Lactase Persistence and Lipid Pathway Selection in the Maasai

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.

Novel genomic signals of recent selection in an Ethiopian population

“…For every SNP we computed F ST using the method of Reynolds, Weir and Cockerham, 19 and assessed statistical significance using a Bonferroni corrected permutation test p-value as described elsewhere. 20 …”

Localization of adaptive variants in human genomes using averaged one-dependence estimation

“…XP-EHH was computed with a minor alteration of selscan in which EHH is computed as in Wagh et al 34 (see "Adaptation of selscan for better performance on incomplete sweeps"), and XP-EHH values were also normalized with population-specific mean and standard deviation, learned from neutral simulations, to correct for inherent biases based on linkage disequilibrium structure.…”

“…In the case of incomplete sweeps from a de novo mutation, this definition somewhat counterintuitively leads to negative values of XP-EHH. This is due to the fact that the numerator has an upper bound of Following Wagh et al 34 , we instead define EHH as follows:…”

“…CISH may also play a role in susceptibility to infectious diseases, including malaria 38 . C-D) In CEU, we uncover multiple loci in genes involved in pigmentation, including rs1426654 in SLC24A5, which is involved in light skin color 32 , and rs12913832 in the promotor region of OCA2, which is functionally linked with eye color and correlates with skin and hair pigmentation 34 . rs1426654 has the highest sweep probability reported by SWIF(r) in SLC24A5 (0.999173321, after smoothed calibration; see Supplementary Table 2); note each panel depicts genomic windows containing multiple genes.…”

Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPAR<i>α/δ/γ</i> SNPs Associated with Disease

“…The two alleles (A/G) of this SNP generates sixteen common punitive TFBS between the alleles while the common A allele generates twelve unique punitive TFBS and the minor A allele generates one unique TFBS (Table 2). Of the common A allele unique TFBS, the HOXC11 TFBS whose TF also binds to a promoter element of the lactase-phlorizin hydrolase gene which may in part be associated with low-density lipoprotein-cholesterol in Han Chinese [43] (Supplement).…”