Life Sciences Research for Lifelong Health

Causes of genome change

The idea that genome change can be regulated in response to the environment has major implications. It is generally thought that genome changes leading to adaptation occur through random mutation followed by selection, however, we are accumulating evidence that cells can focus genome changes on certain genomic regions in response to the environment, accelerating adaptation. We have demonstrated that this occurs in the ribosomal DNA, and are now extending these ideas to other loci.
 
We use the yeast ribosomal DNA as a model of regulated copy number variation. This region contains ~150 tandem copies and ribosomal DNA copy number is carefully maintained. Cells with too few copies of the ribosomal DNA cannot produce sufficient ribosomes for maximum growth, and rapidly amplify the ribosomal DNA copy number back to normal levels.

This is by far the clearest example of copy number variation as a regulated process in any organism. Non-protein coding RNA produced from the ribosomal DNA is involved in regulating copy number, and we have found that proteins which interact with these RNAs are important for copy number regulation (see Figure).

Surprisingly, we have found that copy number amplification occurs by a highly unusual mechanism which does not require the well-understood homologous recombination machinery. Instead, amplification proceeds through a poorly understood mechanism previously known for causing occasional pathogenic chromosomal rearrangements.
 
Genome change figureWe have recently shown that ribosomal DNA copy number is controlled by a specific signalling pathway, TOR, which responds to nutrient availability, allowing cells to specifically optimise their genome for current environmental conditions.

This provides a mechanism by which an apparently Lamarckian inheritance event can occur, with the ribosomal DNA undergoing heritable genetic changes in response to the environment. It will be fascinating to examine whether similar effects occur at other loci, and a major aim of the lab is to determine how often genetic changes at protein coding genes are driven by the environment.

We are comfortable with the idea that signalling events can orchestrate transcriptional epigenetic changes at specific loci, and we suggest that genome changes can be focused in response to the environment by similar mechanisms (see Figure). Indeed, all the genome changes that we study occur downstream of epigenetic and/or transcriptional changes, so many of the same mechanisms may be involved.
 
Ribosomal DNA recombination is tightly linked to ageing in yeast, and many of the mutations we have found that alter ribosomal DNA recombination also impact lifespan. We are very interested in understanding how regulated recombination processes can change lifespan, as some of these mechanisms are likely to be highly conserved amongst eukaryotes.