title: Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids.
abstract: Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.
authors.affiliation: Department of Immunology, Genetics and Pathology, SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.forename: Asa
authors.initials: A
authors.lastname: Johansson
authors.forename: Ghazal
authors.initials: G
authors.lastname: Zaboli
authors.forename: Wilmar
authors.initials: W
authors.lastname: Igl
authors.forename: Anna C V
authors.initials: AC
authors.lastname: Johansson
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.forename: Ben
authors.initials: B
authors.lastname: Oostra
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
mesh_terms: D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D017523:Croatia; D003430:Cross-Sectional Studies; D000090943:Delta-5 Fatty Acid Desaturase; D004032:Diet; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008019:Life Style; D008969:Molecular Sequence Data; D005810:Multigene Family; D059125:Neanderthals; D058974:Phylogeography; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012606:Scotland; D017422:Sequence Analysis, DNA; D013548:Sweden; D044465:White People / Q000235:genetics
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; C533241:FADS2 protein, human