Although it has a reputation for stability, the genome is malleable—and not just by means of random mutation in chain with natural selection. The genome has some capacity to change in response to environmental factors. This capacity is most evident in single-celled organisms such as yeast, whole populations of which have been known to produce the same genomic alteration at more or less the same time, spontaneously, not gradually as though the alteration had propagated through rounds of fission.
Yeast cells, scientists insist, must optimize their genomes by means of one mechanism or another, but exactly which mechanism has remained in doubt. Now scientists from the Babraham Institute and the University of Cambridge say that they have uncovered a likely mechanism, a signaling pathway that yeast cells can use to accomplish a specific kind of gene amplification, or gene duplication.
The mechanism was detailed July 20 in the Proceedings of the National Academy of Sciences, in an article entitled, “Regulation of ribosomal DNA amplification by the TOR pathway.” According to this article, TOR (target of rapamycin) signaling stimulates ribosomal DNA amplification in budding yeast, linking external nutrient availability to ribosomal DNA copy number.
TOR is a signaling pathway that coordinates growth rate in response to nutrient availability and controls the rate of ribosome synthesis. TOR signaling is conserved from yeast to mammals and controls numerous processes, one notable example being the response to caloric restriction which slows growth and can extend lifespan.
“Because the TOR pathway responds to environmental nutrient availability and represses rDNA recombination during caloric restriction, we asked whether TOR signaling controls rDNA amplification,” wrote the authors of the PNAS article. “Here we show that rDNA amplification in budding yeast occurs through two pathways that are coordinately regulated by TOR signaling, providing a clear demonstration that the copy number of certain loci can be tailored to suit the current environment.”
The article noted that yeast cells engineered to carry a suboptimal complement of ribosomal DNA genes are known to undergo gene amplification to correct this deficit. The researchers found that these cells perceive the normal environment as containing an excess of calories because they struggle to produce enough ribosomes to maintain normal levels of protein synthesis. TOR signaling responds to this caloric excess and initiates ribosomal DNA gene amplification.
“We show that ribosomal DNA amplification is regulated by three histone deacetylases: Sir2, Hst3, and Hst4,” explained the authors. “These enzymes control homologous recombination-dependent and nonhomologous recombination-dependent amplification pathways that act in concert to mediate rapid, directional ribosomal DNA copy number change. Amplification is completely repressed by rapamycin, an inhibitor of the nutrient responsive TOR pathway; this effect is separable from growth rate and is mediated directly through Sir2, Hst3, and Hst4.”
The rDNA copy number amplification observed in the current study, the authors noted, “departs from the standard model of adaptation through random mutation followed by selection, as there is no growth difference between low and normal rDNA copy number cells.” In addition, this amplification was seen to provide a long-term, heritable increase in ribosome synthesis capacity to enable optimum reproduction rate and make best use of available nutrients.
The fact that the amplification is specifically regulated by a signaling pathway “raises the fascinating possibility that copy number of other regions of the genome may also be controllable in response to environmental conditions.” The authors speculate that the signaling pathway they uncovered can also drive genome changes in higher organisms in response to an excess of calories, with consequences on health and lifespan.