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. 2015 Feb 3;10(2):e0117093.
doi: 10.1371/journal.pone.0117093. eCollection 2015.

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

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Free PMC article

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

Xuanshi Liu et al. PLoS One. .
Free PMC article

Abstract

Background and aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Neighbor-joining phylogenetic tree of 35 species on FTO coding sequences showing the evolutionary relationship.
The bootstrap consensus tree inferred from 1000 replicates is generated to present the evolutionary relationship among 35 species on FTO coding sequences which were retrieved from Ensembl or NCBI. Accession numbers are listed at S1 Table. Alignment was carried out by ClustalW (1581 nucleotides left) and phylogenetic tree is constructed by neighbor-joining method in MEGA6. Branches corresponding to partitions reproduced in less than 50% bootstrap replicates did no display. This tree works as the initial tree for further PAML analysis.
Figure 2
Figure 2. Tajima’s D within the FTO locus from five populations showing signals of selection.
Sliding window analysis of Tajima’s D in the whole gene locus (∼ 1 Mb) was conducted with DnaSP version 4.50.0.3. Populations of European, African, Chinese, Japanese and Sorbs were included in the analysis. Closely related individuals were removed, i.e. trios from Chinese and Japanese populations and individuals with IBD > 0.05 from Sorbs. Higher values of Tajima’s D were observed at the intron 3.

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Grant support

This project was supported by grants from the Boehringer Ingelheim Foundation to P.K., from the IFB AdiposityDiseases (ADI-K50D and ADI-K7-45 to Y.B. and ADI-K60E to P.K.), and from the Collaborative Research Center granted by the DFG (CRC 1052; B03). The work was further funded by the German Research Foundation (BO 3147/4-1 to Y.B.). IFB AdiposityDiseases is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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