Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid.
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 US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (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 (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This 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.
['Kothapalli|Kumar S D|KS|', 'Ye|Kaixiong|K|', 'Gadgil|Maithili S|MS|', 'Carlson|Susan E|SE|', "O'Brien|Kimberly O|KO|", 'Zhang|Ji Yao|JY|', 'Park|Hui Gyu|HG|', 'Ojukwu|Kinsley|K|', 'Zou|James|J|', 'Hyon|Stephanie S|SS|', 'Joshi|Kalpana S|KS|', 'Gu|Zhenglong|Z|', 'Keinan|Alon|A|', 'Brenna|J Thomas|JT|']
D000328:Adult D000483:Alleles D016718:Arachidonic Acid D030561:Databases, Nucleic Acid D000090943:Delta-5 Fatty Acid Desaturase D044943:Fatty Acid Desaturases D005231:Fatty Acids, Unsaturated D005260:Female D005787:Gene Frequency D014644:Genetic Variation D006239:Haplotypes D006801:Humans D054643:INDEL Mutation D008297:Male D010743:Phospholipids D020641:Polymorphism, Single Nucleotide D012641:Selection, Genetic D055815:Young Adult
positive selection arachidonic acid long chain polyunsaturated fatty acids fatty acid desaturases indel (insertion–deletion) population divergence.