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 under/nhuman-specific selection. We sought to confirm this finding by using an extended set of orthologous sequences./nAdditionally, we explored for signals of natural selection within humans by sequencing the gene in 20 Europeans,/n20 East Asians and 20 Yorubas and by analysing SNP variation in a 2 Mb region centered on FOXI1 in 39/nworldwide human populations from the HGDP-CEPH diversity panel./nResults: The genome sequences recently available from other primate and non-primate species showed that FOXI1/ndivergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in/nEuropeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb/nstatistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent/nepisode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the/nputatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly/ncorrelated with the absolute geographical latitude of the populations sampled./nConclusions: We present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might/nbe related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated/nwater-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)