Documented cases of convergent molecular evolution due to selection are fairly unusual, and examples to date have involved only a few amino acid positions. However, because convergence mimics shared ancestry and is not accommodated by current phylogenetic methods, it can strongly mislead phylogenetic inference when it does occur. Here, we present a case of extensive convergent molecular evolution between snake and agamid lizard mitochondrial genomes that overcomes an otherwise strong phylogenetic signal. Evidence from morphology, nuclear genes, and most sites in the mitochondrial genome support one phylogenetic tree, but a subset of mostly amino acid-altering substitutions (primarily at the first and second codon positions) across multiple mitochondrial genes strongly supports a radically different phylogeny. The relevant sites generally evolved slowly but converged between ancient lineages of snakes and agamids. We estimate that Ϸ44 of 113 predicted convergent changes distributed across all 13 mitochondrial protein-coding genes are expected to have arisen from nonneutral causes-a remarkably large number. Combined with strong previous evidence for adaptive evolution in snake mitochondrial proteins, it is likely that much of this convergent evolution was driven by adaptation. These results indicate that nonneutral convergent molecular evolution in mitochondria can occur at a scale and intensity far beyond what has been documented previously, and they highlight the vulnerability of standard phylogenetic methods to the presence of nonneutral convergent sequence evolution.adaptation ͉ convergence ͉ phylogenetics ͉ reptile

Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209–222

BackgroundAdaptive evolutionary episodes in core metabolic proteins are uncommon, and are even more rarely linked to major macroevolutionary shifts.Methodology/Principal FindingsWe conducted extensive molecular evolutionary analyses on snake mitochondrial proteins and discovered multiple lines of evidence suggesting that the proteins at the core of aerobic metabolism in snakes have undergone remarkably large episodic bursts of adaptive change. We show that snake mitochondrial proteins experienced unprecedented levels of positive selection, coevolution, convergence, and reversion at functionally critical residues. We examined Cytochrome C oxidase subunit I (COI) in detail, and show that it experienced extensive modification of normally conserved residues involved in proton transport and delivery of electrons and oxygen. Thus, adaptive changes likely altered the flow of protons and other aspects of function in CO, thereby influencing fundamental characteristics of aerobic metabolism. We refer to these processes as “evolutionary redesign” because of the magnitude of the episodic bursts and the degree to which they affected core functional residues.Conclusions/SignificanceThe evolutionary redesign of snake COI coincided with adaptive bursts in other mitochondrial proteins and substantial changes in mitochondrial genome structure. It also generally coincided with or preceded major shifts in ecological niche and the evolution of extensive physiological adaptations related to lung reduction, large prey consumption, and venom evolution. The parallel timing of these major evolutionary events suggests that evolutionary redesign of metabolic and mitochondrial function may be related to, or underlie, the extreme changes in physiological and metabolic efficiency, flexibility, and innovation observed in snake evolution.

Background: The mitochondrial genomes of snakes are characterized by an overall evolutionary rate that appears to be one of the most accelerated among vertebrates. They also possess other unusual features, including short tRNAs and other genes, and a duplicated control region that has been stably maintained since it originated more than 70 million years ago. Here, we provide a detailed analysis of evolutionary dynamics in snake mitochondrial genomes to better understand the basis of these extreme characteristics, and to explore the relationship between mitochondrial genome molecular evolution, genome architecture, and molecular function. We sequenced complete mitochondrial genomes from Slowinski's corn snake (Pantherophis slowinskii) and two cottonmouths (Agkistrodon piscivorus) to complement previously existing mitochondrial genomes, and to provide an improved comparative view of how genome architecture affects molecular evolution at contrasting levels of divergence.