Modeling DNA Base Substitution in Large Genomic Regions from Two Organisms

We studied the substitution patterns in 7661 well-conserved human–mouse alignments corresponding to the intergenic regions of human chromosome 22. Alignments with a high average GC content tend to have a higher human GC content than mouse GC content, indicating a lack of stationarity. Segmenting the alignments into four groups of GC content and fitting the general reversible substitution model (REV) separately gave significantly better fits than the overall fit and the levels of fit are close to that expected under an REV model. In addition, most of the fitted rate matrices are not of the HKY type but are remarkably strand-symmetric, and we constructed a number of substitution matrices that should be useful for genomic DNA sequence alignment. We did not find obvious signs of temporal inhomogeneity in the substitution rates and concluded that the conserved intergenic regions in human chromosome 22 and mouse appear to have evolved from their common ancestors via a process that is approximately reversible and strand-symmetric, assuming site homogeneity and independence.