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J. Li, W. Miller, ``Significance of inter-species matches when
evolutionary rate varies,'' Journal of Computational Biology ,
10(3-4):537-554, 2003.
(download)
Abstract:
We develop techniques to estimate the statistical significance
of gap-free alignments between two genomic DNA sequences, using human-mouse
alignments as an example. The sequences are assumed to be sufficiently similar
that some but not all of the neutrally evolving regions (i.e., those under no
evolutionary constraint) can be reliably aligned. Our goal is to model the
situation in which the neutral rate of evolution, and hence the extent of the
aligning intervals, varies across the genome. In some cases, this permits the
weaker of two matches to be judged as less likely to have arisen by chance,
provided it lies in a genomic interval with a high level of background
divergence. We employ a Hidden Markov Model to capture variations in
divergence rates, and assign probability values to gap-free alignments using
techniques of Dembo and Karlin, which are related to those used for the same
purpose by Blast. Our methods are illustrated in detail using a 1.49 Mb
genomic region. Results obtained from the analysis of human chromosome 22
using these techniques are also provided.
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With R. Waterston, K. Lindblad-Toh, et al., ``Initial sequencing and
comparative analysis of the mouse genome,'' Nature, 420:520-562, 2002.
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With D. Kolbe, J. Taylor, et al., ``Regulatory potential scores from
genome-wide 3-way alignments of human, mouse and rat,'' Genome
Research, 2004.
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With L. Elnitski, R.C. Hardison, et al.,
``Distinguishing regulatory DNA from neutral sites,''
Genome Research, 13(1):64-72, 2003.
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With R.C. Hardison, K.M. Roskin, et al., ``Co-variation in frequencies
of substitution, deletion, transposition and recombination during eutherian
evolution,'' Genome Research, 13(1):13-26, 2003.
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