Evolution of Imprinted Growth Regulatory Genes

Randy Jirtle
Duke University Medical Center; Duke University

Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. The inheritance of this parent-of-origin dependent form of gene regulation is a notable exception to the Mendelian laws of genetics. Imprinted genes play critical roles in embryonic growth and behavioral development, and also function as cancer susceptibility loci because their functional haploid state makes them vulnerable to being either inactivated or overexpressed. We have recently determined that imprinting at both the M6P/IGF2R and IGF2 loci evolved approximately 150 million years ago, most likely in an ancestor common to marsupials and eutherian mammals. Since imprinted genes are present in marsupials, invasive placentation and gestational fetal growth were not required for the evolution of imprinting. Although M6P/IGF2R is imprinted in Marsupialia (e.g. opossum), as it is in Artiodactyla (e.g. sheep, cows and pigs) and Rodentia (e.g. mice and rats), it is not imprinted in Scandentia (i.e. tree shrew), Dermoptera (i.e. colugo/"flying lemur") or Primates, including ringtail lemurs and humans The most parsimonious interpretation of these results is that a single ancestral origin of M6P/IGF2R imprinting was followed by lineage-specific imprint loss about 75 million years ago. The absence of M6P/IGF2R imprinting in extant primates demonstrates that M6P/IGF2R imprinting does not predispose to human disease such as cancer. This provides one plausible explanation of why mice, for example, are more susceptible to cancer than humans. Moreover, the divergent evolution of M6P/IGF2R imprinting predicts that the success of in vitro embryo procedures such as cloning may be species-dependent. (Supported by the NIH grants CA25951 and ES08823, Sumitomo Chemical Company and AstraZeneca Pharmaceuticals)


1) Killian, J.K., Byrd, J.C, Jirtle, J.V., Munday, B.L., Stoskopf, M.K., and Jirtle, R.L. M6P/IGF2R imprinting evolution in mammals. Mol. Cell 5: 707-716, 2000.

2) Killian, J.K., Nolan, C.M., Stewart, N., Munday, B.L. Andersen, N.A., Nicol, S., and Jirtle, R.L. Monotreme IGF2 expression and ancestral origin of genomic imprinting. J. Exp. Zoology 291:205-212, 2001.

3) Killian, J.K., Nolan, C.M., Wylie, A.A., Li, T., Vu, T.H., Hoffman, A.R., and Jirtle, R.L. Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary. Hum. Mol. Genet. 10: 1721-1728, 2001.