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Placing Probes along the Genome Using Pairwise Distance Data
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Placing Probes along the Genome Using Pairwise Distance Data
Will Casey6 , Bud Mishra6 and Mike Wigler7 
| (6) |
Courant Institute, New York University, 251 Mercer St., New York, NY 10012, USA |
| (7) |
Cold Spring Harbor Laboratory, P.O. Box 100, 1 Bungtown Rd., Cold Spring Harbor, NY 11724, USA |
Abstract
We describe the theoretical basis of an approach using microarrays of probes and libraries of BACs to construct maps of the
probes, by assigning relative locations to the probes along the genome. The method depends on several hybridization experiments:
in each experiment, we sample (with replacement) a large library of BACs to select a small collection of BACs for hybridization
with the probe arrays. The resulting data can be used to assign a local distance metric relating the arrayed probes, and then
to position the probes with respect to each other. The method is shown to be capable of achieving surprisingly high accuracy
within individual contigs and with less than 100 microarray hybridization experiments even when the probes and clones number
about 10 5, thus involving potentially around 10 10 individual hybridizations.
This approach is not dependent upon existing BAC contig information, and so should be particularly useful in the application
to previously uncharacterized genomes. Nevertheless, the method may be used to independently validate a BAC contig map or
a minimal tiling path obtained by intensive genomic sequence determination.
We provide a detailed probabilistic analysis to characterize the outcome of a single hybridization experiment and what information
can be garnered about the physical distance between any pair of probes. This analysis then leads to a formulation of a likelihood
optimization problem whose solution leads to the relative probe locations. After reformulating the optimization problem in
a graphtheoretic setting and by exploiting the underlying probabilistic structure, we develop an efficient approximation algorithm
for our original problem. We have implemented the algorithm and conducted several experiments for varied sets of parameters.
Our empirical results are highly promising and are reported here as well. We also explore how the probabilistic analysis and
algorithmic efficiency issues affect the design of the underlying biochemical experiments.
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