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. 2008 Jan;82(1):57-72.
doi: 10.1016/j.ajhg.2007.09.012.

Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture (V体育官网入口)

Nabil Sabri Enattah  1 , Tine G K Jensen, Mette Nielsen, Rikke Lewinski, Mikko Kuokkanen, Heli Rasinpera, Hatem El-Shanti, Jeong Kee Seo, Michael Alifrangis, Insaf F Khalil, Abdrazak Natah, Ahmed Ali, Sirajedin Natah, David Comas, S Qasim Mehdi, Leif Groop, Else Marie Vestergaard, Faiqa Imtiaz, Mohamed S Rashed, Brian Meyer, Jesper Troelsen, Leena Peltonen
Affiliations

Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture

Nabil Sabri Enattah et al. Am J Hum Genet. 2008 Jan.

Abstract

The T(-13910) variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations among Saudis, also known for the high prevalence of LP. We confirmed the absence of the European T(-13910) and established two new mutations found as a compound allele: T/G(-13915) within the -13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C(-3712), -3712 bp from the LCT gene. The compound allele is driven to a high prevalence among Middle East population(s). Our functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor 1 alpha (HNF1 alpha). High selection coefficient (s) approximately 0. 04 for LP phenotype was found for both T(-13910) and the compound allele. The European T(-13910) and the earlier identified East African G(-13907) LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergent ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption VSports手机版. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture. .

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Figures

Figure 1
Figure 1
A Strategy to Identify the Causing Variant(s) from Random Population Samples through the Exclusion of the Target Region by Comparing the Haplotype of Nonphenotyped Individuals with a Matched Haplotype from Phenotyped Individuals as a Proxy for Establishing the Correlation Small yellow circles represent the variants between the reference sequence in databases and the matched haplotypes. In our case, there were 71 such variants. Based on the matched haplotype approach, we reduced the number of potentially causative LP variants from 71 to 8 (represented by the blue and the red circles) showing an accumulation on the LP samples. The green circles represent the variants that originate on the LNP samples. Further genotyping of these variants in population samples showed that only two variants (red circles) stand out as candidates for LP.
Figure 2
Figure 2
Map Showing the Sequenced Region and the LP-Related SNPs within Intron 13 and Exon 17 of the MCM6 Gene (A) The physical map showing the restricted LP locus between markers D2S3013 and D2S3014 and the region that was sequenced between the markers D2S3012 and D2S3016 (marked as a green box). (B) The physical map of the MCM6 gene showing the location of the SNPs identified within intron 13 and exon 17 of MCM6 gene. (C) The sequence of the LP region indicating the European LP variant C/T−13910 and showing clustering of the LP mutations within a very short region and the Arab T/C−3712 variant in exon 17 of the MCM6 gene.
Figure 3
Figure 3
EMSA for Analyses of Protein/DNA Interactions and Relative Luciferase Activity of Intestinal Caco2 Cell Line Cotransfected with Lactase Promoter-Reporter Constructs Containing the Identified Variants (A) Electrophoretical mobility shift assay (EMSA) for analyses of protein/DNA interactions of the identified variants (lanes 1–5) with double-stranded oligonucleotides primers and nuclear extracts from the intestinal cell line Caco2. The arrow indicates the Oct-1 complexes. (B) The EMSA for the T/C−3712 showing the specific binding of HNF1α to both probes. The HNF1α supershift analyses were performed by adding a polyclonal antibody against rat HNF1α. (C and D) Relative luciferase activity of intestinal Caco2 cell line cotransfected with lactase promoter-reporter constructs containing the 455 bp fragments of the regions flanking the T/G−13915 and 685 bp fragment of the region flanking T/C−3712. (D) The G−13915-C−3712 and T−13915-T−3712 regions were analyzed together for the effect of overexpression of HNF1α and Oct-1 on the G−13915-C−3712 and T−13915-T−3712. The luciferase activity was corrected for transfection efficiency and normalized to the expression of pGL3-hLPH1085, n = 4.
Figure 4
Figure 4
Long-Range Extended Haplotypes for the LP-Associated Alleles Constructed at Various Distances Haplotypes are depicted from Saudi Arabia (A) and Utah (B) samples showing the core haplotype containing the European LP allele G−22018-T−13910 and the Arab LP allele C−3712-G−13915 at various distances. The core region containing G−22018-T−13910 and C−3712-G−13915 are shown in dark and light green, respectively, and the haplotypes are oriented from left to right. The derived allele at each SNP is shown in red while the ancestral allele is shown in yellow.
Figure 5
Figure 5
Haplotype Networks Showing the Relationships of the LP-Associated Alleles to Each Other in the Networks (A) Haplotype network of intron 13 of MCM6 gene in the global population sample. The network was constructed with 26 SNPs (identified by sequence analysis of 170 global population samples) spanning 3218 bp of the intron 13 of the MCM6 gene. The network shows that the European LP European allele T−13910 (H98) and the African G−13907 allele (H100) have the same lactase nonpersistence (LNP) ancestral background allele (H84). The root was based on the chimpanzee sequence of intron 13 of MCM6 gene. Yellow circles represent LNP alleles whereas the green represent the LP alleles. Size of the circles is proportional to the frequency in our global samples. The G−13915 (H99) has a different background haplotype (H107) (potentially coevolved with the domestication of camels), whereas T−13910 (H98) and G−13907 (referred here as H100) share a same background haplotype (H105) (most likely coevolved with the domestication of cattle). The derived mutations are shown on the branches; the bold red mutations represent mutations associated with LP. (B) Haplotype network consisting of 47 SNPs spanning 31 kb region between intron 1 of LCT gene and intron 7 of MCM6 gene in 170 global samples. The network obtained with data across this wider DNA region still indicates that H98 and H100 share a common ancestor background allele (H84, gray), whereas the LP H99 shows a different ancestral background allele (H107). (C) Plot of the haplotypes H84, H98, and H100 spanning more than 1.1 Mb showing that the LNP H84 shares the same ancestral background haplotypes with LP H98 and H100 up to 1.1 Mb. The red indicates the derived allele; yellow indicates the ancestral allele at the SNP sites analyzed. Blue indicates the derived allele G−13907 at the SNP site; green indicates the derived alleles T−13910 and G−22018 at those SNP sites. (D) Phylogenetic relationship between the haplotypes H98, H100, and H84 at 31 kb and 1137 kb resolution would provide genetic evidence that the Europeans and the Africans most probably have a shared a cattle domestication culture in very recent historical times.
Figure 6
Figure 6
The Extended Haplotype Analyses for the LP-Associated Alleles (A–E) The EHH and REHH analyses of the two alleles for the Arab LP/LPN variant T/G−13915 in the Saudi Arabian population (A and B) and European C/T−13910 variant in the Utah population (C and D) plotted against the distance in kb from the analyzed consecutive SNPs on both sides via Sweep software program. (E–G) The REHH for G−13915 and T−13910 (small squares pointed by the arrows) are plotted against allele frequency in comparison with the coalescence simulation data of 1000 replica under constant population size (E), recent expansion (F), and bottleneck model (G), with recombination 1 cM = 1 Mb by ms program.
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