BACKGROUND: Glucose is an important source of energy for living organisms. In 
vertebrates it is ingested with the diet and transported into the cells by 
conserved mechanisms and molecules, such as the trans-membrane Glucose 
Transporters (GLUTs). Members of this family have tissue specific expression, 
biochemical properties and physiologic functions that together regulate glucose 
levels and distribution. GLUT4 -coded by SLC2A4 (17p13) is an insulin-sensitive 
transporter with a critical role in glucose homeostasis and diabetes 
pathogenesis, preferentially expressed in the adipose tissue, heart muscle and 
skeletal muscle. We tested the hypothesis that natural selection acted on 
SLC2A4.
METHODOLOGY/PRINCIPAL FINDINGS: We re-sequenced SLC2A4 and genotyped 104 SNPs 
along a approximately 1 Mb region flanking this gene in 102 ethnically diverse 
individuals. Across the studied populations (African, European, Asian and 
Latin-American), all the eight common SNPs are concentrated in the N-terminal 
region upstream of exon 7 ( approximately 3700 bp), while the C-terminal region 
downstream of intron 6 ( approximately 2600 bp) harbors only 6 singletons, a 
pattern that is not compatible with neutrality for this part of the gene. Tests 
of neutrality based on comparative genomics suggest that: (1) episodes of 
natural selection (likely a selective sweep) predating the coalescent of human 
lineages, within the last 25 million years, account for the observed reduced 
diversity downstream of intron 6 and, (2) the target of natural selection may 
not be in the SLC2A4 coding sequence.
CONCLUSIONS: We propose that the contrast in the pattern of genetic variation 
between the N-terminal and C-terminal regions are signatures of the action of 
natural selection and thus follow-up studies should investigate the functional 
importance of different regions of the SLC2A4 gene.