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Letter

Characterization of Evolutionary Rates and Constraints in Three Mammalian Genomes

¹ Department of Genetics, Stanford University, Stanford, California 94305, USA ² Department of Computer Science, Stanford University, Stanford, California 94305, USA ³ Department of Statistics, Stanford University, Stanford, California 94305, USA ⁴ Department of Pathology, Stanford University, Stanford, California 94305, USA ⁵ Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA

We present an analysis of rates and patterns of microevolutionary phenomena that have shaped the human, mouse, and rat genomes since their last common ancestor. We find evidence for a shift in the mutational spectrum between the mouse and rat lineages, with the net effect being a relative increase in GC content in the rat genome. Our estimate for the neutral point substitution rate separating the two rodents is 0.196 substitutions per site, and 0.65 substitutions per site for the tree relating all three mammals. Small insertions and deletions of 1–10 bp in length ("microindels") occur at 5% of the point substitution rate. Inferred regional correlations in evolutionary rates between lineages and between types of sites support the idea that rates of evolution are influenced by local genomic or cell biological context. No substantial correlations between rates of point substitutions and rates of microindels are found, however, implying that the influences that affect these processes are distinct. Finally, we have identified those regions in the human genome that are evolving slowly, which are likely to include functional elements important to human biology. At least 5% of the human genome is under substantial constraint, most of which is noncoding.

⁶ Corresponding author.
E-MAIL: arend{at}stanford.edu; FAX (650) 725-4905.

[Supplemental material is available online at www.genome.org and the multiple sequence alignments analyzed are available at http://pipeline.lbl.gov. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: V. Solovyev.]

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