Dietary adaptation of FADS genes in Europe varied across time and geography


Fatty acid desaturase (FADS) genes encode rate-limiting enzymes for the biosynthesis of omega-6 and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). This biosynthesis is essential for individuals subsisting on LCPUFA-poor diets (for example, plant-based). Positive selection on FADS genes has been reported in multiple populations, but its cause and pattern in Europeans remain unknown. Here we demonstrate, using ancient and modern DNA, that positive selection acted on the same FADS variants both before and after the advent of farming in Europe, but on opposite (that is, alternative) alleles. Recent selection in farmers also varied geographically, with the strongest signal in southern Europe. These varying selection patterns concur with anthropological evidence of varying diets, and with the association of farming-adaptive alleles with higher FADS1 expression and thus enhanced LCPUFA biosynthesis. Genome-wide association studies reveal that farming-adaptive alleles not only increase LCPUFAs, but also affect other lipid levels and protect against several inflammatory diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Ancient DNA-based test for recent positive selection.
Figure 2: Tests for recent positive selection based solely on modern DNA.
Figure 3: Varying selection and frequency patterns between southern and northern Europe.
Figure 4: Temporal frequency pattern and selection signals in pre-Neolithic European hunter–gatherers.
Figure 5: Haplotype network and geographical frequency distribution.
Figure 6: Geographical frequency distribution for SNPs rs174594 and rs174570 in present-day global populations.


  1. 1

    Fan, S., Hansen, M. E. B., Lo, Y. & Tishkoff, S. A. Going global by adapting local: a review of recent human adaptation. Science 354, 54–59 (2016).

    CAS  Article  Google Scholar 

  2. 2

    Nakamura, M. T. & Nara, T. Y. Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases. Annu. Rev. Nutr. 24, 345–376 (2004).

    CAS  Article  Google Scholar 

  3. 3

    Raphael, W. & Sordillo, L. M. Dietary polyunsaturated fatty acids and inflammation: the role of phospholipid biosynthesis. Int. J. Mol. Sci. 14, 21167–21188 (2013).

    Article  Google Scholar 

  4. 4

    Bazinet, R. P. & Layé, S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat. Rev. Neurosci. 15, 771–785 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Mathias, R. A. et al. Adaptive evolution of the FADS gene cluster within Africa. PLoS One 7, e44926 (2012).

    CAS  Article  Google Scholar 

  6. 6

    Ameur, A. et al. Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids. Am. J. Hum. Genet. 90, 809–820 (2012).

    CAS  Article  Google Scholar 

  7. 7

    The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

  8. 8

    Kothapalli, K. S. et al. Positive selection on a regulatory insertion–deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid. Mol. Biol. Evol. 33, 1726–1739 (2016).

    CAS  Article  Google Scholar 

  9. 9

    Fumagalli, M. et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science 349, 1343–1347 (2015).

    CAS  Article  Google Scholar 

  10. 10

    Amorim, C. E. G. et al. Genetic signature of natural selection in first Americans. Proc. Natl Acad. Sci. USA 114, 2195–2199 (2017).

    CAS  Article  Google Scholar 

  11. 11

    Reardon, H. T. et al. Insertion–deletions in a FADS2 intron 1 conserved regulatory locus control expression of fatty acid desaturases 1 and 2 and modulate response to simvastatin. Prostaglandins Leukot. Essent. Fatty Acids 87, 25–33 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Mathieson, I. et al. Genome-wide patterns of selection in 230 ancient Eurasians. Nature 528, 499–503 (2015).

    CAS  Article  Google Scholar 

  13. 13

    Bar-Yosef, O. in On Human Nature: Biology, Psychology, Ethics, Politics, and Religion (eds Tibayrenc, M. & Ayala, F. J. ) Ch. 19, 297–331 (Academic, 2017).

    Google Scholar 

  14. 14

    Coward, F., Shennan, S., Colledge, S., Conolly, J. & Collard, M. The spread of Neolithic plant economies from the Near East to northwest Europe: a phylogenetic analysis. J. Archaeol. Sci. 35, 42–56 (2008).

