Signatures of Natural Selection at the FTO (Fat Mass and Obesity Associated) Locus in Human Populations

Abstract

Background and aimsPolymorphisms 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.MethodsFirst, 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.ResultsPAML 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.ConclusionPopulation 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.

FTO haplotyping underlines high obesity risk for European populations

“…The ultimate goal of the work was to elucidate and underscore rapid population-specific fixation of the obesity associated genetic variant (haplotype) in European populations based on FTO intron 1 expanded haplotype frequency profiling in the major continental supergroups of the1000 Genome Project. We also observed quite rapid evolutionary rate of the locus displayed by European populations, implying that a selective sweep might have taken place in its evolutionary course [25]. Our conclusions corroborate the BMI WHO report summed up in [21], which contrasted obesity risks in East Asian vs European populations.…”

“…It was corresponded recently that the FTO gene in human has experienced natural selection pressure in the course of evolution [ 25 ], possibly featuring population adaptation to the climatic environment, from the hot climate areas to the cold sustaining regions [ 26 ]. A range of studies underlined its involvement in thermogenesis [ 10 ] and cell metabolism [ 27 ] and it was reported that FTO affects the obesity trait in age- dependent manner [ 9 , 12 ].…”

Medical genomics research at BGRS-2018

“…Vladimir Babenko and colleagues [ 24 ] analyzed the FTO gene locus for its haplotype profiles within eighteen 1000G populations from 4 continental groups. Their study points that this obesity-associated locus evolved rapidly, confirming previously reported evidence of the selective sweep [ 25 ], which took place in the transcription factors binding sites-enriched sequences within intron 3 of FTO .…”

On the origin of obesity: identifying the biological, environmental and cultural drivers of genetic risk among human populations

“…At the molecular level, some data suggest that selection pressures may have acted on obesity-related loci in FTO (60). 'Thrifty variants' in CREBRF in Samoans (61) and variants in LCT are strongly associated with BMI (62,63).…”

“…Because FTO contributes to obesity , is associated with phenotypic variability of BMI and is also highly sensitive to environmental factors such as diet and physical activity , FTO may regulate variation in body type as per Feinberg and Irizarry's model . Comparing genomes of humans and vertebrates, a recent paper demonstrates that most coding sites in FTO show signals of strong purifying selection and neutral mutation, leading Liu and colleagues to argue that FTO was historically under positive selection. Recent research, however, provides evidence against the applicability of Feinberg and Irizarry's model to obesity .…”