Evidence of Still-Ongoing Convergence Evolution of the Lactase Persistence T-13910 Alleles in Humans

Abstract

A single-nucleotide variant, C/T(-13910), located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T(-13910) variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T(-13910) H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T(-13910) H98 allele (approximately 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (approximately 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T(-13910) allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans.

Low prevalence of lactase persistence in Neolithic South-West Europe

“…2 The association of this allele with the phenotype of lactase persistence strongly supports its importance, and is a suggestive example of convergent evolution. The frequency of the À13910T allele in Europe is the greatest in the North-Western parts of the continent, with intermediary and sometimes low frequencies in the Southern parts.…”

“…Although lactase persistence reaches up to 60-90% in Central-European and Northern European populations, it is much less frequently present in Southern European, Middle-Eastern, African and some South-Asian populations, while being completely absent in the rest of the world population. [1][2][3] The persistent activity of the lactase enzyme (ie, lactase phlorizin hydrolase, encoded by the lactase gene LCT) during adulthood, expressed especially in the intestine, has been demonstrated to be linked with variations in the lactase promoter, such as a C/T transition in the promoter region 13910 basepairs upstream of the LCT gene (rs4988235), which is suggested to influence LCT gene expression. 4 The T allele, dominant over the C allele, has been described to be the allele associated with lactase persistence in European populations.…”

“…6 Several studies support the perspective that these differences in lactase persistence between populations can be ascribed to processes of positive selection. 1,2 Indeed, it has been suggested that the frequency of lactase persistence has increased in several populations as cattle domestication and dairy consumption was introduced in Europe. From that point a strong selective advantage of the ability to digest milk would have become apparent, which has resulted in a survival benefit of the already existing rare lactase persistent individuals in the population.…”

“…12 In Northern Europe, the advantage of the calcium assimilation hypothesis is likely to be the cause of the high lactase persistence at this latitude, 13 but in Southern Europe the presence of the À13910T allele displays a large variation between present populations. 2 The Iberian Peninsula represents one of the end points of Neolithic migration. The arrival or adoption of the Neolithic way of life in the Northern part of the Iberian Peninsula, here referred to as the Basque Country, is believed to have taken place around 7000 YBP.…”

Genomic signatures of diet-related shifts during human origins

“…The most prominent example is the ability to digest milk solids (lactose) into adulthood (lactase persistence) in some human populations [2,3,74,75]. Multiple regulatory polymorphisms in these different populations help drive lactose-phlorizin hydrolase (LPH) gene expression in adults.…”