Arthur D. Riggs, Ph.D.｜Lectures｜Special Symposium in Commemoration of Dr. Susumu Ohno 20 years following his passing

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Random Monoallelic Expression, Development and Evolution

Arthur D. Riggs
Samuel Rahbar Chair in Diabetes & Drug Discovery, Diabetes Metabolism Res Inst

What impact does epigenetics have on evolution by gene duplication? This question was of interest to Susumu Ohno, and was addressed by Sergei Rodin and I, with the finding that epigenetic silencing soon after gene duplication is likely to be quite important, even essential, for evolution by gene duplication [Rodin and Riggs, 2003, J. Mol Evol, 56:718]. These studies led to the proposal by Branciamore, et al [2014, Proc Natl Acad Sci, USA, 111:6353] that stochastic epigenetic changes during a developmental window should enhance the rate of evolution. Extending this study to a treatment of transposons [Branciamore et al., 2015, AIMS Genetics 2:148] led to a surprising prediction that one should find evidence for balancing selection. This prediction is supported by our recently published studies on hybrid cell lines [Branciamore et al., 2018, Proc Natl Acad Sci, USA, 115: E10379] where we do, indeed, find evidence for balancing selection, and we also find that a high percentage of developmentally-specific autosomal genes are expressed from only one allele in any given astrocyte-like cell, i.e., they show monoallelic expression. It is thus likely that no two astrocyte cells have the same epigenetic identity. Whether this is true in vivo and for other cell types remains to be determined. The implications of stochastic changes during relatively brief developmental windows, leading to frequent cell-lineage-specific monoallelic expression, will be considered. It is proposed that mammals are cellular mosaics for many autosomal genes, as they are for X-linked genes.

Biography

Arthur D. Riggs, Ph.D.

Director, Diabetes and Metabolism Research Institute of the City of Hope,
and Director Emeritus Beckman Research Institute of the City of Hope, Duarte, California, USA

Arthur D. Riggs, Ph.D. received his B.A in Chemistry from University of California at Riverside in 1960 and his Ph.D. in Biochemistry from the California Institute of Technology in 1966. He did postdoctoral training at the Salk Institute during 1966-1969, and since then he has been at the City of Hope Medical Center, serving as Chair of the Biology Department most of the period 1982-2001. In 1984 the City of Hope became the site of the first Beckman Research Institute. In 1994, Dr. Riggs was the founding dean of the City of Hope’s now fully accredited graduate school. From 2001 through 2007 he was the Director of the Beckman Research Institute of the City of Hope. Among other awards, he received the Juvenile Diabetes Foundation Research Award in 1979 for work leading to the bacterial production of insulin. In 2006 he was elected to the United States National Academy of Sciences. Dr. Riggs is presently Director of the Diabetes and Metabolism Research Institute of the City of Hope.
His thesis work led to the Huberman and Riggs classic studies on mammalian DNA replication. His postdoctoral work resulted in the Riggs and Bourgeois series of papers on the lac repressor and bacterial gene regulation. He was the first to study a pure transcription factor, the lac repressor, and its specific biding to DNA. In his laboratories at City of Hope Dr. Riggs turned his attention to mammalian gene regulation, X chromosome inactivation, DNA methylation, and what is now called epigenetics -- which is the study of persistent changes in gene expression that do not involve changes in primary base sequence. He correctly proposed DNA methylation as an epigenetic mechanism. He also first proposed the extrusion/reeling model for 3D chromatin/chromosome structure.
In the late 1970s, in addition to studying epigenetics and X chromosome inactivation, Riggs collaborated with a number of colleagues, including Keiichi Itakura, Herbert Heyneker, Herbert Boyer and David Goeddel, on work that used chemically synthesized DNA for novel recombinant DNA techniques and the expression in E. coli of the first man-designed and man-made genes -- the genes for somatostatin and human insulin. The success of the somatostatin/insulin project catalyzed the development of the biotech industry, aided by key, dominant patents held by Genentech Inc., on which Itakura and Riggs are the sole inventors. In the early 80s Riggs and his postdoc Shmuel Cabilly worked with Heyneker on recombinant antibodies, leading to patents, known as the Cabilly patents, which describe the technology now used for many therapeutically useful chimeric and humanized antibodies.