Signatures of natural selection in the drug metabolizing enzyme genes: Opportunity for developing personalized and precision medicine

Abstract

Modern human experienced various selective pressures; including range of xenobiotics which contributed to heterogeneity of drug response. Many genes involve in pharmacokinetics and dynamics of drug, have been reported under natural selection. However, none of the studies have utilized comprehensive information of drug-centered PharmGKB pathways. We have extended this work and aimed to investigate sweep signals, using 1,798 subjects, from 53 Indian and 15 other world populations. We observed that modifiers which alters the biochemical function of other genes, have excess of natural selection (median std-z score=0.033{+/-}0.95; p-value=1.7x10-9-3.7x10-3). Taxane and statin primarily used for chemotherapy and lowering cholesterol level, respectively; and well known for heterogeneous drug response. We observed that pharmacokinetic pathway of taxane and statins are under natural selection (p-value=2.53x10-9and 2.73x10-9-1.09x10-4; q-value=1.28x10-7 and 6.91x10-6-1.1x10-3). We also observed signal of selection in Ibuprofen pharmacokinetics (p-value=1.76x10-5; q-value =2.22x10-4), beta-agonist/beta-blocker pharmacodynamics (p-value=4.79x10-4; q-value =4.04x10-4) and Zidovudin pharmacokinetics/dynamic pathway (p-value=7.0x10-4; q-value =5.06x10-4). Hard sweeps signals were observed in a total of 322 loci. Of which, 53 affect mRNA expression (p-value<0.001) and 16 were already reported with therapeutic response. Interestingly, we observed that Africans have experience 2 phases of natural selection, one at ~30,000 another at ~10,000 years before present.