O R I G I N A L A R T I C L E doi:10.1111/j.1558-5646.2010.01213.x A CASE-BY-CASE EVOLUTIONARY ANALYSIS OF FOUR IMPRINTED RETROGENES Ruth B. McCole,1,2 Noeleen B. Loughran,3,4,5 Mandeep Chahal,1,6 Luis P. Fernandes,7,8 Roland G. Roberts,1,9 Franca Fraternali,7,10 Mary J. O’Connell,3,4,11 and Rebecca J. Oakey1,12 1Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, United Kingdom 2E-mail: ruth.mccole@genetics.harvard.edu 3Bioinformatics and Molecular Evolution Group, School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin Dublin 9, Ireland 4Centre for Scientiﬁc Computing & Complex Systems modeling (SCI-SYM), Dublin City University, Glasnevin Dublin 9, Ireland 5E-mail: noeleen.loughran@gmail.com 6E-mail: mandeep.chahal@kcl.ac.uk 7Randall Division of Cell and Molecular Biophysics, King’s College London, London SE1 1UL, United Kingdom 8E-mail: lpfernandes@gmail.com 9E-mail: roli.roberts@genetics.kcl.ac.uk 10E-mail: franca.fraternali@kcl.ac.uk 11E-mail: mary.oconnell@dcu.ie 12E-mail: rebecca.oakey@kcl.ac.uk Received March 24, 2010 Accepted November 30, 2010 Retroposition is a widespread phenomenon resulting in the generation of new genes that are initially related to a parent gene via very high coding sequence similarity. We examine the evolutionary fate of four retrogenes generated by such an event; mouse Inpp5f_v2, Mcts2, Nap1l5, and U2af1-rs1. These genes are all subject to the epigenetic phenomenon of parental imprinting. We ﬁrst provide new data on the age of these retrogene insertions. Using codon-based models of sequence evolution, we show these retrogenes have diverse evolutionary trajectories, including divergence from the parent coding sequence under positive selection pressure, purifying selection pressure maintaining parent-retrogene similarity, and neutral evolution. Examination of the expression pattern of retrogenes shows an atypical, broad pattern across multiple tissues. Protein 3D structure modeling reveals that a positively selected residue in U2af1-rs1, not shared by its parent, may inﬂuence protein conformation. Our case-by-case analysis of the evolution of four imprinted retrogenes reveals that this interesting class of imprinted genes, while similar in regulation and sequence characteristics, follow very varied evolutionary paths. K E Y W O R D S : Epigenetics, gene expression, imprinting, molecular evolution, retrogene. Retrogenes are functional protein-coding genes derived from the RNA-mediated retroposition of a “parent” gene (Kaessmann et al. Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen# OnlineOpen Terms 2009). Because a retrogene is formed on the basis of the mature spliced mRNA of a parental gene, it will normally be mono- exonic, and hence is easily recognizable as a retroposed copy of its parent gene. Retrogene generation in mammals depends upon the en- zymatic machinery of LINE1 elements reverse transcribing 1 4 1 3 C 2011 The Author(s). Evolution C 2011 The Society for the Study of Evolution. Evolution 65-5: 1413–1427