Adaptive evolution of the FADS gene cluster within Africa

Abstract

Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya.

Figure 1. Overview of PUFA metabolism illustrating the critical involvement of FADS1 and FADS2 genes in desaturation steps necessary for the metabolism of intermediate chain unsaturated PUFAs (top dark gray panel) to long chain highly unsaturated PUFAs (bottom light gray panel).

Omega 3 (right) and Omega 6 (left) pathways are illustrated along with known genes (in center rectangles) and dietary sources of the PUFAs.

Figure 2. Summary of sliding window analysis across a 300 kb region (chr11∶61467097–61759006, hg19) centered on the FADS gene cluster for two African (YRI and LWK) versus eight non-African populations (IBS, CEU, GBR, FIN, TSI, JPT, CHB and CHS).

Genetic diversity π, Tajima’s D, Fay & Wu’s H, and pairwise F_ST were calculated using a window size of 5 kb and an overlap of 1 kb. The teal shaded box represents the ∼30 kb haplotype block noted within the African samples and the three black bars represent FADS1, FADS2 and FADS3 from left to right, respectively along with direction of transcription. Dotted lines represent the threshold for an empirical P = 0.01 comparing across all windows in the genome for Tajima’s D, Fay & Wu’s H.

Figure 3. Geographic distribution of derived allele frequencies in a 100

kb region surrounding rs174537 in the 52 populations represented in the Human Genome Diversity Panel Data. Panel A represents physical position of the SNPs relative to genes in the region, Panel B is SNP name (derived allele), Panel C is frequency of derived allele (in orange) in the populations clustered based on geography, Panel D is an indication of the allele associated with increased LC-PUFA metabolism in published association studies, and Panel E is the detailed overview of rs174537 showing is near fixation within Africa.

Figure 4. XP-EHH scores across the 300kb region (chr11∶61467097–61759006, hg19) around the FADS gene cluster in populations from Africa (blue) and Europe (red) within the HGDP.

SNP rs174737 is illustrated with the black dot on the African curve. The teal shaded box represents the ∼30 kb haplotype block noted within the African samples and the three black bars represent FADS1, FADS2 and FADS3 from left to right, respectively along with direction of transcription. Dotted line represents the threshold for an empirical P = 0.01 comparing across all windows in the genome for XP-EHH.

Figure 5. Median-joining network for the relationship of haplotypes of 1,092 individuals in a ∼30

kb block of LD including FADS1 . Circles represent haplotypes with an area proportional to frequency. Singleton haplotypes were not shown. “Ancestral” is a reconstructed haplotype carrying the ancestral (chimpanzee) allele at each position as illustrated in black.