post-doctoral positions at Duke University

[John McCusker]

Postdoctoral Positions are available in three NIH funded project areas:

1.) S. cerevisiae -- a model to study phenotypic variation & genetic 
instability: Extensive genetic instability and phenotypic variation 
exists in clonal populations of microorganisms, which is thought to 
play a role in adaptation to novel environments.  This genetic 
instability, which occurs by multiple mechanisms, is a form of 
cellular differentiation in microorganisms and a stochastic means for 
modulating gene expression.  This genetic instability may also play a 
role in human genetic diseases.  One case of genetic instability and 
phenotypic variation that we have dissected in S. cerevisiae involves 
the high frequency formation of translational suppressors in the 
eight identical member tRNA-Tyr gene family.  Most interestingly, 
within the tRNA-Tyr gene family there is a strong genomic position 
effect on mutation frequency; this position effect on mutation 
frequency has many implications and is completely novel 
(Ito-Harashima, Hartzog and McCusker, manuscript submitted).  In 
addition to the tRNA-Tyr-mediated phenotypic variation, other genetic 
instability systems are under study, which involve other genes and 
mechanisms.

2.) S. cerevisiae -- a microbial model for quantitative genetics: One 
observes a range of phenotypes (quantitative traits) in natural 
populations which is due to the complex interaction of multiple 
alleles of many different genes.  Although these quantitative traits 
are very important, the genetic complexity of quantitative traits has 
made the identification of the genes underlying quantitative traits 
difficult.  To better understand quantitative traits, we developed S. 
cerevisiae as a microbial model for quantitative genetics; we focus 
on the ability to grow at high temperatures, a virulence trait in 
pathogenic fungi.  We combine genome-wide mapping and a new genetic 
technique named reciprocal hemizygosity analysis to dissect 
quantitative trait loci (QTL) in S. cerevisiae and find that QTL 
architecture is considerably more complex than anticipated.  We also 
find a genetic explanation for heterosis (hybrid vigor), the 
increased fitness of the hybrid compared to the parent strains 
(Steinmetz, et al. Nature in press).  S. cerevisiae is a superb model 
for understanding quantitative genetics as well as the evolution of a 
harmless saprophyte into an emerging opportunistic pathogen.

3.) Using genetics to identify novel antifungal drug targets: The 
currently available antifungal drugs are few in number, are less 
effective than clinicians would like, and tend to have severe side 
effects.  Therefore, there is a great need to develop new 
antifungals. The goal of these experiments is to identify Candida 
albicans and Cryptococcus neoformans mutants that are 
avirulent/non-pathogenic in experimental infections and thereby 
identify good potential drug targets.  The choice of genes is 
dictated by (i) their absence in humans and (ii) the highly 
deleterious in vitro phenotypes of specific mutants.  We have 
identified a number of fungal mutants with severe defects (e.g. Yang, 
et al. manuscript submitted).  In addition to drug target 
identification, analysis of the pathogenic fungi has a number of 
surprises with respect to gene regulation and gene structure; for 
example, SPE3 (spermidine synthase) and LYS9 (saccharopine 
dehydrogenase) are fused into one gene in C. neoformans (Z. Yang, J. 
Kingsbury, J.H. McCusker, manuscript accepted for publication).  This 
project provides an entry into the field of medical mycology and will 
be a good background for either job in either a research university 
or the pharmaceutical industry.

Selected references:

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.

Goldstein, A.L., and J.H. McCusker. 2001. Development of 
Saccharomyces cerevisiae as a model pathogen: a system for the 
genetic identification of gene products required for survival in the 
mammalian host environment. Genetics 159:499-513.

L.M. Steinmetz, H. Sinha, D.R. Richards, J.I. Spiegelman, P.J. 
Oefner, J.H. McCusker, & R.W. Davis. 2002. Dissecting the complex 
architecture of a quantitative trait locus in yeast. Nature (in 
press).

For a look at the lab, a full list of publications & work in 
progress, 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.  E-mail curriculum vitae, 
with contact information for three references including current 
mentor, to mccus001 at mc.duke.edu.

Dr. John H. McCusker
Dept. of Microbiology, 3020
Duke University Medical Center
Durham, NC 27710
e-mail:		mccus001 at mc.duke.edu
web site:	http://www.duke.edu/web/microlabs/mccusker/
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