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Research
Focus & Philosophy |
While constraint
and random genetic drift are the primary forces acting on the evolution
of most gene sequences over evolutionary time, positive selection
does happen at the molecular level and can play a significant role
in the development of specific gene sequences. By quantifying the
nature of positive and negative selection within and between species,
the role that different types of selection can play on the overall
"adaptation" of an organism to it's environment can eventually be
explored. It is the interplay between these forces and how they can
be measured that interests me.
Comparative Genomics:
I have developed a methodology to search for the contrasting effects
of positive and negative selection by looking at the physico-chemical
properties of amino acids which are differing between species (Wyckoff,
Wang, and Wu, 2000). I have also extended this work to a larger data
set between humans and old world monkeys (OWM), and have examined
human polymorphism in order to determine the rate of fixation of selectively
advantageous mutations in primates (Fay, Wyckoff, and Wu, 2001). As
I have been collaborating with Dr. Chung-I Wu looking at data coming
from a consortium of people working on Macaca fascicularis testis
and brain cDNA library sequence, the lab is building in large part
upon this work. In addition, we have preliminary data on several reproduction
related genes and we are interested in examining these genes more
thoroughly. These projects are well suited for graduate thesis work
and undergraduate research projects.
Polymorphism analysis:
By extensive human coding region sequence analysis and evolutionary
comparisons to outgroup primate species, an appropriate weighting
factor can be derived for nonsynonymous polymorphisms. The goal is
to use this weighting method to help determine the likelihood that
a specific mutation isolated by any of a variety of methods as putatively
disease causing is indeed causal within a given population. In addition,
the interface between complex disease mapping and evolutionary genomics
can provide information which informs mapping experiments while mapping
experiments provide data for further evolutionary analysis. This is
a major part of the work taking place in the lab to date.
Bioinformatics:
A major effort during my postdoctoral research was to obtain the resources
necessary to put together a relational database of genomic sequences
and associated information. This includes expression information,
divergence information, polymorphism information, and disease linkage
information. We envision several types of publications coming directly
from the techniques and programs built to handle and query the data,
but more importantly, observations made using this tool will lead
to hypothesis testing experiments performed at the bench. We in the
lab actively seek collaborations with people who work in a variety
of systems, including in model organisms such as mice, yeast, and
Drosophila, where experimental manipulation of genes and gene pathways
will allow for the testing of the effects of predictions made in silico.
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