Abstract
BackgroundThe 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 human-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 39 worldwide human populations from the HGDP-CEPH diversity panel.ResultsThe genome sequences recently available from other primate and non-primate species showed that FOXI1 divergence patterns are compatible with neutral evolution. Sequence-based neutrality tests were not significant in Europeans, East Asians or Yorubas. However, the Long Range Haplotype (LRH) test, as well as the iHS and XP-Rsb statistics revealed significantly extended tracks of homozygosity around FOXI1 in Africa, suggesting a recent episode of positive selection acting on this gene. A functionally relevant SNP, as well as several SNPs either on the putatively selected core haplotypes or with significant iHS or XP-Rsb values, displayed allele frequencies strongly correlated with the absolute geographical latitude of the populations sampled.ConclusionsWe present evidence for recent positive selection in the FOXI1 gene region in Africa. Climate might be related to this recent adaptive event in humans. Of the multiple functions of FOXI1, its role in kidney-mediated water-electrolyte homeostasis is the most obvious candidate for explaining a climate-related adaptation.
Highlights
The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney
In order to test such a hypothesis, we evaluated the patterns of nucleotide variation and looked for signals of positive natural selection in the human FOXI1 gene by resequencing 20 Europeans, 20 Asians and 20 Yorubas and by assaying SNP variation in 971 individuals from the Human Genome Diversity Panel (HGDP-CEPH Diversity Panel; [10])
For part of the analysis, populations were further grouped into seven geographical regions: Sub-Saharan Africa (SSAFR), Middle EastNorth Africa (MENA), Europe (EUR), Central-South Asia (CSASIA), East Asia (EASIA), Oceania (OCE) and America (AME)
Summary
The human FOXI1 gene codes for a transcription factor involved in the physiology of the inner ear, testis, and kidney. Using human-chimpanzee-mouse orthologous gene trios, FOXI1 was suggested as an example of a gene involved in hearing that appeared to present a subset of sites with accelerated amino acid substitution in the human lineage [5]. Variants influencing salt homeostasis in the CYP3A5 and AGT loci have been shown to be targets of a selective pressure varying in intensity in correlation with latitude [9] It is of great interest, to investigate whether FOX1I has been the target of local adaptation in humans. In order to test such a hypothesis, we evaluated the patterns of nucleotide variation and looked for signals of positive natural selection in the human FOXI1 gene by resequencing 20 Europeans, 20 Asians and 20 Yorubas and by assaying SNP variation in 971 individuals from the Human Genome Diversity Panel (HGDP-CEPH Diversity Panel; [10])
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