Genomic and geographic distribution of private SNPs and pathways in human populations

Abstract

AIMS: Geography-based genetic differentials operating on entire biochemical pathways may reflect different adaptive evolutionary processes that separated populations may have undergone. They may also influence treatment outcome for a variety of drugs - an emerging and important area of study. This research article leverages the International HapMap Consortium data to identify pathway components that differ in genotype frequency for four populations: individuals of Northern European descent from the USA (CEU), individuals from West Africa (YRI), Japan (JPT) and China (CHB). MATERIALS #ENTITYSTARTX00026; METHODS: By identifying loci with fixed or large frequency differences (δ = 1) between paired population samples (CEU vs YRI, CEU vs CHB, CEU vs JPT, YRI vs CHB, YRI vs JPT and CHB vs JPT), and reconstructing the physiological functions of genes at these loci, we report a list of pathways affected by natural selection during human evolution. RESULTS: Of the 3.7 million HapMap SNPs, 463 loci (which mapped to 38 genes) were fixed (δ = 1) in at least one population pair. These private loci included four nonsynonymous coding SNPs: rs4536103 (NEUROG3), rs1385699 (EDA2R), rs11946338 (ARHGAP24) and rs4422842 (CACNA1B). A total of four additional genes demonstrated evidence of recent positive selection: three genes in European subjects (IER5L, NPNT and SESTD1) and a single gene in Asian subjects (EXOC6B). DISCUSSION: Gene ontology and pathway analyses suggest that cellular differentiation, apoptosis and activation of the NF-κB transcription factor vary between populations in genomic regions of fixed (private) SNPs identified in this study. Variability in these pathways may provide important clues into the mechanisms of human adaptation to different environments. An improved understanding of their variability may also help to explain race-specific differences in the treatment outcomes observed for a variety of modern drugs.

Figure 1. Schematic presentation of private SNP mining and analysis strategy

There are approximately 3.7 million SNPs in the HapMap data release. Genotypes were summarized for each population. For each dataset, the number of alleles per locus (SNP) was coded to a string of numbers to obtain a full design matrix of alleles (the cells give the number of copies of each major allele for each individual: 0, 1 or 2). Two criteria were used to filter the SNPs included in the analysis: first, the SNP should be shared by at least two populations; second, all filtered SNPs were required to show polymorphism in one or more HapMap population(s) for over 90% of the samples in each population. From the total of approximately 3.7 million SNPs in the HapMap data release, only 809,624 SNPs were polymorphic across the population and were eligible for analysis. CEU: North Americans with European ancestry; CHB: Han Chinese from Beijing; JPT: Japanese from Tokyo; nsSNP: Nonsynonymous SNP; YRI: Yorubans from Ibadan, Nigeria.

Figure 2. HapMap SNP allele frequency differences (δ) between HapMap populations

The populations studied were 60 CEPH North Americans with European ancestry, 60 Yorubans from Ibadan, Nigeria, 45 Japanese from Tokyo and 45 Han Chinese from Beijing. Private loci and various levels of marker informativeness were studied as a measure of ancestry among populations using the allele frequency difference termed ‘δ procedure’. Marker informativeness for ancestry is defined as the absolute value of the difference of the frequency of a particular allele observed for two ancestral populations. For example, if we let p₁₁ represent the frequency of a reference allele in the first parental population and p₂₁ represent the frequency of the same allele in the second parental population, then the δ value is given by: $$\delta =\mid p_{11}-p_{21}\mid .$$ CEPH: Centre d’etude du polymorphisme humain; CEU: North Americans with European ancestry; CHB: Han Chinese from Beijing; JPT: Japanese from Tokyo; YRI: Yorubans from Ibadan, Nigeria.

Figure 3. IPA network and pathway analyses for 38 genes mapped to 463 private SNPs (see right)

(A) IPA network for 38 genes mapped to 463 private SNPs. Genes with shaded nodes are focused genes in our analysis, the others are generated through the network analysis from the Pathways Knowledge Base [112]. Edges are displayed with labels that describe the nature of the relationship between the nodes. The lines between genes represent known interactions, with solid lines representing direct interactions and dashed lines representing indirect interactions. Nodes are displayed using various shapes that represent the functional class of the gene product. (B) The 38 genes linked to 463 private SNPs canonical pathways from IPA. The significance threshold, shown in yellow, represents a p-value of greater than 0.05. The first two sets of functions shown below represent a p-value of less than 0.01. Bars that are above the line indicate significant enrichment of a pathway. IPA: Ingenuity Pathways Analysis.

Figure 4. Four networks merged and centered around the four genes (NEUROG3, EDA2R, CACNA1B and ARHGAP24) mapped to private nsSNPs

The light blue line connection indicates focus genes of interest. No overlapping networks exist between ARHGAP24 and the other three focused genes. Edges are displayed with labels that describe the nature of the relationship between the nodes. The lines between genes represent known interactions, with solid lines representing direct interactions and dashed lines representing indirect interactions. Nodes are displayed using various shapes that represent the functional class of the gene product.

Figure 5. Genes under recent positive selection

(A) EXOC6B chromosome 2 (72314768:72964925) in ASN (red). (B) SESTD1 chromosome 2 (179799037:179882102). (C) NPNT chromosome 4 (107174209:107250432). (D) IER5L Chr 9 [129018502:129020080] in CEU population (blue). X-axis is genomic position (Hapmap release 22, dbSNP b126). Y-axis is ∣iHS∣ score. The ∣iHS∣ cut-off for selection is 2. The target gene is marked by a vertical dashed black bar. The 100-kb flanking regions are also shown. The horizontal bars displayed under each panel of the graphic display represent genes present in the region. ASN: Asian sample made up of the Han Chinese and Japanese populations; CEU: North Americans with European ancestry; ∣iHS∣: Integrated haplotype score; YRI: Yorubans from Ibadan, Nigeria.

Figure 6. Four networks centered around genes that were under recent selection (NPNT, IER5L, EXOC6B and SESTD1)

Nonoverlapping networks were generated among the four genes except between NPNT and IER5L. The light blue line connection indicates focus genes of interest. The lines between genes represent known interactions, with solid lines representing direct interactions and dashed lines representing indirect interactions.