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Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid

Kumar S.D. Kothapalli, Kaixiong Ye, Maithili S. Gadgil, Susan E. Carlson, Kimberly O. O’Brien, Ji Yao Zhang, Hui Gyu Park, Kinsley Ojukwu, James Zou, Stephanie S. Hyon, Kalpana S. Joshi, Alon Keinan, J. Thomas Brenna
doi: https://doi.org/10.1101/042549
Kumar S.D. Kothapalli
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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  • For correspondence: jtb4@cornell.edu ksk25@cornell.edu ak735@cornell.edu
Kaixiong Ye
2Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York
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Maithili S. Gadgil
3Department of Biotechnology, Sinhgad College of Engineering, University of Pune, Pune, India
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Susan E. Carlson
4Department of Dietetics and Nutrition, The University of Kansas, Kansas City, KS-66160
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Kimberly O. O’Brien
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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Ji Yao Zhang
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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Hui Gyu Park
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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Kinsley Ojukwu
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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James Zou
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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Stephanie S. Hyon
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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Kalpana S. Joshi
3Department of Biotechnology, Sinhgad College of Engineering, University of Pune, Pune, India
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Alon Keinan
2Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York
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  • For correspondence: jtb4@cornell.edu ksk25@cornell.edu ak735@cornell.edu
J. Thomas Brenna
1Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 USA
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  • For correspondence: jtb4@cornell.edu ksk25@cornell.edu ak735@cornell.edu
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Abstract

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.

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Posted March 06, 2016.
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Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid
Kumar S.D. Kothapalli, Kaixiong Ye, Maithili S. Gadgil, Susan E. Carlson, Kimberly O. O’Brien, Ji Yao Zhang, Hui Gyu Park, Kinsley Ojukwu, James Zou, Stephanie S. Hyon, Kalpana S. Joshi, Alon Keinan, J. Thomas Brenna
bioRxiv 042549; doi: https://doi.org/10.1101/042549
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Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid
Kumar S.D. Kothapalli, Kaixiong Ye, Maithili S. Gadgil, Susan E. Carlson, Kimberly O. O’Brien, Ji Yao Zhang, Hui Gyu Park, Kinsley Ojukwu, James Zou, Stephanie S. Hyon, Kalpana S. Joshi, Alon Keinan, J. Thomas Brenna
bioRxiv 042549; doi: https://doi.org/10.1101/042549

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