Genome Duplication at the Beginning of Mammalian Development

Nothing is more fundamental to mammalian development than the ability to accurately reproduce its genome once-but only once-each time a cell divides. In fact, the basic mechanism for replicating DNA has been conserved throughout evolution, even though the magnitude of the problem became monumental. A human cell contains 670 times the DNA in an E. coli cell, and human development requires trillions of cell divisions that produce about 37 billion miles of DNA! But instead of increasing the speed of replication forks to compensate for increasing genome size and organism complexity, evolution simply increased the number of replication origins. This allowed mammalian development regulate initiation of DNA replication during cell proliferation without interfering with the ever-changing demands of gene expression during cell differentiation. Moreover, it allowed developing tissues to complete genome duplication before beginning mitosis and to restrict genome duplication to once per cell division. And yet, to overproduce gene products during development, some cells are allowed to differentiate into nonproliferating polyploid cells. This chapter summarizes the mechanisms that make these events possible. Ironically, aberrations in these mechanisms are linked to cancer. In fact, the pluripotent cells produced during preimplantation development not only share characteristics of cancer cells, but they can also initiate cancer.