Genetic Origins of Lactase Persistence and the Spread of Pastoralism in Africa

TLDR

Lactose digestion normally declines after weaning, but some individuals retain high lactase activity into adulthood, a trait that has been shaped by selection in pastoral societies. The study aimed to identify genetic variants linked to lactase persistence and to reconstruct its evolutionary history across Africa. Researchers sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter in 819 Africans and 154 non‑Africans, genotyped microsatellites in 252 individuals, and examined regulatory region variation in 513 eastern African subjects. They confirmed associations with three intron 13 variants (C‑14010, G‑13907, G‑13915), discovered two additional SNPs (G‑12962, T‑956), detected strong recent positive selection in eastern Africans and the Fulani, and traced the C‑14010 mutation’s origin to eastern Africa.

Abstract

In humans, the ability to digest lactose, the sugar in milk, declines after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase, encoded by LCT. However, some individuals maintain high enzyme amounts and are able to digest lactose into adulthood (i.e., they have the lactase-persistence [LP] trait). It is thought that selection has played a major role in maintaining this genetically determined phenotypic trait in different human populations that practice pastoralism. To identify variants associated with the LP trait and to study its evolutionary history in Africa, we sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter region in 819 individuals from 63 African populations and in 154 non-Africans from nine populations. We also genotyped four microsatellites in an ~198 kb region in a subset of 252 individuals to reconstruct the origin and spread of LP-associated variants in Africa. Additionally, we examined the association between LP and genetic variability at candidate regulatory regions in 513 individuals from eastern Africa. Our analyses confirmed the association between the LP trait and three common variants in intron 13 (C-14010, G-13907, and G-13915). Furthermore, we identified two additional LP-associated SNPs in intron 13 and the promoter region (G-12962 and T-956, respectively). Using neutrality tests based on the allele frequency spectrum and long-range linkage disequilibrium, we detected strong signatures of recent positive selection in eastern African populations and the Fulani from central Africa. In addition, haplotype analysis supported an eastern African origin of the C-14010 LP-associated mutation in southern Africa.