PMC:4570283 / 16383-18279 JSONTXT

{"project":"2_test","denotations":[{"id":"25937445-17701907-2051096","span":{"begin":912,"end":914},"obj":"17701907"},{"id":"25937445-23358679-2051097","span":{"begin":1307,"end":1309},"obj":"23358679"}],"text":"Consequences of Ancient Isolation\nWe also examined the effect of the inferred long-term isolation on genetic drift and natural selection in the Kalash. Our PBS analysis showed evidence of possible positive selection on 1,709 SNPs, of which 762 lie within 548 genes, including RYR2 (MIM: 180902) and ACTN3 (MIM: 102574) (Table S5). IPA showed an enrichment of selection signals in 28 genes associated with cardiovascular physiology and disease pathways (Fisher’s exact test p value = 4.61 × 10−9).\nTwo variants that were highly differentiated between the Kalash and the neighboring Pakistani populations stood out. One variant, rs4988235 (c.−13910C\u003eT), which influences lactase (LCT [MIM: 603202]) expression and confers lactose tolerance, is fixed for the ancestral lactose-intolerant allele in the Kalash. The derived allele, however, is reported to be present at a moderate frequency (average 29%) in Pakistan.32 Forward-time simulations demonstrated that the observed pattern cannot easily be explained by recent genetic drift, given that only 0.1% of the 1,000 simulations achieved fixation for the ancestral allele after 500 generations (Figure 4A).\nThe second variant, rs1815739 (c.1729C\u003eT [p.Arg577Ter]), is a natural knockout variant in ACTN3 and has been associated with elite athletic performance.33 The derived T allele is present at a very high frequency (93%) in the Kalash. The average frequency in the remaining Pakistani populations is 47%. Using this (47%) frequency as a starting point for the forward-time simulations, we found that the very high frequency for this variant in the Kalash cannot be explained by genetic drift alone, even after 500 generations (Figure 4B). A selection signal (selection coefficient s = 0.01) achieved the observed frequency in 80% of the simulations after 500 generations. Both of these results support the long-standing isolation of the Kalash."}