Adaptive Evolution of the <em>FADS</em> Gene Cluster within Africa

<div><p>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 (<em>FADS</em>) 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 <em>FADS</em> gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at <em>FADS</em> 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.</p> </div

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

<p>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 <i>FADS1, FADS2</i> and <i>FADS3</i> 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.</p

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

<p> <b>kb block of LD including </b><b><i>FADS1</i></b><b>.</b> 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.</p

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

<p>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 <i>FADS1, FADS2</i> and <i>FADS3</i> 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.</p

Overview of PUFA metabolism illustrating the critical involvement of <i>FADS1</i> and <i>FADS2</i> 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).

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

Geographic distribution of <i>derived</i> allele frequencies in a 100

<p> <b>kb region surrounding rs174537 in the 52 populations represented in the Human Genome Diversity Panel Data. </b><b>Panel A</b> represents physical position of the SNPs relative to genes in the region, <b>Panel B</b> is SNP name (derived allele), <b>Panel C</b> is frequency of derived allele (in orange) in the populations clustered based on geography, <b>Panel D</b> 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.</p

Pairwise linkage disequilibrium (LD) within Haploview using the D’ statistic for <i>IL13</i>.

<p>Intensity of shading indicates the degree of confidence in the D’ value. Dark filled squares indicate a D’ value of 1. Untranslated regions are indicated with black bars, exons with dark gray bars and introns with light gray bars. Exons are numbered from 5′ to 3′.</p

Linkage Disequilibrium for 5 SNPs in the <i>AQP5</i> Gene in European American participants with COPD.

<p>Pairwise LD in subjects is represented as red squares for strong LD, blue squares for non-significant LD, and white squares for little or no LD. LD blocks are identified as noted.</p

Exposure to shear stress leads to a decrease in wild-type AQP5 but no change in N228K AQP5 (n = 3; * p<0.05 with ANOVA one-way).

<p>Exposure to shear stress leads to a decrease in wild-type AQP5 but no change in N228K AQP5 (n = 3; * p<0.05 with ANOVA one-way).</p

Eight hours of 10% CSE leads to a decrease in wild-type AQP5 but no change in N228K AQP5 (n = 3; * p<0.05 with ANOVA one-way).

<p>Eight hours of 10% CSE leads to a decrease in wild-type AQP5 but no change in N228K AQP5 (n = 3; * p<0.05 with ANOVA one-way).</p