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Dr. Long's research focuses on the underlying
genetic basis of variation in complex traits. Approaches range from
the use of cutting edge modern genomic tools, to the use of computer
simulations based on population genetics theory, to purely statistical
approaches that make maximal use of experimental data. Below a subset
of projects are outlined:
Using linkage disequilibrium
to dissect complex traits (empirical). By sequencing 16
alleles of the Delta gene region (approximately 30 kb of contiguous
DNA) we have identified every common Single Nucleotide Polymorphism
(SNP) in this gene region that could contribute to standing variation
in bristle number. We are now using identified SNPs to carry out
large scale association studies in large samples of wild caught
flies. These studies will be important as a validation of the association
study methods that human geneticists plan to carry out. (Long et
al., 1997; Long et al., 2000).
Using linkage disequilibrium
to dissect complex traits (theoretical). We
are carrying out large scale simulation based on the gene coalescent
theory of population genetics to assess the power of association
studies to detects gene regions contributing to complex traits.
Some of this work has already been published and more recent work
has focused on extended the simulations to examine: additional statistical
tests, more realistic models of human population structure and demography,
and the case control design. (Long et al, 1997; Long and Langley,
1999).
Using high density arrays to
study adaptation (empirical). We are using high density
arrays to examine the genetic architecture of thermal adaptation
in experimentally evolved populations of E. coli. We have observed
that adaptation in quite replicable at the molecular level and involves
a region that is tandemly duplicated in 3 out of 6 experimental
replicates. The duplicated regions contain candidate genes important
in adaptation, that were not a priori strong candidates for adaptation
to high temperature. We are now extending these results and looking
at genome wide patterns of gene expression in these and other evolved
lines of E. coli. We have also examined expression changes in lines
of Drosophila adapted to resist high levels of ammonia in the larval
environment (i.e., their food!). Again, we were able to identify
a set of genes important in adaptation that were not strong a priori.
In both projects, the discovery of genes and pathways important
in adaptation raise the exciting possibility of interactions between
physiologists, molecular biologists, and experimental evolutionists.
(Riehle et al., 2001).
Statistical inference from high
density arrays (theory): We have developed statistical
methods that employ the t-test, but incorporate a Bayesian prior
into estimates of the within treatment variance. This approach results
in improved statistical inference with minimal levels of replication.
We have implemented this approach into a set of web-based statistical
tools that are widely used at UCI, and beginning to see use at an
international level. (Arfin et al., 2000, Baldi and Long, 2001;
Long et al., 2001).
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Long, A.D., and C.H. Langley. 1999. The
power of association studies to detect the contribution of candidate
genetic loci to variation in complex traits. Genome Research 9:
720-731.
Long, A.D., R.F. Lyman, A.H. Morgan, C.H. Langley, and T.F.C. Mackay.
2000. Both naturally occurring insertions of transposable elements
and intermediate frequency polymorphisms at the achaete-scute complex
are associated with variation in bristle number in Drosophila melanogaster.
Genetics 154: 1255-69.
Riehle, M.M., A.F. Bennett, and A.D. Long. 2001. Genetic architecture
of thermal adaptation in Escherichia coli. PNAS 98: 525-530.
Baldi, P. and A.D. Long. 2001. A Bayesian framework for the analysis
of microarray expression data: regularized t-test and statistical
inferences of gene changes. Bioinformatics 17: 509-19.
Beldade, P., P.M. Brakefield, and A.D. Long. 2002. Contribution
of Distal-less to quantitative variation in butterfly eyespots.
Nature 415: 315-8.
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