RT Journal Article SR Electronic T1 Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid JF bioRxiv FD Cold Spring Harbor Laboratory SP 042549 DO 10.1101/042549 A1 Kumar S.D. Kothapalli A1 Kaixiong Ye A1 Maithili S. Gadgil A1 Susan E. Carlson A1 Kimberly O. O’Brien A1 Ji Yao Zhang A1 Hui Gyu Park A1 Kinsley Ojukwu A1 James Zou A1 Stephanie S. Hyon A1 Kalpana S. Joshi A1 Alon Keinan A1 J. Thomas Brenna YR 2016 UL http://biorxiv.org/content/early/2016/03/06/042549.abstract AB Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22 bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the U.S. A much higher I/I genotype frequency was found in Indians (68%) than in the U.S. (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African and some East Asian populations. Basal plasma phospholipid arachidonic acid status was 8% greater in I/I compared to D/D individuals. The biochemical pathway product-precursor difference, arachidonic acid minus linoleic acid, was 31% and 13% greater for I/I and I/D compared to D/D, respectively. Our study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.