Hubbard Center: New Research On Mutation In Yeast Can Enhance Understanding Of Human Diseases
By Beth Potier, Media Relations
June 25, 2008
Yeast, a model organism heavily relied upon for studying basic biological
processes as they relate to human health, mutates in a distinctly different
pattern than other model organisms, a finding that brings researchers closer
to understanding the role of evolutionary genetics in human diseases and cancer.
The study, by researchers from UNH, Indiana University, Harvard University,
and the University of Utah, appears in Proceedings of the National Academy
of Science (PNAS) Online Early Edition this week (June 16 – 20, 2008).
“In biology, the mutation is an absolutely fundamental process, essential
to evolution but also the source of all genetic disease,” says Kelley
Thomas, associate professor of biochemistry and director of the Hubbard Center
for Genome Studies at UNH. “Despite its importance, we still don’t
know much about the basic processes of mutation.” Cancers are caused
by mutations, as are inherited diseases like Huntington’s disease and
fragile X syndrome, the most common inherited form of mental retardation.
“If we know more about the patterns of mutation, we’d be able
to better understand the origins of these diseases – and maybe prevent
them,” says Thomas.
The researchers asked a fundamental question: “What is the baseline
rate and spectrum of mutation in yeast?” They found that, like the previously
studied mutations in the nematode Caenorhabditis elegans, the yeast Saccharomyces
cerevisiae had a very high rate of mutation from generation to generation.
Its patterns of mutation, however, turned out to be unique. While C. elegans
mutations were largely the result of inserting or deleting base pairs of DNA,
yeast’s patterns of mutation were characterized by changing one base
pair for another. “That was really surprising, that we didn’t find
that adding or subtracting in yeast,” says Thomas. He adds that the consequences
of inserting and deleting base pairs can be much more dramatic than substituting
one base pair for another.
Comparing the mutation rates and spectrums of these two model organisms informs
researchers’ assumptions about mutation relevant to human health. “We
were surprised that there isn’t a common spectrum of mutation,” says
Thomas. “However, it’s exciting, because if we can describe patterns
of mutation, maybe we can understand why some organisms, including people,
are susceptible to certain mutations and not others.”
The approach used in this study allows yeast to accumulate mutations in the
near absence of natural selection. By doing this, cells with mutations that
might otherwise be lost because their cell is outgrown by others can continue
to survive and be analyzed for their mutations. With this study, Thomas and
his colleagues overcome a major limitation to the study of mutation by using
a new generation of sequencing technology that let them sequence the entire
genome of each yeast strain and to identify the rare mutational events that
have taken place. This way, the yeast accumulate mutations that might otherwise
make them “bad yeast” – the weak survive – and look
for them across the entire 10 million base pair genome.
“The beer you make with this yeast is horrible,” Thomas jokes.
Indiana University’s Michael Lynch was the principal investigator on
this paper, “A Genome-wide view of the spectrum of spontaneous mutations
in yeast.” Thomas credits former UNH graduate student Shilpa Kulkarni
and current graduate student Way Sung with contributing powerful bioinformatics
work to this research, which he calls “a big computational problem” due
to the volume of data. Other UNH contributors from the Hubbard Center were
Krystalynne Morris and Kazufusa Okamoto. Daniel Hartl, Christian Landry and
Erik Dopman from Harvard; Nicole Coffey from Indiana University; and W. Joseph
Dickinson from the University of Utah also contributed. The work was supported
by the National Institutes for Health.
The Hubbard Center for Genome Studies at UNH was established in 2001 to lead
the development of genomics research at UNH. It is a leader in comparative
and environmental genomics, with a special emphasis on novel model species.