Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes

► We found that DHRS2 and DHRS4 genes are syntenic outparalogues. ► DHRS2 originated from the DHRS4 gene by duplication. ► The duplication occurred before the formation of the mammalian clade. ► DHRS2 gene underwent positive selection on more sites than the DHRS4 gene. ► Substrate specificity drove the functional divergence from the DHRS4 enzyme.