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, 7 (9), e44751

Lactase Persistence and Lipid Pathway Selection in the Maasai

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Lactase Persistence and Lipid Pathway Selection in the Maasai

Kshitij Wagh et al. PLoS One.

Abstract

The Maasai are a pastoral people in Kenya and Tanzania, whose traditional diet of milk, blood and meat is rich in lactose, fat and cholesterol. In spite of this, they have low levels of blood cholesterol, and seldom suffer from gallstones or cardiac diseases. Field studies in the 1970s suggested that the Maasai have a genetic adaptation for cholesterol homeostasis. Analysis of HapMap 3 data using Fixation Index (Fst) and two metrics of haplotype diversity: the integrated Haplotype Score (iHS) and the Cross Population Extended Haplotype Homozygosity (XP-EHH), identified genomic regions and single nucleotide polymorphisms (SNPs) as strong candidates for recent selection for lactase persistence and cholesterol regulation in 143-156 founder individuals from the Maasai population in Kinyawa, Kenya (MKK). The non-synonmous SNP with the highest genome-wide Fst was the TC polymorphism at rs2241883 in Fatty Acid Binding Protein 1(FABP1), known to reduce low density lipoprotein and tri-glyceride levels in Europeans. The strongest signal identified by all three metrics was a 1.7 Mb region on Chr2q21. This region contains the genes LCT (Lactase) and MCM6 (Minichromosome Maintenance Complex Component) involved in lactase persistence, and the gene Rab3GAP1 (Rab3 GTPase-activating Protein Catalytic Subunit), which contains polymorphisms associated with total cholesterol levels in a genome-wide association study of >100,000 individuals of European ancestry. Sanger sequencing of DNA from six MKK samples showed that the GC-14010 polymorphism in the MCM6 gene, known to be associated with lactase persistence in Africans, is segregating in MKK at high frequency (∼58%). The Cytochrome P450 Family 3 Subfamily A (CYP3A) cluster of genes, involved in cholesterol metabolism, was identified by Fst and iHS as candidate loci under selection. Overall, our study identified several specific genomic regions under selection in the Maasai which contain polymorphisms in genes associated with lactase persistence and cholesterol regulation.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Population structure components for individuals from CEU, ASW, LWK, MKK and YRI.
Results from STRUCTURE version 2.3 on genotype data for 12,999 randomly selected SNPs in 578 founder (unrelated) individuals from the CEU, ASW, LWK, MKK and YRI HapMap populations. The no-admixture model showed that the data was best fit by 6 inferred ancestral populations. Each column represents an individual, and the colors indicate the fractions of their genotype attributable to ancestry from each of the 6 ancestral populations.
Figure 2
Figure 2. (a) Genome-wide significant scores identifying candidate regions under selection on Chromosome 2.
Chromosome wide plot of SNPs with significant scores using Fst (empirical p-value <0.001 and Bonferroni corrected permutation test pB <8.6E−6), iHS (normalized |iHS|>2), and XP-EHH (XP-EHH ≥4.796, two-tailed Bonferroni corrected p≤0.05). The SNPs thus identified were clustered on the basis of linkage disequilibrium to identify contiguous genomic regions that are candidates for selections (Table 1,2,3,4). The locus containing the genes LCT and MCM6 (135–137 Mb) was identified by all three metrics as the top candidate for selection. The non-synonymous TC polymorphism at rs2241883 in the FABP1 gene had most significant genome-wide Fst (Fst = 0.25, pE = 3.13E−5). The MKK samples have a high frequency (∼0.45) of the protective C allele, known to be associated with low cholesterol levels in Europeans (plots for other chromosomes in Appendix S6). (b) Inset of the LCT locus on Chromosome 2.An inset of the Fst, iHS and XP-EHH scores for SNPs in the ∼ 1 Mb locus (from 135.8–136.8 Mb) on Chr 2 containing the genes LCT and MCM6. The uniformly high values for all three metrics in this region suggest that this locus has undergone strong selection pressure. The blue marker indicates the position of the lactase associated SNP in MCM6 that we sequenced, which was polymorphic in MKK with frequency pC = 0.58+/−0.14 (68% CI) for the protective C allele.

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