Keck School of Medicine Events

Keck School of Medicine of USC Research Seminar Series

"Certain Spermatogonial Stem Cell Mutations can Disproportionately Increase the Frequency of Human Genetic Diseases"
April 2013
Monday, April 15, 2013
11:30 AM - 1:00 PM
Norris Research Towers Aresty Auditorium

Norman Arnheim, PhD

Distinguished Professor of Biological Sciences, Molecular Biology and Biochemistry, Ester Dornsife Chair in Biological Sciences, University of Southern California will be presenting.
Abstract: Some new germline mutations that arise in the testis may confer a selective advantage to the mutated germ cell relative to non-mutated cells. Theoretically, if a new mutation provided a germline selective advantage it could increase the frequency at which the mutated allele was introduced into the population by orders of magnitude even though, much to the species detriment, it reduced the fitness of the individuals that inherited it. We have shown examples of positive germline selection for three human disease mutations that arise sporadically each generation at frequencies ranging from 1/2,000 to 1/70,000 births. These sporadic disease cases occur at rates 100-1,000 times greater than would be expected based on what we know about genome average mutation rates. Using a testis dissection/mutation detection approach along with mathematical modeling we have shown that the high frequency of these de novo disease mutations cannot be explained by hyper-mutation at the disease-causing sites. Instead, our data are consistent with the idea that the newly mutated germline stem cells have a proliferative advantage over non-mutated stem cells resulting in germline mosaicism. Plausible molecular mechanisms can explain the selective advantage for each of the three disease mutations. Others previously suggested that alleles conferring a selective advantage in the germline may be disadvantageous in the adult and might lead to "mitotic drive" systems that increase the mutational load of a population. The three disease mutations we examined may be realizations of this idea. Biography Norman Arnheim is a Distinguished Professor of Biological Sciences, Molecular Biology and Biochemistry and holds the Ester Dornsife Chair at the University of Southern California. He earned his Ph.D in genetics at UC Berkeley followed by postdoctoral work in Berkeley's Biochemistry Department. As an assistant professor at SUNY Stony Brook's Biochemistry Department, he studied protein evolution. He spent his first sabbatical with Ed Southern in Edinburgh where he learned the then new nucleic acid approaches for studying the organization of the genome. Back in Stony Brook, his group examined the evolution of a tandemly-arranged multigene family with special emphasis on the genetic interactions that routinely occur between gene family members. This work unexpectedly led to the discovery of simple repeat microsatellite DNA sequences and their location throughout animal genomes. Later these same sequences became the foundation for mapping human disease genes. During his next sabbatical period Dr. Arnheim worked at the biotechnology company Cetus where he was co-leader of the group that originally developed the polymerase chain reaction (PCR). Shortly after, he went to USC where his group devised PCR methods to study the sequence characteristics of single DNA molecules. The techniques developed for this purpose were integral to the development of preimplantation human genetic disease diagnosis. Using single cells, his group also studied the exchange of genetic material between chromosomes during the formation of sperm. The same basic approach revealed the characteristics of "dynamic" mutations which can lead to many neurodegenerative hereditary diseases. Currently, the Arnheim lab is studying certain rare newly arising human disease mutations to explain why some occur at unexpectedly high frequencies.

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