Signatures of natural selection at the FTO (fat mass and obesity associated) locus in human populations.

Abstract

Polymorphisms in the first intron of FTO have been robustly replicated for associations with obesity. In the Sorbs, a Slavic population resident in Germany, the strongest effect on body mass index (BMI) was found for a variant in the third intron of FTO (rs17818902). Since this may indicate population specific effects of FTO variants, we initiated studies testing FTO for signatures of selection in vertebrate species and human populations.First, we analyzed the coding region of 35 vertebrate FTO orthologs with Phylogenetic Analysis by Maximum Likelihood (PAML, ω = dN/dS) to screen for signatures of selection among species. Second, we investigated human population (Europeans/CEU, Yoruba/YRI, Chinese/CHB, Japanese/JPT, Sorbs) SNP data for footprints of selection using DnaSP version 4.5 and the Haplotter/PhaseII. Finally, using ConSite we compared transcription factor (TF) binding sites at sequences harbouring FTO SNPs in intron three.PAML analyses revealed strong conservation in coding region of FTO (ω<1). Sliding-window results from population genetic analyses provided highly significant (p<0.001) signatures for balancing selection specifically in the third intron (e.g. Tajima's D in Sorbs = 2.77). We observed several alterations in TF binding sites, e.g. TCF3 binding site introduced by the rs17818902 minor allele.Population genetic analysis revealed signatures of balancing selection at the FTO locus with a prominent signal in intron three, a genomic region with strong association with BMI in the Sorbs. Our data support the hypothesis that genes associated with obesity may have been under evolutionary selective pressure.