Whole genome activity, letter-by-letter (5/26/2008)

A new study using next-generation DNA sequencing shows that almost all of the yeast genome is genetically active. Until recently, it was thought that much of a genome sequence was silent, but the new work identifies many new regions of activity and markedly improves understanding of this well-studied organism.

Yeasts are important models in research for human biology and medicine, and this work is the first application of next-generation DNA sequencing to define all the regions that are active. The research was conducted on the fission yeast Schizosaccharomyces pombe.

The team, led by Dr Jürg Bähler from the Wellcome Trust Sanger Institute, converted messenger RNAs into DNA copies and produced 122 million DNA sequences - equivalent to sequencing the yeast genome 250 times over. Importantly, they were able to examine messenger RNA transcripts from a range of growth conditions in order to gain as comprehensive a picture as possible of global activity of the yeast genome.

"Fission yeast is one of the best-studied organisms and to find such widespread transcription is exciting," explains Dr Jürg Bähler. "We show that 94% of the yeast genome is active and that we can use sequencing to measure how active each region is and also to obtain insight into transcript structures at maximal resolution."

"This global survey, the first of its kind, will be invaluable in understanding this model organism both in its global genetic activity and in detailed studies. It sets a standard for other organisms."

To try to capture all or most genes in action, the team analysed RNAs from growing cells, differentiating cells, cells under stress, as well as in mutants of RNA processing pathways. The sequence results from these samples were strengthened and verified by combining them with results from DNA chips that provided a dense and strand-specific coverage of the genome.

The study found hundreds of regions that were thought to be genetically inactive: using the two methods together, the team could determine, in most cases, which of these regions of activity were derived from known genes and which had not been previously described. Conservatively, they estimate that there are more than 450 novel transcripts.

Most of these regions would not be detected by current microarray-based methods - only this novel sequencing approach is sensitive enough to reveal this regulatory complexity.

"Most of the newly discovered transcripts seem to be non-coding, and it will be important to figure out their regulatory or other roles," continues Dr Bähler.

The study also shows that genes can be used in different ways under different conditions - possibly leading to alternative protein structure. Different start and end sites can be used, with much of this alternative transcription activity being seen during differentiation.

Moreover, transcripts from more than 250 genes were processed more efficiently during differentiation: most of these are genes that are also more active during differentiation, suggesting that increased gene activity can stimulate higher efficiency of RNA processing.

Dr Bähler explains: "Overall, transcription and RNA processing seem to be tightly coordinated to streamline gene expression, adding an additional layer to gene control."

This study across the genome and in different conditions gives a new view of the global activity of the yeast genome and the possibly connected contributions of transcription and RNA processing for gene activity in cell division, stress and differentiation. It is a view that we have not been able to uncover until now.

"Does this study have lessons for the human genome and genomes of other larger organisms?" asks Dr Bähler. "I would be very surprised if it does not. We have learned numerous lessons about human biology from yeast, and I expect that these findings and new approaches will be equally powerful to unravel genome activity at unprecedented detail in our own genome."

Note: This story has been adapted from a news release issued by the Sanger Institute

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