    Article  Google Scholar 

  15. 15

    Bogaard, A. et al. Crop manuring and intensive land management by Europe’s first farmers. Proc. Natl Acad. Sci. USA 110, 12589–12594 (2013).

    CAS  Article  Google Scholar 

  16. 16

    Richards, M. P. in The Evolution of Hominin Diets: Integrating Approaches to the Study of Palaeolithic Subsistence (eds Hublin, J. J. & Richards, M. P. ) 251–257 (Springer Science + Business Media, 2009).

    Google Scholar 

  17. 17

    Richards, M. P., Schulting, R. J. & Hedges, R. E. Archaeology: sharp shift in diet at onset of Neolithic. Nature 425, 366 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Richards, M. P., Price, T. D. & Koch, E. Mesolithic and Neolithic subsistence in Denmark: new stable isotope data. Curr. Anthropol. 44, 288–295 (2003).

    Article  Google Scholar 

  19. 19

    Fraser, R. A., Bogaard, A., Schäfer, M., Arbogast, R. & Heaton, T. H. E. Integrating botanical, faunal and human stable carbon and nitrogen isotope values to reconstruct land use and palaeodiet at LBK Vaihingen an der Enz, Baden-Württemberg. World Archaeol. 45, 492–517 (2013).

    Article  Google Scholar 

  20. 20

    Knipper, C. et al. What is on the menu in a Celtic town? Iron Age diet reconstructed at Basel-Gasfabrik, Switzerland. Archaeol. Anthropol. Sci. (2016).

  21. 21

    López-Costas, O., Müldner, G. & Martínez Cortizas, A. Diet and lifestyle in Bronze Age northwest Spain: the collective burial of Cova do Santo. J. Archaeol. Sci. 55, 209–218 (2015).

    Article  Google Scholar 

  22. 22

    Ferrer-Admetlla, A., Liang, M., Korneliussen, T. & Nielsen, R. On detecting incomplete soft or hard selective sweeps using haplotype structure. Mol. Biol. Evol. 31, 1275–1291 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Field, Y. et al. Detection of human adaptation during the past 2000 years. Science 354, 760–764 (2016).

    CAS  Article  Google Scholar 

  24. 24

    Fu, Q. et al. The genetic history of Ice Age Europe. Nature 534, 200–205 (2016).

    CAS  Article  Google Scholar 

  25. 25

    Schraiber, J. G., Evans, S. N. & Slatkin, M. Bayesian inference of natural selection from allele frequency time series. Genetics 203, 493–511 (2016).

    CAS  Article  Google Scholar 

  26. 26

    Ferrer-Admetlla, A., Leuenberger, C., Jensen, J. D. & Wegmann, D. An approximate Markov model for the Wright–Fisher diffusion and its application to time series data. Genetics 203, 831–846 (2016).

    CAS  Article  Google Scholar 

  27. 27

    GTEx Consortium. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

  28. 28

    Welter, D. et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

    CAS  Article  Google Scholar 

  29. 29

    Mozaffarian, D. et al. Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE consortium. Am. J. Clin. Nutr. 101, 398–406 (2015).

    CAS  Article  Google Scholar 

  30. 30

    den Hoed, M. et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat. Genet. 45, 621–631 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Buckley, M. T. et al. Selection in Europeans on fatty acid desaturases associated with dietary changes. Mol. Biol. Evol. (2017).

  32. 32

    Pan, G. et al. PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c. Nucleic Acids Res. 45, 2408–2422 (2017).

    CAS  Article  Google Scholar 

  33. 33

    Richards, M. P. & Hedges, R. E. M. Stable isotope evidence for similarities in the types of marine foods used by late Mesolithic humans at sites along the Atlantic coast of Europe. J. Archaeol. Sci. 26, 717–722 (1999).

