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

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 & methods: By identifying loci with fixed or large frequency differences (delta = 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 (delta = 1) in at leastone 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-kappa B 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.