It is absent in all other African populations tested, including East African pastoralist populations with a high prevalence of the lactase persistence trait19. Thus, the lactase persistence trait has evolved independently in most African populations owing to distinct genetic events15,19,20. Here, we examine genotype-phenotype associations in 470 East Africans, and we identify three previously undescribed variants associated with the lactase persistence trait, each of which arose independently from the European T-13910 allele and resulted in enhanced transcriptional activity in LCT promoter-driven reporter gene assays. We demonstrate that the most common variant in Kenyans and Tanzanians spread rapidly to high frequency in East Africa over the past ~7,000 years owing to the strong selective force of adult milk consumption, and we show that chromosomes with these variants have one of the strongest genetic signatures of natural selection yet reported in humans.