Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau

Abstract

Background: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products.

Results: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe.

Conclusions: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

Keywords: Admixture; Dog; Lactase persistence; Pastoralism; Selection; Tibetan.

Fig. 1

The origin and spread of pastoralism and dairying in the Tibetan Plateau. Archaeological evidence for dogs, dairy ruminants, and dairying practices in the Tibetan Plateau and the neighboring regions. The geographic mapping for each site is referred to three phases: ~ 6000–4700 BP, ~ 4700–3600 BP, and ~ 3600–2200 BP. Some sites spanning two or even three phases are mapped accordingly. Details are reported in Additional file 1: Table S1

Fig. 2

The inferred demographic history of Tibetan dogs. The time for divergence and gene flow inferred by momi2 is indicated. Estimation for other parameters is shown in Additional file 2: Fig. S4

Fig. 3

Haplotype pattern in the genomic regions with LP alleles in human and dog populations. a The haplotype blocks (chr2: 136,569,848–136,673,605 of GRCh37) for Tibetan, CHB, and CEU populations. b The haplotype blocks (chr19: 38,607,365–38,659,515 of Canfam3.1) for Tibetan dog, southern East Asian indigenous dogs, and European breeds. Each column is a polymorphic genomic location, each row is a phased haplotype from human or dog populations noted with different colors

Fig. 4

Tests of selective sweep on LP alleles in Tibetans and their dogs. a EHH of the derived − 13838*A haplotypes (in red) in comparison with the ancestral − 13838*G haplotypes (in blue). b iHS for − 13838G > A (in red) and its surrounding region. c The delta DAF for the region around − 13838G > A between the Tibetan and Han Chinese populations. d EHH of the derived 10974*G haplotypes (in red) in comparison with the ancestral 10974*A haplotypes (in blue). e iHS for 10974A > G (in red) and its surrounding region. f The delta DAF for the region around 10974A > G between the Tibetan dogs and southern East Asian indigenous dogs

Fig. 5

Functional analysis of − 13838G > A as enhancer in Caco-2 cells. a The luciferase reporter assays of LCT promoter and enhancer constructs. As a control, cells were transfected with the promoterless pGL3-basic vector. Basal levels of expression were assessed using hLPH1085 constructed with a pGL3-basic vector and 1085 bp LCT promoter. Three different enhancer haplotypes were inserted upstream of the hLPH1085. Differences in expression of the reporter gene were indicated by the relative luciferase activities. b ChIP-qPCR for the DNA–protein complex enriched by anti-HNF4A antibody. The complex enriched by anti-IgG antibody was amplified as the control. c Electrophoretic mobility shift assays with Caco-2 cell nuclear extracts and oligonucleotide probes spanning − 13838G > A SNP. Specific competitors: − 13838*A (lane 4) or − 13838*G (lane 9) probes without biotinylation; unspecific competitor: unlabeled oligonucleotide probe in which the 8 bp nucleotides surrounding − 13838G > A were mutated (lanes 5 and 10). d The luciferase reporter assays for caco-2 cells co-transfected with the LCT promoter and enhancer constructs harboring − 13838*A or − 13838*G in the presence of HNF4A (hLPH1085 − 13910C − 13838A/G + HNF4A) and pcDNA3.1 expression constructs (hLPH1085 − 13910C − 13838A/G + pcDNA3.1). Statistical significance was tested using the unpaired Student’s t-test: *0.01 < P < 0.05; **P < 0.01