Simons Foundation Lectures are free public colloquia related to basic science and mathematics. These high-level talks are intended for professors, students, postdocs and business professionals, but interested people from the metropolitan area are welcome as well.
The evolution of organisms requires the generation of some diversity in the offspring and then the selection of the fittest in the present environment from among this diversity in the population. Diversity is accomplished by several mechanisms including novel combinatorial trials that arise by having two sexes, recombination of maternal and paternal chromosomes and mutations or errors in the transmission of information. The rates of evolution can be influenced by mutation rates that are in turn influenced by a wide variety of stresses that can occur as sperm or eggs are produced or even as the organism develops. There is a dramatic increase in error frequency when the genetic information, DNA, is duplicated in cells under stress. Stress can be initiated by inadequate nutrients, hypoxia, DNA damage from various sources, thermal variation and other environmental changes. If the error frequency increases too much an error catastrophe threshold is reached and disabled offspring can be produced. Thus there is a tension between fidelity and a useful error frequency that generates enough diversity to permit selection and changes in the species.
About a billion years ago common ancestors of today’s humans and sea anemones developed a mechanism to detect stress leading to a high error frequency in germ cells and eliminate these cells by death. A relative of the gene and protein in sea anemones can be found in flies and worms and three related copies of this gene are observed in humans. One of these genes and its protein is called p53 and it is employed to prevent cancers from arising in somatic cells of humans. Two other genes found in the female germ line are called p63 and p73 and they are responsible for killing eggs that are damaged so as to prevent altered offspring. Like all genes in a population the p63 and p73 genes exist in several forms with a variation in the efficiency with which they monitor mistakes and kill cells. These are called genetic polymorphisms in the population and it suggests that some parents and families have higher mutation rates than others. Because of these polymorphisms or variations in the parents the offspring can have mutations not found in the chromosomes of the parents, termed de novo mutations. One type of de novo mutation that has been detected in offspring is called a copy number variation, a deletion or duplication of the DNA, which results in one to three copies of a gene in the offspring. De novo copy number variations have been observed in developmental abnormalities, autism and some early onset cancers in offspring but not observed in the parents. Evidence will be presented linking mutations and polymorphisms in the, p53, p63 and p73 genes of humans with these disorders.
Belyi, V.A., Ak, P., Markert, E., Wang, H., Hu, W., Puzio-Kuter, A., and Levine, A.J. 2010. The Origins and Evolution of the p53 Family of Genes. The P53 Family: Chapter 1, Cold Spring Harbor Perspectives in Biology. Cold Spring Harbor Laboratory Press.
Feng Z., Zhang C., Kang H., Sun Y., Wang H., Naqvi A., Frank A., Rosenwaks Z., Murphy M., Levine A., Hu W. (2011) The regulation of female reproduction by p53 and its family members. FASEB J., Epub ahead of print.
Levine, A.J., Tomasini, R., McKeon, F.D., Mak, T.W. Melino, G., The p53 family: guardians of maternal reproduction. Nature Reviews Molecular Cell Biology, April 2011, 12:259-265.
About the Speaker
Arnie Levine is a Systems Biology Professor Emeritus at the School of Natural Sciences at the Institute for Advanced Study. Levine is a widely acclaimed leader in cancer research. In 1979, Levine and others discovered the p53 tumor suppressor protein, a molecule that inhibits tumor development. He established the Simons Center for Systems Biology at the Institute, which concentrates on research at the interface of molecular biology and the physical sciences: on genetics and genomics, polymorphisms and molecular aspects of evolution, signal transduction pathways and networks, stress responses, and pharmacogenomics in cancer biology.