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Flip-Flopping Genes Would Have Bewildered Gregor Mendel

One gene for pea pod color generates green pods while a variant of that gene gives rise to the yellow-pod phenotype, a feature that helped Gregor Mendel, the 19th century Austrian priest and scientist, first describe genetic inheritance. However, UC San Diego researchers and many modern-day geneticists are focused on the strange ability of some genes to be expressed spontaneously in either of two possible ways.

In order to better understand this phenomenon of epigenetic multistability, a major complication for Mendelian genetics, scientists grew virtual bacterial cells in a computer experiment at the Jacobs School. They created a two phenotype model system programmed to grow in ways that matched natural growth. In a deceptively simple experiment, they then recorded the degree to which the two phenotypes varied over time in individual cells, and then repeated the experiment over and over. They reported in Proceedings of the National Academy of Sciences that variability due to epigenetic multistability is larger and persists much longer than they had expected.

Postdoctoral fellow Matthew R. Bennett, left, and professor Jeff Hasty studied two phenotypes in an ensemble of virtual cells grown three times.
Postdoctoral fellow Matthew R. Bennett, left, and professor Jeff Hasty studied two phenotypes in an ensemble of virtual cells grown three times.

While the phenomenon is yet to be discovered in the human genome, the new results suggest that researchers studying bacteria should carefully design their experiments to measure variability due to epigenetic multistability. Even in human cells, multistability may play a role in genes that alternate between "on" and "off" settings.

"Scientists studying bacteria have simply not had the tools to understand phenotypic variability," said Ting Lu, lead author of the study who was a physics graduate student in the lab of bioengineering professor Jeff Hasty. (Lu is currently a postdoctoral fellow at Princeton University .) "We've arrived at a theoretical framework that allows experimenters to measure the ephemeral nature of epigenetics."

Epigenetic multistability may be vital to cells that are outwardly different, but genetically identical. Only one of the two phenotypes might thrive in a given environmental condition; however, the less advantageous phenotype could come in handy if the environmental conditions change.

"Different results can emerge depending on how cells are grown," said Jeff Hasty, a professor of bioengineering at UCSD and senior author of the paper. "Our results should allow all researchers studying bacteria to better understand the variability they routinely see from one experiment to the next."


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