Population genomics on the origin of lactase persistence in Europe and South Asia

Abstract

<jats:title>A<jats:sc>bstract</jats:sc></jats:title><jats:p>The C to T mutation at rs4988235 located upstream of the lactase (<jats:italic>LCT</jats:italic>) gene is the primary determinant for lactase persistence (LP) that is prevalent among Europeans and South Asians. Here, we review evolutionary studies of this mutation based on ancient and present-day human genomes with the following concluding remarks: the mutation arose in the Pontic Steppe somewhere between 23,000 and 5000 years ago, emigrated into Europe and South Asia in the Bronze Age via the expansion of the Steppe ancestry, and experienced local hard sweeps with their delayed onsets occurring in the last 3600 years. We also argue that the G to A mutation at rs182549 arose earlier than 23,000 years ago, the intermediate CA haplotype ancestral to the LP-related TA haplotype is still represented by samples from Tuscans, admixed Americans and South Asians, and the great majority of G to A mutated descendants have hitchhiked since the C to T mutation was favored by local selection.</jats:p>

Low Prevalence of Lactase Persistence in Bronze Age Europe Indicates Ongoing Strong Selection over the Last 3,000 Years

“…The inferred allele age is highly dependent on the unknown effective population size between the time of mutation and the Bronze age, as well as the dominance coefficient h. Assuming dominance (h = 1), the MAP estimate varied between 3,550 (90% CI 3,200-5,100) and 7,140 (90% CI 5,525-7,650) years BP for population sizes 2N = 10 2 and 2N = 10 5 , respectively, and was about 20% older when assuming additivity (h = 0.5). In line with the low frequency for the Tollense sample, these estimates are at the lower end of the age range [36] (3,280-23,100 BP) or considerably younger [34] (17,500 BP) than recent estimates from modern data. However, we note that all such estimates make strong assumptions about the demographic history, the strength of selection, as well as the origin of the selected allele.…”

“…The spread of the rs4988235-A allele has previously been attributed to a Steppe-associated expansion during the early Bronze Age [36]. Based on imputed data, Allentoft et al…”

“…To illustrate this, we inferred the age of the rs4988235-A allele from the Tollense data using a novel Bayesian method and assuming a hard sweep [36] with selection coefficient of 6% since the mutation occurred ( Figure 3C). The inferred allele age is highly dependent on the unknown effective population size between the time of mutation and the Bronze age, as well as the dominance coefficient h. Assuming dominance (h = 1), the MAP estimate varied between 3,550 (90% CI 3,200-5,100) and 7,140 (90% CI 5,525-7,650) years BP for population sizes 2N = 10 2 and 2N = 10 5 , respectively, and was about 20% older when assuming additivity (h = 0.5).…”

Whole-Genome Sequencing Reveals Lactase Persistence Adaptation in European Dogs

“…This time is longer than 4,000 years that LP-associated allele earliest appeared in ancient Europeans ( Gamba et al 2014 ; Mathieson et al 2015 ), and longer than the t coa (3,280 ± 480 years ago) of T at rs4988235 in Europeans inferred by 2D SFS ( Satta et al 2020 ; Satta and Takahata 2020 ). Because T at rs4988235 in Europeans is under hard sweep, its onset time of positive selection ( t SEL ) is longer than t coa (3,280 years) ( Satta and Takahata 2020 ). On the contrary, the t SEL of A-to-G mutation in European dogs is younger than t coa (6,535 years) due to its soft sweep.…”

“…However, lactase persistence (LP) is common in adult humans who live at northern and western Europe, as well as in African and Middle Eastern pastoralist groups, providing for by mutations in LCT and MCM6 ( Hollox et al 2001 ; Enattah et al 2002 ; Ingram et al 2009 ). A Steppe-associated expansion during the early Bronze Age contributed to advance LP in South Asians ( Satta and Takahata 2020 ). Positive selection always creates long linkage disequilibrium (LD).…”