Rates of nucleotide substitution and mammalian nuclear gene evolution: Approximate and maximum-likelihood methods lead to different conclusions

Rates and patterns of synonymous and nonsynonymous substitutions have impor tant implications for the origin and maintenance of mammalian isochores and the effectiveness of selection at synonymous sites. Previous studies of ma mmalian nuclear genes largely employed approximate methods to estimate rate s of nonsynonymous and synonymous substitutions. Because these methods did not account for major features of DNA sequence evolution such as transition /transversion rate bias and unequal codon usage, they might not have produc ed reliable results. To evaluate the impact of the estimation method, we an alyzed a sample of 82 nuclear genes from the mammalian orders Artiodactyla, Primates, and Rodentia using both approximate and maximum-likelihood metho ds. Maximum-likelihood analysis indicated that synonymous substitution rate s were positively correlated with GC content at the third codon positions, but independent of nonsynonymous substitution rates. Approximate methods, h owever, indicated that synonymous substitution rates were independent of GC content at the third codon positions, but were positively correlated with nonsynonymous rates. Failure to properly account for transition/transversio n rate bias and unequal codon usage appears to have caused substantial bias es in approximate estimates of substitution rates.