gene dosage effects of the imprinted delta-like homologue 1 (dlk1pref1) in development implications for the evolution of imprinting基因剂量效应的印delta-like同系物1(dlk1pref1)对印迹的进化发展的影响.pdfVIP

Gene Dosage Effects of the Imprinted Delta-Like Homologue 1 (Dlk1/Pref1) in Development: Implications for the Evolution of Imprinting 1 1 2 1 1 Simao Teixeira da Rocha , Marika Charalambous , Shau-Ping Lin , Isabel Gutteridge , Yoko Ito , Dionne 1 3 1 Gray , Wendy Dean , Anne C. Ferguson-Smith * 1 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom, 2 Institute of Biotechnology, College of Bioresources and Agriculture, National Taiwan University, Taipei, Taiwan, 3 Developmental Genetics and Imprinting Laboratory, The Babraham Institute, Cambridge, United Kingdom Abstract Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantage conferred by imprinting is not understood but is hypothesised to act on dosage-critical genes. Here, we report a unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1, normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosage and survival that fixes an upper limit on growt