African signatures of recent positive selection in human FOXI1

Background: The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using three interspecies comparisons, it has been suggested that this may be a gene underhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences.Additionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39worldwide human populations from the HGDP-CEPH diversity panel.Results: The genome sequences recently available from other primate and non-primate species showed that FOXI1divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant inEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsbstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recentepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on theputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies stronglycorrelated with the absolute geographical latitude of the populations sampled.Conclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate mightbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediatedwater-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.

This research was funded by grant BFU2005-00243 awarded by Dirección General de Investigación, Ministerio de Educación y Ciencia (Spain), by grant BFU2008-01046/BMC awarded by Subdirección General de Proyectos de Investigación, Ministerio de Ciencia e Innovación (Spain), and by the Direcció General de Recerca, Generalitat de Catalunya (2009SGR1101). AME was supported by a CONACYT fellowship from the Mexican government (grant 179339), MS by a PhD fellowship from the Programa de becas FPU del Ministerio de Educación y Ciencia, Spain (AP2005-3982) and JE by a Volkswagenstiftung scholarship (I/82 750). SNP genotyping services were provided by the Spanish “Centro Nacional de Genotipado” (http://www.cegen.org).