Molecular evolution of UCP1 and the evolutionary history of mammalian non-shivering thermogenesis

Models of adaptive evolution through phylogenetic analysis of amino acid sequences by maximum likelihood were implemented to determine the mode of UCP1 protein evolution in Eutherians. An increase in the rate of amino acid substitutions on the branch leading to Eutherians is observed, but is best explained by relaxed constraints, not positive selection. Further, evidence for branch and site heterogeneity in selection pressures, as well as divergent selection pressures between UCP1 and its paralogs (UCP2-3) is observed.We propose that the unique thermogenic function of UCP1 in Eutherians may be best explained by neutral processes. Along with other evidence, this suggests that the primary biochemical properties of UCP1 may not differ between Eutherians and non-Eutherians.Uncoupling protein 1 (UCP1) is a mitochondrial protein carrier which, until recently, was thought to be found only in endothermic placental (Eutherian) mammals [1,2]. In Eutherians, UCP1 is the only gene known to be exclusively expressed in brown adipose tissue (BAT), accounting for up to 5% of the total mitochondrial protein in BAT [3]; UCP1 (also known as thermogenin) provides Eutherians, particularly small mammals, hibernators and newborns, with a unique mechanism of non-shivering thermogenesis (NST) [4]. UCP1-dependent NST is probably a feature of most Eutherian mammals, as it has been found recently in the rock elephant shrew, a member of the Afrotherian mammalian lineage which separated early during the evolution of the Eutherians [5]. NST is produced by increasing the proton conductance in the inner membrane of brown adipocyte mitochondria. This increased proton conductance uncouples mitochondrial respiration from ATP synthesis and thereby dissipates the proton motive force as heat [6-9]. It is the high oxidative capacity of mitochondria in BAT and the cellular composition of BAT that allows heat dissipation rates at a power of 300 – 400 W/kg [10-12]. It is these properties of BAT, their mitoch