Postdoctoral Positions are available in three NIH funded project areas:
I. Saccharomyces cerevisiae Pathogenesis and Quantitative Genetics (one
position).
We have developed the model eukaryote S. cerevisiae as a model for
the pathogenic fungi and as a microbial model for quantitative genetics.
Quantitative genetics is the study of polygenic traits. Since most of the
phenotypic variation in natural populations is polygenic, quantitative
genetics is fundamentally important. Quantitative traits have been most
extensively studied in higher eukaryotes. However, detailed genetic and
molecular analysis in higher eukaryotes is quite difficult compared to
microbial systems. We will use the simplicity/genetic manipulability of S.
cerevisiae and whole genome analysis (1, 2, 3) to dissect the ability to
grow at high temperatures -- high temperature growth is both a quantitative
trait and a virulence trait (4, 5).
With respect to fungal pathogenesis S. cerevisiae is not only a
model eukaryote, this species is also a close relative of many pathogenic
fungi and is an emerging opportunistic pathogen in its own right.
Quantitative genetics is highly relevant to fungal pathogenesis because the
phenotypic differences between the avirulent S. cerevisiae laboratory
strain genetic background and the virulent S. cerevisiae clinical isolates
are quantitative in nature, e.g. the ability to grow at high temperatures.
In addition to aiding our understanding of quantitative genetics and fungal
pathogenesis, our genetic analysis will help us understand the evolution of
a harmless saprophyte into an emerging opportunistic pathogen.
II. Saccharomyces cerevisiae Phase Variation (one position).
S. cerevisiae phase variation, which is distinct from pseudohyphal
formation, MAT switching, Ty elements & silencing, is a novel eukaryotic
microbial model for cellular differentiation and gene regulation. Phase
variation, which has been extensively characterized in bacteria, involves
the regulation of gene expression through reversible DNA sequence changes
(reviewed in Trends in Genetics 8:422-427, Adv. Microb. Ecol. 13:263-300,
Curr. Biol. 4:24-33, Micro. Mol. Biol. Rev. 61:281-294); specific genes are
phase variable and specific regions of these genes are highly mutable. One
of the most common mechanisms of bacterial phase variation involves changes
in simple repetitive sequences -- similar to a number of human genetic
diseases.
Clinical S. cerevisiae isolates undergo phase variation at multiple
loci with each phase variable locus having distinct phenotypic effects on,
for example, the utilization of novel carbon sources and on gene
expression. This work will be a detailed characterization of phase
variation including (i) the mechanism of phase variation at each locus and
(ii) the regulation by phase variable gene products of gene expression.
This work will use whole genome analysis to clone the phase variable loci
(1) and examine phase variable gene expression (2, 3).
3.) Genetic identification of antifungal drug targets (one position).
This project is focused on Cryptococcus neoformans; there are more
C. neoformans labs at Duke than any other institution in the country. The
project will involve the (i) construction of fungal specific gene mutations
in C. neoformans and (ii) determination of their virulence phenotypes. The
goal is to identify novel antifungal drug targets -- any fungal specific
gene product that is critical for virulence is a good antifungal drug
target. This project provides an entry into the field of medical mycology
and will provide a good background for either a basic research job or a
pharmaceutical industry job.
1.) Winzeler, E.A., D. Richards, A. Conway, A.L. Goldstein, S. Kalman, M.J.
McCullough, J.H. McCusker, D.A. Stevens, L. Wodicka, D.J. Lockhart, and
R.W. Davis. 1998. Direct allelic variation scanning of the yeast genome.
Science 281:1194-1197.
2.) Lashkari, D.A., J.L. DeRisi, J.H. McCusker, A.F. Namath, C. Gentile, S.
Hwang, P.O. Brown, and R.W. Davis. 1997. Yeast micro-arrays for genome wide
parallel genetic and gene expression analysis. PNAS 94:13057-13062.
3.) Lashkari, D.A., J.H. McCusker, and R.W. Davis. 1997. Whole genome
analysis: experimental access to all genome sequenced segments through
larger scale efficient oligonucleotide synthesis and PCR. PNAS 94:8945-8947.
4.) McCusker, J.H., K.V. Clemons, D.A. Stevens, and R.W. Davis. 1994.
Saccharomyces cerevisiae virulence phenotype as determined in CD-1 mice is
associated with the ability to grow at 42ºC and form pseudohyphae. Infec.
Immun. 62:5447-5455.
5.) McCusker, J.H., K.V. Clemons, D.A. Stevens, and R.W. Davis. 1994.
Genetic characterization of pathogenic Saccharomyces cerevisiae isolates.
Genetics 136:1261-1269.
For a look at work in progress,
1.) go to the GSA Yeast Genetics & Molecular Biology 2000 web site
<http://www.faseb.org/genetics/gsa/yeast/spe-yea.htm> and search for
abstracts with McCusker as an author,
2.) go to the lab web site <http://www.duke.edu/web/microlabs/mccusker/>
Extensive molecular biology expertise is required and yeast/fungal
genetics experience is highly desirable. The start date is flexible. Duke
University is an AA/EOE. Send curriculum vitae as e-mail text (ABSOLUTELY
NO ATTACHMENTS OR ENCLOSURES) with contact information for three references
to:
Dr. John H. McCusker
Dept. of Microbiology, 3020
Duke University Medical Center
Durham, NC 27710
e-mail: mccus001@ mc.duke.edu
web site: http://www.duke.edu/web/microlabs/mccusker/
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