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Whole-Genome Sequencing Uncovers Nature of Yeast Spontaneous Mutations

NEW YORK (GenomeWeb News) – Whole-genome sequencing is providing new insights into the frequency and nature of spontaneous genetic mutations in yeast.
 
In a paper appearing online in Proceedings of the National Academy of Sciences last Thursday, a team of American researchers used 454 pyrosequencing to detect spontaneous mutations in four Saccharomyces cerevisiae lines. The work is providing a whole-genome view of the small and large mutations that tend to arise in yeast — findings that can inform comparative studies between organisms and, more broadly, improve scientists’ understanding of evolution.
 
“Mutation provides the resources on which natural selection can act,” lead author Michael Lynch, a biologist at Indiana University, told GenomeWeb Daily News today. “To me, that’s sort of the bottom line for understanding evolution.”
 
Despite the fact that spontaneous mutations influence everything from evolutionary genetics to inheritance and genetic disease, scientists still know relatively little about the frequency and nature of such mutations, particularly on a whole-genome level.
 
For this study, Lynch and his co-workers used 454 pyrosequencing to sequence four haploid lines of the model organism S. cerevisiae. The lines were derived from the same parent strain and put through single-cell bottlenecks for three to four days or roughly 200 cell cycles.
 
About half the genome yielded sequence data that was sufficient for analysis. Overall, the researchers found a genome-wide mutation rate of roughly 0.32 per cell division.
 
The per-base mutation rate wasn’t much different from that reported previously using different methods, Lynch noted. And most of the small-scale mutations detected were base-substitutions.
 
Of the 33 base-substitutions detected, G/C to A/T mutations occurred more often than mutations in the other direction. On the other hand, the researchers detected just one single-base-pair deletion and one three-base-pair inversion.
 
More unexpectedly, the nuclear genome actually had a very high rate of large mutations (more than a thousand base pairs in size), especially segmental duplications and deletions. Indeed, Lynch noted, the whole-genome view uncovered as many large mutations as it did point mutations.
 
The researchers also noticed some unusual things during microarray and sequencing experiments, Lynch said. For instance, during sequencing they got much higher coverage than anticipated for some parts of the genome, while those regions with lower coverage yielded about half as much information as expected.
 
Based on these and other observations, the researchers concluded that the haploid yeast cells were actually diploidizing over time — a phenomenon previously reported by others.
 
“Most of the time when you think you’re dealing with a haploid line, you’re probably dealing with a diploid,” Lynch said. “[The yeast] clearly like to be diploid.” What drives this diploidization and how it occurs is still largely unknown, though Lynch noted that individual chromosomes seem to diploidize individually such that the whole genome doesn’t seem to become diploid at once.
 
More research is necessary to get a genome-wide view of mutation rates in other organisms. But preliminary comparisons presented in the paper suggest the yeast nuclear mutation rates are comparable to those observed in Drosophila and humans. C.  elegans, on the other hand, appears to have a much higher mutation rate, based on PCR analysis and sequencing of limited regions of the genome.
 
The team is currently using the whole-genome sequencing approach to understand spontaneous mutation in other organisms, such as a type of paramecium, Daphnia (water flea), and Arabidopsis.
 
Lynch said the team is also interested in understanding how specific mutations — for example, in mismatch repair genes or polymerase genes — affect spontaneous mutation rates. “I think we’ll be able to do that in the not too distant future,” he said.

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