    Article  Google Scholar 

  34. 34

    Lubell, D., Jackes, M., Schwarcz, H., Knyf, M. & Meiklejohn, C. The Mesolithic–Neolithic transition in Portugal: isotopic and dental evidence of diet. J. Archaeol. Sci. 21, 201–216 (1994).

    Article  Google Scholar 

  35. 35

    Richards, M. P. & Mellars, P. A. Stable isotopes and the seasonality of the Oronsay middens. Antiquity 72, 178–184 (1998).

    Article  Google Scholar 

  36. 36

    Bonsall, C. et al. Mesolithic and early Neolithic in the Iron Gates: A Palaeodietary perspective. J. Eur. Archaeol. 5, 50–92 (1997).

    Article  Google Scholar 

  37. 37

    Abedi, E. & Sahari, M. A. Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties. Food Sci. Nutr. 2, 443–463 (2014).

    CAS  Article  Google Scholar 

  38. 38

    Simopoulos, A. P. Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain. Mol. Neurobiol. 44, 203–215 (2011).

    CAS  Article  Google Scholar 

  39. 39

    Mannino, M. A., Thomas, K. D., Leng, M. J., Di Salvo, R. & Richards, M. P. Stuck to the shore? Investigating prehistoric hunter–gatherer subsistence, mobility and territoriality in a Mediterranean coastal landscape through isotope analyses on marine mollusc shell carbonates and human bone collagen. Quat. Int. 244, 88–104 (2011).

    Article  Google Scholar 

  40. 40

    Mannino, M. A. et al. Origin and diet of the prehistoric hunter–gatherers on the mediterranean island of Favignana (Egadi Islands, Sicily). PLoS One 7, e49802 (2012).

    CAS  Article  Google Scholar 

  41. 41

    Lightfoot, E., Boneva, B., Miracle, P. T., Šlaus, M. & O'Connell, T. C. Exploring the Mesolithic and Neolithic transition in Croatia through isotopic investigations. Antiquity 85, 73–86 (2011).

    Article  Google Scholar 

  42. 42

    Bocquet-Appel, J.-P., Naji, S., Vander Linden, M. & Kozlowski, J. Understanding the rates of expansion of the farming system in Europe. J. Archaeol. Sci. 39, 531–546 (2012).

    Article  Google Scholar 

  43. 43

    Rowley-Conwy, P. Westward Ho! The spread of agriculture from central Europe to the Atlantic. Curr. Anthropol. 52, S431–S451 (2011).

    Article  Google Scholar 

  44. 44

    Vigne, J.-D. in The Neolithic Demographic Transition and its Consequences (eds Bocquet-Appel, J.-P. & Bar-Yosef, O. ) 179–205 (Springer Science + Business Media, 2008).

    Google Scholar 

  45. 45

    Cramp, L. J. et al. Immediate replacement of fishing with dairying by the earliest farmers of the Northeast Atlantic archipelagos. Proc. R. Soc. B 281, 20132372 (2014).

    Article  Google Scholar 

  46. 46

    Curry, A. Archaeology: the milk revolution. Nature 500, 20–22 (2013).

    CAS  Article  Google Scholar 

  47. 47

    Salque, M. et al. Earliest evidence for cheese making in the sixth millennium bc in northern Europe. Nature 493, 522–525 (2013).

    CAS  Article  Google Scholar 

  48. 48

    Lidén, K., Eriksson, G., Nordqvist, B., Götherström, A. & Bendixen, E. “The wet and the wild followed by the dry and the tame” — or did they occur at the same time? Diet in Mesolithic – Neolithic southern Sweden. Antiquity 78, 23–33 (2004).

    Article  Google Scholar 

  49. 49

    Rottoli, M. & Castiglioni, E. Prehistory of plant growing and collecting in northern Italy, based on seed remains from the early Neolithic to the Chalcolithic (c. 5600–2100 cal b.c.). Veg. Hist. Archaeobot. 18, 91–103 (2009).

    Article  Google Scholar 

  50. 50

    Lazaridis, I. et al. Genomic insights into the origin of farming in the ancient Near East. Nature 536, 419–424 (2016).

    CAS  Article  Google Scholar 

  51. 51

    Li, J. Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319, 1100–1104 (2008).

    CAS  Article  Google Scholar 

  52. 52

    Nelson, M. R. et al. The Population Reference Sample, POPRES: a resource for population, disease, and pharmacological genetics research. Am. J. Hum. Genet. 83, 347–358 (2008).

    CAS  Article  Google Scholar 

  53. 53

    Lazaridis, I. et al. Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature 513, 409–413 (2014).

    CAS  Article  Google Scholar 

  54. 54

    The UK10 Consortium. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

  55. 55

    Browning, B. L. & Browning, S. R. Genotype imputation with millions of reference samples. Am. J. Hum. Genet. 98, 116–126 (2016).

    CAS  Article  Google Scholar 

  56. 56

    Gamba, C. et al. Genome flux and stasis in a five millennium transect of European prehistory. Nat. Commun. 5, 5257 (2014).

    CAS  Article  Google Scholar 

  57. 57

    Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

  58. 58

    Paradis, E. pegas: an R package for population genetics with an integrated-modular approach. Bioinformatics 26, 419–420 (2010).

    CAS  Article  Google Scholar 

  59. 59

    Dannemann, M., Andres, A. M. & Kelso, J. Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human Toll-like receptors. Am. J. Hum. Genet. 98, 22–33 (2016).

    CAS  Article  Google Scholar 

  60. 60

    Patterson, N. et al. Ancient admixture in human history. Genetics 192, 1065–1093 (2012).

    Article  Google Scholar 

  61. 61

    Gazave, E. et al. Neutral genomic regions refine models of recent rapid human population growth. Proc. Natl Acad. Sci. USA 111, 757–762 (2014).

    CAS  Article  Google Scholar 

  62. 62

    Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–595 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Fay, J. C. & Wu, C. I. Hitchhiking under positive Darwinian selection. Genetics 155, 1405–1413 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

    Article  Google Scholar 

  65. 65

    Szpiech, Z. A. & Hernandez, R. D. selscan: an efficient multithreaded program to perform EHH-based scans for positive selection. Mol. Biol. Evol. 31, 2824–2827 (2014).

    CAS  Article  Google Scholar 

  66. 66

    Gautier, M. & Vitalis, R. rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure. Bioinformatics 28, 1176–1177 (2012).

    CAS  Article  Google Scholar 

  67. 67

    Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  68. 68

    Wang, J. et al. a Wiki-based database for transcription factor-binding data generated by the ENCODE consortium. Nucleic Acids Res. 41, D171–D176 (2013).

    CAS  Article  Google Scholar 

Download references


We thank M. Slatkin and J. Schraiber for their help in running their software, D. Reich and I. Mathieson for making their data publicly available, L. Arbiza, C. Liang, D. Marburgh, E. Li, K. Kothapalli, T. Brenna and all the members of the Keinan laboratory for helpful discussion and comments on the manuscript. This work was supported by the National Institutes of Health (grants R01HG006849 and R01GM108805 to A.K.) and the Edward Mallinckrodt Jr Foundation (A.K.).

Author information




A.K. and K.Y. conceived and designed the project; K.Y. performed data collection and analysis, with contributions from D.W. and F.G.; K.Y. and A.K. interpreted the results, with contribution from O.B.-Y. on the anthropological perspective; K.Y. and A.K. wrote the manuscript. All authors read, edited and approved the final version of the manuscript.

Corresponding author

Correspondence to Alon Keinan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Notes; Supplementary Methods; Supplementary Tables 2–9; Supplementary Figures 1–32. (PDF 12959 kb)

Supplementary Table 1

Ancient DNAs used in this study. (XLSX 26 kb)

Supplementary Data 1

Computational scripts developed in this study. (ZIP 231 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ye, K., Gao, F., Wang, D. et al. Dietary adaptation of FADS genes in Europe varied across time and geography. Nat Ecol Evol 1, 0167 (2017).

Download citation

Further reading